JPWO2010007651A1 - Composition having anti-periodontal disease effect - Google Patents
Composition having anti-periodontal disease effect Download PDFInfo
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- JPWO2010007651A1 JPWO2010007651A1 JP2010520690A JP2010520690A JPWO2010007651A1 JP WO2010007651 A1 JPWO2010007651 A1 JP WO2010007651A1 JP 2010520690 A JP2010520690 A JP 2010520690A JP 2010520690 A JP2010520690 A JP 2010520690A JP WO2010007651 A1 JPWO2010007651 A1 JP WO2010007651A1
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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Abstract
安全性が高い天然由来の化合物を有効成分とし、歯周組織において血流を促進し、かつ歯周組織または歯槽骨において、塩基性線維芽細胞増殖因子を誘導し、歯周病により破壊・退縮した歯周組織または歯槽骨を再生する機能を有する薬剤または飲食品を提供する。アデノシンまたはＡＭＰといったアデニン系核酸化合物単独またはアデニン系核酸化合物とポリリン酸を有効成分として含有する薬剤または飲食品。A highly safe naturally-derived compound is used as an active ingredient, promotes blood flow in periodontal tissue, induces basic fibroblast growth factor in periodontal tissue or alveolar bone, and is destroyed / regressed by periodontal disease Provided is a drug or a food or drink having a function of regenerating the periodontal tissue or alveolar bone. A drug or food or drink containing an adenine nucleic acid compound such as adenosine or AMP alone or an adenine nucleic acid compound and polyphosphate as active ingredients.
Description
本発明は、抗歯周病効果を有する薬剤、飲食品または口腔用組成物に関するものである。 The present invention relates to a drug, food or drink, or oral composition having an anti-periodontal disease effect.
歯周病は、歯面に沈着したプラーク中に存在する細菌等の刺激が引き金となり、歯肉と歯の支持組織に発生する慢性炎症疾患の総称である。主な原因菌は病巣から頻繁に検出されるＰｏｒｐｈｙｒｏｍｏｎａｓ ｇｉｎｇｉｖａｌｉｓ、Ａｃｔｉｎｏｂａｃｉｌｌｕｓ ａｃｔｉｎｏｍｙｃｅｔｅｍｃｏｍｉｔａｎｓ、Ｆｕｓｏｂａｃｔｅｒｉｕｍ ｎｕｃｌｅａｔｕｍ、およびＰｒｅｖｏｔｅｌｌａ ｎｉｇｒｅｓｃｅｎｓ 等とされている。これら嫌気性グラム陰性菌はプラーク中での増殖にともない悪臭の発生やプロテアーゼ等の酵素の分泌をひきおこす。この酵素が歯肉組織を分解し、歯根と歯肉の間に歯周ポケットと呼ばれる隙間を形成する。菌の増殖に伴い、炎症が誘発され、その炎症による歯槽骨の破壊（骨吸収）がひきおこされる。また、歯周病リスクの因子としては、歯周組織の血流量の低下などが知られている（非特許文献１）。Periodontal disease is a general term for chronic inflammatory diseases that occur in the gums and the supporting tissues of the teeth triggered by stimulation of bacteria and the like present in plaques deposited on the tooth surface. The main cause Porphyromonas gingivalis bacteria detected frequently from lesions, Actinobacillus actinomycetemcomitans, which is a Fusobacterium nucleatum, and Prevotella nigrescens like. These anaerobic gram-negative bacteria cause the generation of malodor and secretion of enzymes such as protease as they grow in the plaque. This enzyme decomposes gingival tissue and forms a gap called a periodontal pocket between the root and the gingiva. As the bacteria grow, inflammation is induced, and destruction of alveolar bone (bone resorption) is caused by the inflammation. Moreover, as a factor of a periodontal disease risk, the fall of the blood flow rate of a periodontium etc. are known (nonpatent literature 1).
歯周ポケットは、歯ブラシ等が入りにくく、食物が詰まったりプラークが溜まりやすい部位であるため、ここで歯周病原因菌はさらに増殖する。その結果、出血や歯肉減退、化膿、さらには歯の動揺や移動が起こる。歯周病の罹患率は高齢化の進行とともに増加していることに加え、他の病気との関連も明らかになりつつあり、これを治療、予防することは全身の健康に貢献すると期待されている。 Since the periodontal pocket is a site where a toothbrush or the like is difficult to enter, and food is clogged or plaque easily accumulates, periodontal disease-causing bacteria further grow here. As a result, bleeding, gingival decline, suppuration, and tooth movement and movement occur. The incidence of periodontal disease is increasing with the aging of the disease, and its relation to other diseases is also becoming clear, and it is expected that treatment and prevention will contribute to general health. Yes.
一般に、歯周病の改善には、その原因とされる細菌の増殖を抑制することが有効とされており、歯の表面につくプラーク、すなわち歯垢（細菌が巣食う塊）を除去するための日々の歯磨きの重要性が従来から唱えられているが、プラーク除去が適切に行われずに歯周病となる事例が多いのが現状である。これらのことから歯周病予防薬や歯磨剤として、生薬の抽出物など歯周病菌に対して殺菌性または抗菌性のある物質を含有するものが数多く提案されている。 In general, for the improvement of periodontal disease, it is effective to suppress the growth of bacteria that cause it, and to remove plaque on the tooth surface, that is, plaque (bacteria that nest bacteria). Although the importance of daily brushing has been advocated in the past, there are many cases where periodontal disease is caused by the inadequate removal of plaque. Based on these facts, many anti-periodontal drugs and dentifrices have been proposed that contain substances that are bactericidal or antibacterial against periodontal pathogens, such as herbal extracts.
しかしながら、このような歯周病予防薬は、歯周病におけるＰｏｒｐｈｙｒｏｍｏｎａｓ ｇｉｎｇｉｖａｌｉｓなどの細菌への殺菌または抗菌作用により治療を行なうものであり、歯周組織および歯槽骨を損なわれ始めた段階の症状に対しては歯周組織および歯槽骨損傷の進行を抑制するだけで、歯周組織および歯槽骨の再生を促進し、治癒を促すものではない。However, such preventive agents for periodontal disease are those that are treated by sterilization or antibacterial action against bacteria such as Porphyromonas gingivalis in periodontal disease, and the periodontal tissue and alveolar bone are at the stage of being damaged. On the other hand, it only suppresses the progression of periodontal tissue and alveolar bone damage, and does not promote regeneration and promote healing of periodontal tissue and alveolar bone.
このため、歯周病の発症から進行に対して様々な予防法や外科的治療法が研究されており、退縮または溶解してしまった歯周組織や歯槽骨を再生させるため、塩基性線維芽細胞増殖因子（ｂａｓｉｃ ｆｉｂｒｏｂｌａｓｔ ｇｒｏｗｔｈ ｆａｃｔｏｒ：ｂＦＧＦ）を用いた歯周組織再生療法も報告されている（非特許文献２）。 For this reason, various preventive and surgical treatments have been studied for the onset and progression of periodontal disease, and basic fibroblasts are used to regenerate periodontal tissues and alveolar bone that have regressed or dissolved. Periodontal tissue regeneration therapy using a cell growth factor (basic fibroblast growth factor: bFGF) has also been reported (Non-patent Document 2).
一方、口腔用組成物においてアデノシンやＡＭＰを配合することは知られていたが、これらの化合物を配合する目的は、抗菌活性であったり（ただし、アデノシンには弱い抗菌活性しか報告されていない：特許文献１）、たとえばＡＭＰと抗酸化剤とを併用することで、抗酸化剤の抗酸化作用を高め、歯周病原因菌の感染時の生体からの活性酸素の産生を抑制するためであった（特許文献２）。 On the other hand, it has been known to incorporate adenosine and AMP in oral compositions, but the purpose of incorporating these compounds is antibacterial activity (however, only weak antibacterial activity has been reported for adenosine: Patent Document 1), for example, to increase the antioxidant action of an antioxidant by using AMP and an antioxidant together, and to suppress the production of active oxygen from the living body during infection with periodontal disease-causing bacteria. (Patent Document 2).
また、口腔用組成物にポリリン酸を配合することも以前より知られており、ポリリン酸配合の目的は、リン酸カルシウム等を含有する歯石の沈着を防いだり（特許文献３）、変色を抑制したりするためであった（特許文献４）。
上述したｂＦＧＦを用いた歯周組織再生療法は、生理活性タンパク質であるｂＦＧＦそのものを有効成分としており、これを商品化しようとすると、ｂＦＧＦの安価な調製や配合したｂＦＧＦの安定性や安全性など様々な問題をクリアする必要があることから、必ずしも今すぐに実現可能な実用的な方法とはいえなかった。 Periodontal tissue regeneration therapy using bFGF as described above uses bFGF itself, which is a physiologically active protein, as an active ingredient. When trying to commercialize this, the inexpensive preparation of bFGF, the stability and safety of blended bFGF, etc. Because it is necessary to clear various problems, it was not always a practical method that could be realized immediately.
また、単一化合物または組成物で歯周組織の血流を促進し、かつ歯周組織または歯槽骨において、ｂＦＧＦを誘導・産生し、ｂＦＧＦの作用を持続させる効果を兼ね備えたものは報告されていない。 In addition, a single compound or composition has been reported to promote the blood flow of periodontal tissue and induce and produce bFGF in the periodontal tissue or alveolar bone, and to maintain the action of bFGF. Absent.
従来、上述したように、アデニン系核酸化合物、ポリリン酸をそれぞれ個別に口腔用組成物に配合する例は知られていたが、両者を併用した例は全く報告されていない。 Conventionally, as described above, an example in which an adenine nucleic acid compound and polyphosphoric acid are individually added to an oral composition has been known, but no example of using both in combination has been reported.
また、アデニン系核酸化合物またはポリリン酸の配合時における目的・効果は上述のとおりであって、アデニン系核酸化合物単独またはアデニン系核酸化合物とポリリン酸を併用したときにｂＦＧＦを誘導し、歯周組織の血流を増加させ、歯周組織または歯槽骨を再生する機能を持続的に発揮することは全く予想されるものではなかった。 The purpose and effect at the time of blending the adenine nucleic acid compound or polyphosphate are as described above. When the adenine nucleic acid compound alone or a combination of the adenine nucleic acid compound and polyphosphate is induced, bFGF is induced, and periodontal tissue It has never been expected to continuously exert the function of increasing the blood flow and regenerating periodontal tissue or alveolar bone.
さらに、アデノシンが心臓冠血管での血流増加作用を有することは知られているが（非特許文献３）、歯周組織において血流増加作用を有することは全く知られていないし、ＡＭＰにおいては、血流増加作用を有すること自体知られていない。 Furthermore, although it is known that adenosine has an effect of increasing blood flow in the heart coronary blood vessels (Non-patent Document 3), it is not known at all that it has an effect of increasing blood flow in periodontal tissues. It is not known per se to have an effect of increasing blood flow.
さらにまた、ポリリン酸がｂＦＧＦを安定化させる作用を有することが報告されている（非特許文献４）が、アデニン系核酸化合物とポリリン酸を併用したときにｂＦＧＦを誘導し、歯周組織または歯槽骨を再生する機能を持続的に発揮することは知られていない。 Furthermore, although it has been reported that polyphosphate has an action of stabilizing bFGF (Non-Patent Document 4), when adenine nucleic acid compound and polyphosphate are used in combination, bFGF is induced, and periodontal tissue or alveoli It is not known to continuously exert the function of regenerating bone.
そこで、本発明者らは、歯周組織の血流を促進し、かつ歯周組織または歯槽骨において、ｂＦＧＦを誘導し、抗歯周病により破壊や退縮した歯周組織または歯槽骨を再生する機能を発揮できる化合物を見出すことができれば、ｂＦＧＦを用いた歯周組織再生療法をより実用に近づけ、さらにはこれを超える効果を得ることができると考え、様々な化合物をスクリーニングした。 Therefore, the present inventors promote blood flow of periodontal tissue, induce bFGF in the periodontal tissue or alveolar bone, and regenerate the periodontal tissue or alveolar bone destroyed or retracted due to anti-periodontal disease. If a compound capable of exhibiting a function could be found, it was considered that periodontal tissue regeneration therapy using bFGF could be made more practical, and an effect exceeding this could be obtained, and various compounds were screened.
その結果、アデノシンやアデノシン５’−モノリン酸（ＡＭＰ）等のアデニン系核酸化合物が、歯周組織局所において血流を促進し、かつ歯周組織の再生を強力に誘導するｂＦＧＦを誘導・産生することを見出した。 As a result, adenine nucleic acid compounds such as adenosine and adenosine 5′-monophosphate (AMP) induce and produce bFGF that promotes blood flow in the periodontal tissue and strongly induces regeneration of periodontal tissue. I found out.
さらに、歯周組織の血流を促進し、かつ歯周組織または歯槽骨において、ｂＦＧＦを誘導・産生する化合物としてアデノシンやアデノシン５’−モノリン酸（ＡＭＰ）等のアデニン系核酸化合物とポリリン酸を併用することにより、アデニン系核酸化合物により誘導されたｂＦＧＦが、ポリリン酸との併用でその作用をより強くより長時間持続させることができ、アデニン系核酸化合物を単独で用いたときに比べて著しい効果の増幅が生じることを見出し、本発明を完成させた。したがって、本発明は以下の通りである。 Furthermore, adenine nucleic acid compounds such as adenosine and adenosine 5′-monophosphate (AMP) and polyphosphate are promoted as compounds that promote blood flow in periodontal tissues and induce and produce bFGF in periodontal tissues or alveolar bone. When used in combination, bFGF induced by an adenine nucleic acid compound can maintain its action more strongly and for a longer time in combination with polyphosphate, which is significantly more than when an adenine nucleic acid compound is used alone. The inventors have found that the amplification of the effect occurs and completed the present invention. Therefore, the present invention is as follows.
（１）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を有効成分として含有することを特徴とする歯周組織血流促進および塩基性線維芽細胞増殖因子誘導剤。
（２）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を有効成分として含有することを特徴とする歯周組織または歯槽骨の再生促進剤。(1) A periodontal tissue blood flow promoting and basic fibroblast growth factor inducer comprising an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphate as active ingredients.
(2) A periodontal tissue or alveolar bone regeneration promoter comprising an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid as active ingredients.
（３）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を有効成分として含有することを特徴とする抗歯周病剤。
（４）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を有効成分として含有する口腔衛生剤。(3) An anti-periodontal disease agent comprising an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid as active ingredients.
(4) An oral hygiene agent containing an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid as active ingredients.
（５）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を有効成分とし、歯周組織において血流を促進し、かつ歯周組織または歯槽骨において、塩基性線維芽細胞増殖因子を誘導し、歯周病により破壊・退縮した歯周組織または歯槽骨を再生する機能を発揮できる量を含有する飲食品。
（６）アデニン系核酸化合物がアデノシン、アデノシン５’−モノリン酸（ＡＭＰ）、アデノシン５’−ジリン酸（ＡＤＰ）および／またはアデノシン５’−トリリン酸（ＡＴＰ）である、上記（１）〜（５）のいずれか１項に記載の薬剤または飲食品。(5) An adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphate are used as active ingredients, promote blood flow in periodontal tissue, and induce basic fibroblast growth factor in periodontal tissue or alveolar bone, A food or drink containing an amount capable of exerting a function of regenerating periodontal tissue or alveolar bone destroyed or retracted due to periodontal disease.
(6) The above (1) to (1), wherein the adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP). 5. The drug or food or drink according to any one of 5).
（７）ポリリン酸が、直鎖状もしくは枝分かれ状のポリリン酸もしくはその塩、環状のメタリン酸もしくはその塩、および枝分かれ状のウルトラリン酸もしくはその塩から選択されたものである、上記（１）〜（５）のいずれか１項に記載の薬剤または飲食品。
（８）歯周組織血流促進および塩基性線維芽細胞増殖因子誘導剤を製造するためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の使用。(7) The above (1), wherein the polyphosphoric acid is selected from linear or branched polyphosphoric acid or a salt thereof, cyclic metaphosphoric acid or a salt thereof, and branched ultraphosphoric acid or a salt thereof. The chemical | medical agent or food-drinks of any one of-(5).
(8) Use of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphate for producing a periodontal tissue blood flow promoting and basic fibroblast growth factor inducer.
（９）歯周組織または歯槽骨の再生促進剤を製造するためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の使用。
（１０）歯周病予防治療剤を製造するためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の使用。(9) Use of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid to produce a periodontal tissue or alveolar bone regeneration promoter.
(10) Use of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid for producing a periodontal disease preventive or therapeutic agent.
（１１）口腔衛生剤を製造するためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の使用。
（１２）歯周組織において血流を促進し、かつ歯周組織または歯槽骨において、塩基性線維芽細胞増殖因子を誘導し、歯周病により破壊・退縮した歯周組織または歯槽骨を再生する機能を発揮する食品を製造するためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の使用。(11) Use of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid for producing an oral hygiene agent.
(12) Promote blood flow in periodontal tissue and induce basic fibroblast growth factor in periodontal tissue or alveolar bone to regenerate periodontal tissue or alveolar bone destroyed or retracted due to periodontal disease Use of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid for producing a food exhibiting a function.
（１３）アデニン系核酸化合物がアデノシン、アデノシン５’−モノリン酸（ＡＭＰ）、アデノシン５’−ジリン酸（ＡＤＰ）および／またはアデノシン５’−トリリン酸（ＡＴＰ）である、上記（８）〜（１２）のいずれか１項に記載のいずれか記載の使用。
（１４）ポリリン酸が、直鎖状もしくは枝分かれ状のポリリン酸もしくはその塩、環状のメタリン酸もしくはその塩、および枝分かれ状のウルトラリン酸もしくはその塩から選択されたものである、上記（８）〜（１２）のいずれか１項に記載の使用。(13) The above (8) to (8), wherein the adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP). The use according to any one of 12).
(14) The above (8), wherein the polyphosphoric acid is selected from linear or branched polyphosphoric acid or a salt thereof, cyclic metaphosphoric acid or a salt thereof, and branched ultraphosphoric acid or a salt thereof. Use of any one of-(12).
（１５）歯周組織血流促進および塩基性線維芽細胞増殖因子誘導のためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を含有する組成物。
（１６）歯周組織または歯槽骨の再生促進のためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を含有する組成物。(15) An adenine nucleic acid compound or a composition containing an adenine nucleic acid compound and polyphosphate for promoting periodontal tissue blood flow and inducing basic fibroblast growth factor.
(16) An adenine nucleic acid compound or an adenine nucleic acid compound for promoting regeneration of periodontal tissue or alveolar bone and a composition containing polyphosphoric acid.
（１７）歯周病予防治療のためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を含有する組成物。
（１８）口腔衛生のためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を含有する組成物。(17) An adenine nucleic acid compound or a composition containing an adenine nucleic acid compound and polyphosphoric acid for periodontal disease prevention and treatment.
(18) A composition containing an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid for oral hygiene.
（１９）食品形態で歯周組織において血流を促進し、かつ歯周組織または歯槽骨において、塩基性線維芽細胞増殖因子を誘導し、歯周病により破壊・退縮した歯周組織または歯槽骨を再生する機能を発揮するためのアデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸を含有する組成物。
（２０）アデニン系核酸化合物がアデノシン、アデノシン５’−モノリン酸（ＡＭＰ）、アデノシン５’−ジリン酸（ＡＤＰ）および／またはアデノシン５’−トリリン酸（ＡＴＰ）である、上記（１５）〜（１９）のいずれか１項に記載の化合物または組成物。(19) Periodontal tissue or alveolar bone that promotes blood flow in periodontal tissue in a food form and induces basic fibroblast growth factor in periodontal tissue or alveolar bone, and is destroyed or retracted due to periodontal disease An adenine nucleic acid compound or a composition containing an adenine nucleic acid compound and polyphosphoric acid for exerting a function of regenerating the phospholipid.
(20) The above (15) to (15), wherein the adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP). The compound or composition according to any one of 19).
（２１）ポリリン酸が、直鎖状もしくは枝分かれ状のポリリン酸もしくはその塩、環状のメタリン酸もしくはその塩、および枝分かれ状のウルトラリン酸もしくはその塩から選択されたものである、上記（１５）〜（１９）のいずれか１項に記載の化合物または組成物。
（２２）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の有効量を投与することを特徴とする、歯周組織血流促進および塩基性線維芽細胞増殖因子誘導方法。(21) The above (15), wherein the polyphosphoric acid is selected from linear or branched polyphosphoric acid or a salt thereof, cyclic metaphosphoric acid or a salt thereof, and branched ultraphosphoric acid or a salt thereof. The compound or composition of any one of-(19).
(22) A method for inducing periodontal tissue blood flow and inducing basic fibroblast growth factor, comprising administering an effective amount of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphate.
（２３）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の有効量を投与することを特徴とする、歯周組織または歯槽骨の再生促進方法。
（２４）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の有効量を投与することを特徴とする、歯周病予防治療方法。(23) A method for promoting periodontal tissue or alveolar bone regeneration, comprising administering an effective amount of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphate.
(24) A method for preventing and treating periodontal disease, comprising administering an effective amount of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphate.
（２５）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の有効量を投与することを特徴とする、口腔衛生方法。
（２６）アデニン系核酸化合物またはアデニン系核酸化合物とポリリン酸の有効量を経口投与することを特徴とする、歯周組織において血流を促進し、かつ歯周組織または歯槽骨において、塩基性線維芽細胞増殖因子を誘導し、歯周病により破壊・退縮した歯周組織または歯槽骨を再生する方法。(25) An oral hygiene method comprising administering an effective amount of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid.
(26) Oral administration of an effective amount of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid promotes blood flow in periodontal tissue and basic fibers in periodontal tissue or alveolar bone A method of regenerating periodontal tissue or alveolar bone that is induced by blast growth factor and destroyed or retracted due to periodontal disease.
（２７）アデニン系核酸化合物がアデノシン、アデノシン５’−モノリン酸（ＡＭＰ）、アデノシン５’−ジリン酸（ＡＤＰ）および／またはアデノシン５’−トリリン酸（ＡＴＰ）である、上記（２２）〜（２６）のいずれか１項に記載の方法。
（２８）ポリリン酸が、直鎖状もしくは枝分かれ状のポリリン酸もしくはその塩、環状のメタリン酸もしくはその塩、および枝分かれ状のウルトラリン酸もしくはその塩から選択されたものである、上記（２２）〜（２６）のいずれか１項に記載の方法。(27) The above (22) to (22), wherein the adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP). The method according to any one of 26).
(28) The above (22), wherein the polyphosphoric acid is selected from linear or branched polyphosphoric acid or a salt thereof, cyclic metaphosphoric acid or a salt thereof, and branched ultraphosphoric acid or a salt thereof. The method of any one of-(26).
本発明は、（１）アデノシンやＡＭＰなどのアデニン系核酸化合物が、歯周組織局所において、血流を促進し、かつ歯周組織の再生を強力に誘導するｂＦＧＦを誘導・産生すること、（２）当該アデニン系核酸化合物とポリリン酸の併用により産生されたｂＦＧＦの作用が増強・持続するという今までにない知見に基づきなされたものであり、アデニン系核酸化合物が、歯周組織局所において、血流を促進し、かつ歯周組織の再生を強力に誘導するｂＦＧＦを誘導・産生し、もって歯周病により破壊・退縮した歯周組織または歯槽骨を再生することができ、アデニン系核酸化合物とポリリン酸の併用によりｂＦＧＦの作用をより強くより長時間持続させることができる。したがって、本発明は、このような機能を有する塩基性線維芽細胞増殖因子誘導剤、歯周組織もしくは歯槽骨の再生促進剤、抗歯周病剤、口腔衛生剤等の薬剤、または飲食品を初めて提供するものである。 In the present invention, (1) an adenine nucleic acid compound such as adenosine or AMP induces and produces bFGF that promotes blood flow and strongly induces regeneration of periodontal tissue in the periodontal tissue locally. 2) Based on an unprecedented finding that the action of bFGF produced by the combined use of the adenine nucleic acid compound and polyphosphate is enhanced and sustained, and the adenine nucleic acid compound is Inducing and producing bFGF that promotes blood flow and strongly induces the regeneration of periodontal tissue, so that it can regenerate periodontal tissue or alveolar bone destroyed or retracted due to periodontal disease, and adenine nucleic acid compound By combining the use of polyphosphoric acid, the action of bFGF can be sustained more strongly and for a longer time. Therefore, the present invention provides a basic fibroblast growth factor inducer having such a function, a periodontal tissue or alveolar bone regeneration promoter, an anti-periodontal agent, an oral hygiene agent, or a food or drink. This is the first time.
また、有効成分であるアデニン系核酸化合物の中でもアデノシンおよびＡＭＰは、安価に入手可能な低分子化合物で、生体成分であることから安全性が高く、かつ毒性の極めて低いことから連続的に摂取可能である。また、ポリリン酸も生体成分で、多くの食品に用いられていることから安全性が高く、かつ毒性の極めて低いことから連続的に摂取可能である。したがって、本発明の薬剤、飲食品または組成物は、現代社会で問題となっている歯周病を軽減、緩和、治癒するのに有効であり、症状発症前に服用すれば、その予防も可能である。 Among the adenine nucleic acid compounds that are active ingredients, adenosine and AMP are low-molecular-weight compounds that can be obtained at low cost. Since they are biological components, they are highly safe and can be ingested continuously because of their extremely low toxicity. It is. Polyphosphoric acid is also a biological component, and since it is used in many foods, it is highly safe and can be ingested continuously because of its extremely low toxicity. Therefore, the drug, food or drink or composition of the present invention is effective in reducing, alleviating and healing periodontal disease, which is a problem in modern society, and can be prevented if taken before onset of symptoms. It is.
本発明の薬剤、飲食品または組成物は、歯周組織局所において血流を促進し、かつ歯周組織の再生を強力に誘導するｂＦＧＦを誘導・産生およびｂＦＧＦの効果を増強・持続し、歯周病の各種症状を減少、緩和あるいは消失させ、歯周組織および歯槽骨を再生させる作用を有し、その作用を示す有効成分としてアデニン系核酸化合物単独またはアデニン系核酸化合物とポリリン酸を含有するものである。 The medicament, food or drink or composition of the present invention induces and produces bFGF that promotes blood flow in the periodontal tissue locally and strongly induces regeneration of periodontal tissue, and enhances and sustains the effect of bFGF, Has the effect of reducing, alleviating or eliminating various symptoms of periodontal disease and regenerating periodontal tissues and alveolar bone, and contains an adenine nucleic acid compound alone or an adenine nucleic acid compound and polyphosphoric acid as an active ingredient exhibiting the action Is.
有効成分としてのアデニン系核酸化合物としては、アデノシン、アデノシン５’−モノリン酸（ＡＭＰ）、アデノシン５’−ジリン酸（ＡＤＰ）、アデノシン５’−トリリン酸（ＡＴＰ）などの天然由来の核酸化合物を例示することができ、その中でも特にアデノシンまたはＡＭＰが好適である。 Examples of adenine nucleic acid compounds as active ingredients include naturally occurring nucleic acid compounds such as adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP), and adenosine 5′-triphosphate (ATP). Among them, adenosine or AMP is particularly preferable.
アデノシンやＡＭＰは、いずれも生体内に存在する天然成分として認知されている化合物であり、特にＡＭＰは食品添加物として使用されており、安全性が高く、好都合な化合物である。 Adenosine and AMP are both recognized as natural ingredients existing in the living body, and in particular, AMP is used as a food additive and is a highly safe and convenient compound.
また、本発明の有効成分は、アデニン系核酸化合物単独であっても、他の核酸化合物との複数混合されているものであってもかまわない。なお、複数混合したものを使用する場合には、核酸化合物中に占めるアデニン系核酸化合物の割合が５０％以上、好ましくは７０％以上のものを使用するのが好ましい。 The active ingredient of the present invention may be an adenine nucleic acid compound alone or a mixture of a plurality of other nucleic acid compounds. In addition, when using what mixed two or more things, it is preferable to use the ratio of the adenine-type nucleic acid compound which occupies in a nucleic acid compound is 50% or more, Preferably it is 70% or more.
このようなアデニン系核酸化合物は、その由来に格別制限されないものの、酵母、細菌、魚介類、動物、植物等の天然物由来のものが好適である。また、アデニン系核酸化合物を複数混合したものとしては、ＲＮＡを酵素分解して得られるヌクレオチド混合物を分画、塩析、沈殿等の簡単な精製処理を施し、アデニン系核酸化合物の含量割合を向上せしめたものを例示することができる。 Such adenine nucleic acid compounds are not particularly limited in their origin, but those derived from natural products such as yeast, bacteria, seafood, animals and plants are preferred. For a mixture of multiple adenine nucleic acid compounds, the nucleotide mixture obtained by enzymatic degradation of RNA is subjected to simple purification treatments such as fractionation, salting out, and precipitation to improve the content ratio of adenine nucleic acid compounds. What has been shown can be exemplified.
また、本発明において使用するポリリン酸は、ポリリン酸が直鎖状もしくは枝分かれ状のポリリン酸もしくはその塩、環状のメタリン酸もしくはその塩、枝分かれ状のウルトラリン酸もしくはその塩を挙げることができる。 Examples of the polyphosphoric acid used in the present invention include linear or branched polyphosphoric acid or a salt thereof, cyclic metaphosphoric acid or a salt thereof, and branched ultraphosphoric acid or a salt thereof.
このような有効成分を含有する本発明の薬剤、飲食品または組成物は、ヒトまたはヒト以外の動物用の医薬品、飲食品、サプリメント、健康飲食品（特定保健用食品を含む）、動物飼餌料用添加物等各種タイプの組成物として用いることができる。 The medicament, food or drink or composition of the present invention containing such an active ingredient is a drug for human or non-human animals, food or drink, supplement, health food or drink (including food for specified health use), animal feed It can be used as various types of compositions such as additives.
たとえば、飲食品、健康飲食品、調製粉乳等として使用する場合には、本発明の有効成分をそのまま使用したり、他の食品ないし食品成分と併用して、定法に従って、固体状、粉末状、顆粒状、ペースト状、液状ないし懸濁状の各種組成物とすることが可能である。 For example, when used as food and drink, health food and drink, prepared powdered milk, etc., use the active ingredient of the present invention as it is, or in combination with other foods or food ingredients, according to a standard method, solid, powder, Various compositions in the form of granules, paste, liquid or suspension can be used.
また、薬剤、具体的には、血流増加および塩基性線維芽細胞増殖因子誘導剤、歯周組織もしくは歯槽骨の再生促進剤、抗歯周病剤、口腔衛生剤等として使用する場合、本発明の有効成分と製剤補助剤（賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤など）を併用し、定法に従って、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、注射剤等の各種組成物とすることが可能である。 In addition, when used as a drug, specifically, an agent for increasing blood flow and basic fibroblast growth factor, periodontal tissue or alveolar bone regeneration, anti-periodontal agent, oral hygiene agent, etc. Tablets and capsules according to conventional methods using the active ingredients of the invention in combination with formulation aids (excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc.) Various compositions such as granules, powders, syrups and injections can be used.
口腔用衛生剤を具体的に説明すれば、練歯磨、液状歯磨、潤性歯磨、顆粒状歯磨等の歯磨類、口腔用パスタ、マウスウォッシュ、口腔トローチ等が挙げられ、その剤型に応じ、本発明の有効成分に加えて任意成分としてその他の添加剤を配合することで調製することができる。たとえば、歯磨類の場合は、本発明の有効成分以外に、通常使用し得る、潤滑剤、研磨剤、粘結剤、粘稠剤、界面活性剤、甘味剤、防腐剤、着色剤などを配合し得、これら成分を水または適当な溶媒と混合して製造することができる。 Specifically describing oral hygiene agents, toothpastes such as toothpaste, liquid toothpaste, moisturized toothpaste, granular toothpaste, oral pasta, mouthwash, oral troche, etc., depending on the dosage form, In addition to the active ingredient of this invention, it can prepare by mix | blending another additive as an arbitrary component. For example, in the case of dentifrice, in addition to the active ingredient of the present invention, a lubricant, an abrasive, a binder, a thickener, a surfactant, a sweetener, an antiseptic, a colorant, etc., which can be usually used, are blended. It can be prepared by mixing these components with water or a suitable solvent.
さらに上記の各種組成物には、有効成分であるアデニン系核酸化合物およびポリリン酸の他に、各種薬効成分を配合することもできる。薬効成分としてはたとえば、抗炎症剤や血流促進剤、フッ化物、殺菌剤等などを配合し得るが、これらに限定されるものではない。 Furthermore, in addition to the adenine nucleic acid compound and polyphosphoric acid which are active ingredients, various medicinal ingredients can also be blended with the various compositions described above. Examples of medicinal ingredients include, but are not limited to, anti-inflammatory agents, blood flow promoters, fluorides, bactericides, and the like.
有効成分の配合量は、使用目的（予防、保健、または症状緩和）、対象者の年令、投与または摂取方法、剤型等に応じて、０．１〜３０％（Ｗ／Ｖ）の範囲から適宜選定すればよい。具体的には、アデニン系核酸化合物の含有量としては特に限定はないが、配合濃度０．０１〜５．０重量％であることが好ましい。また、ポリリン酸の含有量も特に限定はないが、配合濃度０．０１〜１０．０重量％であることが好ましい。 The compounding amount of the active ingredient is in the range of 0.1 to 30% (W / V) depending on the purpose of use (prevention, health, or symptom relief), the age of the subject, administration or intake method, dosage form, etc. May be selected as appropriate. Specifically, the content of the adenine nucleic acid compound is not particularly limited, but the blending concentration is preferably 0.01 to 5.0% by weight. Further, the content of polyphosphoric acid is not particularly limited, but is preferably 0.01 to 10.0% by weight.
投与あるいは摂取方法は、特に制限されるものではないが、口腔内に適時留まる方法が好ましい。また、投与または摂取量は、対象者の年令、体重、症状の程度、投与または摂取方法等に応じて変動するものの、有効成分としてのアデニン系核酸化合物の量は１日１人当たり１ｍｇ〜５００ｇ程度、好ましくは１ｍｇ〜１０ｇの範囲内から抗歯周病作用を発揮できる量を適宜選択すればよい。ポリリン酸の量は１日１人あたり１ｍｇ〜１０ｇ程度、好ましくは１０ｍｇ〜５ｇの範囲内から適宜選択すればよい。 The administration or ingestion method is not particularly limited, but a method of staying in the oral cavity in a timely manner is preferable. In addition, although the administration or intake varies depending on the age, weight, symptom level, administration or intake method of the subject, the amount of the adenine nucleic acid compound as an active ingredient is 1 mg to 500 g per person per day. What is necessary is just to select suitably the quantity which can exhibit an anti-periodontal disease effect | action from the range of a grade, Preferably 1 mg-10 g. The amount of polyphosphoric acid may be appropriately selected from the range of about 1 mg to 10 g, preferably 10 mg to 5 g per person per day.
より具体的に、たとえば経口で使用した場合、１日当たり０．０１ｍｇ／ｋｇ以上、好ましくは０．１ｍｇ／ｋｇ〜１ｇ／ｋｇ程度のアデニン系核酸化合物を摂取することにより、抗歯周病作用を発揮でき、予防もしくは症状の緩和や改善が期待できる。また、ポリリン酸は１日あたり０．０１ｍｇ／ｋｇ以上、好ましくは０．１ｍｇ／ｋｇ〜０．５ｇ／ｋｇを摂取するのが好ましい。 More specifically, for example, when used orally, ingestion of an adenine nucleic acid compound of 0.01 mg / kg or more per day, preferably about 0.1 mg / kg to 1 g / kg, provides anti-periodontal disease action. It can be expected to prevent or alleviate or improve symptoms. Moreover, it is preferable to take polyphosphoric acid in an amount of 0.01 mg / kg or more, preferably 0.1 mg / kg to 0.5 g / kg per day.
なお、本発明の有効成分は、安全性が高いことから、上記範囲よりも多めに摂取しても一向にさしつかえない。 In addition, since the active ingredient of this invention has high safety | security, even if it ingests more than the said range, it will be sufficient.
以下、実施例を示し、本発明を具体的に説明するが、本発明がこれに限定されないことは明らかである。 Hereinafter, the present invention will be described in detail with reference to examples, but it is clear that the present invention is not limited thereto.
実施例１
＜方法＞
ヒト歯肉繊維芽細胞またはヒト歯髄細胞をプラスティックシャーレで培養し、アデノシン０．０２〜０．８ｍＭまたはＡＭＰ０．２〜５０ｍＭを１〜５３時間処置した。細胞表面および細胞内のｂＦＧＦは以下の方法を用いて抽出した。Example 1
<Method>
Human gingival fibroblasts or human pulp cells were cultured in a plastic petri dish and treated with adenosine 0.02-0.8 mM or AMP 0.2-50 mM for 1-53 hours. Cell surface and intracellular bFGF were extracted using the following method.
（細胞表面に存在するｂＦＧＦの抽出）
培地を吸引し、リン酸緩衝液（ＰＢＳ）（２ｍＬ）で２回細胞を洗浄した。その後細胞を０．９ｍＬの２Ｍ ＮａＣｌ、２０ｍＭ酢酸ナトリウムｐＨ４．０の溶出液で２回リンスし、マイクロチューブに採取した。この操作によって細胞表面に結合したｂＦＧＦを溶出し、回収した。回収した溶出液にはキャリアータンパクとして５％ウシ血清アルブミン（シグマ社製）を５マイクロリットル加えてよく混和し、最終濃度で５％になるようにトリクロル酢酸を加えて、氷中に１５分以上放置した。その後１０，０００×ｇで１０分間遠心分離し、沈殿物を回収した。回収した沈殿物に微量の１Ｎ 水酸化ナトリウムを加えて中和し、測定用サンプルとした。(Extraction of bFGF present on the cell surface)
The medium was aspirated and the cells were washed twice with phosphate buffer (PBS) (2 mL). The cells were then rinsed twice with 0.9 mL of 2M NaCl, 20 mM sodium acetate pH 4.0 eluate and collected in a microtube. By this operation, bFGF bound to the cell surface was eluted and collected. Add 5 microliters of 5% bovine serum albumin (manufactured by Sigma) as a carrier protein to the collected eluate, mix well, add trichloroacetic acid to a final concentration of 5%, and keep in ice for at least 15 minutes. I left it alone. Thereafter, the mixture was centrifuged at 10,000 × g for 10 minutes to collect a precipitate. A small amount of 1N sodium hydroxide was added to the collected precipitate for neutralization to obtain a measurement sample.
（細胞内に存在するｂＦＧＦの抽出）
細胞表面に結合しているｂＦＧＦの溶出を行った後、セルスクレイパーを用いて物理的に細胞をシャーレより剥ぎ取った。ＰＢＳを用いてシャーレを洗浄し、はがれた細胞をすべてマイクロチューブに回収した。その後１０，０００×ｇで１０分間遠心分離し、沈殿として細胞を回収した。回収した細胞に５０マイクロリットルのミリＱ水を加えて超音波破砕を行った。細胞破砕後の液を用いてＢＣＡ法にてタンパク定量し、それぞれのサンプルのタンパク量を揃えて測定用サンプルとした。(Extraction of bFGF present in cells)
After elution of bFGF bound to the cell surface, the cells were physically peeled off from the petri dish using a cell scraper. The petri dish was washed with PBS, and all detached cells were collected in a microtube. The cells were then centrifuged at 10,000 × g for 10 minutes, and the cells were collected as a precipitate. 50 microliters of milli-Q water was added to the collected cells and subjected to ultrasonic disruption. Using the solution after cell disruption, protein was quantified by the BCA method, and the amount of protein in each sample was aligned to prepare a measurement sample.
（ｂＦＧＦの定量）
ｂＦＧＦは、ＳＤＳ−ＰＡＧＥ、ウェスタンブロッティング後、ＥＣＬ Ａｄｖａｎｃｅ Ｗｅｓｔｅｒｎ Ｂｌｏｔｔｉｎｇ Ｄｅｔｅｃｔｉｏｎ Ｋｉｔ，（ＲＰＮ２１３５，Ａｍｅｒｓｈａｍ）とＥＣＬ Ｐｌｕｓ Ｗｅｓｔｅｒｎ ｂｌｏｔｔｉｎｇ ｒｅａｇｅｎｔ ｐａｃｋ，（ＰＰＮ２１２４，Ａｍｅｒｓｈａｍ）を用いて検出し、画像解析プログラムソフトＩｍａｇｅＪ（フリーウェア）でｂＦＧＦを定量化した。対照群を１００％としてアデノシンまたはＡＭＰ処置の効果を検討した。(Quantification of bFGF)
bFGF is SDS-PAGE, Western blotting, ECL Advance Western Blotting Detection Kit, (RPN2135, Amersham) and ECL Plus Western blotting reagent pack, (PPN2124, Amer software using PJ2124, Amer analysis software) BFGF was quantified. The effect of adenosine or AMP treatment was examined with the control group as 100%.
＜結果＞
（試験１）
ヒト歯肉繊維芽細胞にＡＭＰ０．２ｍＭまたは５０ｍＭを１５時間処置後に細胞内のｂＦＧＦを定量化し、対照群を１００％としてＡＭＰ処置の効果を検討した。その結果、図１に示すように、ヒト歯肉繊維芽細胞にＡＭＰを処置することによりｂＦＧＦが増加することが確認された。<Result>
(Test 1)
After treatment of human gingival fibroblasts with AMP 0.2 mM or 50 mM for 15 hours, intracellular bFGF was quantified, and the effect of AMP treatment was examined with the control group as 100%. As a result, as shown in FIG. 1, it was confirmed that bFGF increases by treating human gingival fibroblasts with AMP.
（試験２）
ヒト歯肉繊維芽細胞に、アデノシン０．８ｍＭを１５時間処置後に細胞内のｂＦＧＦを定量化し、対照群を１００％としてアデノシン処置の効果を検討した。その結果、図２に示すように、ヒト歯肉繊維芽細胞にアデノシンを処置することによりｂＦＧＦが増加することが確認された。(Test 2)
Human gingival fibroblasts were treated with adenosine 0.8 mM for 15 hours and the intracellular bFGF was quantified, and the effect of adenosine treatment was examined with the control group as 100%. As a result, as shown in FIG. 2, it was confirmed that bFGF was increased by treating adenosine with human gingival fibroblasts.
（試験３）
ヒト歯髄細胞にアデノシン０．０２ｍＭまたは０．１ｍＭを１．５時間処置後に細胞内のｂＦＧＦを定量化し、対照群を１００％としてアデノシン処置の効果を検討した。その結果、図３に示すように、ヒト歯髄細胞にアデノシンを処置することによりｂＦＧＦが増加することが確認された。(Test 3)
After treatment of human dental pulp cells with adenosine 0.02 mM or 0.1 mM for 1.5 hours, intracellular bFGF was quantified, and the effect of adenosine treatment was examined with the control group as 100%. As a result, as shown in FIG. 3, it was confirmed that bFGF is increased by treating human dental pulp cells with adenosine.
（試験４）
ヒト歯髄細胞にアデノシン０．５ｍＭを２２時間処置後に細胞表面のｂＦＧＦを定量化し、対照群を１００％としてアデノシン処置の効果を検討した。その結果、図４に示すように、ヒト歯髄細胞にアデノシンを処置することによりｂＦＧＦが増加することが確認された。(Test 4)
After treating human dental pulp cells with 0.5 mM adenosine for 22 hours, bFGF on the cell surface was quantified, and the effect of adenosine treatment was examined with the control group as 100%. As a result, as shown in FIG. 4, it was confirmed that bFGF was increased by treating adenosine with human dental pulp cells.
（試験５）
ヒト歯髄細胞にＡＭＰ０．５ｍＭを５３時間処置後に細胞表面のｂＦＧＦを定量化し、対照群を１００％としてＡＭＰ処置の効果を検討した。その結果、図５に示すように、ヒト歯髄細胞にＡＭＰを処置することによりｂＦＧＦが増加することが確認された。(Test 5)
After treating human dental pulp cells with AMP 0.5 mM for 53 hours, bFGF on the cell surface was quantified, and the effect of AMP treatment was examined with the control group as 100%. As a result, as shown in FIG. 5, it was confirmed that bFGF increases by treating AMP with human dental pulp cells.
（試験６）
ヒト歯髄細胞にアデノシン０．５ｍＭを５３時間処置後に培養液中のｂＦＧＦを定量化し、対照群を１００％としてアデノシン処置の効果を検討した。その結果、図６に示すように、ヒト歯髄細胞にアデノシンを処置することによりｂＦＧＦが増加することが確認された。(Test 6)
After treatment of human dental pulp cells with 0.5 mM adenosine for 53 hours, bFGF in the culture medium was quantified, and the effect of adenosine treatment was examined with the control group as 100%. As a result, as shown in FIG. 6, it was confirmed that bFGF was increased by treating human dental pulp cells with adenosine.
実施例２
＜方法＞
健康な口腔状態である被験者５名（男性４名 女性１名 ２５〜３０歳）の口腔前庭歯肉に、ＡＭＰ製剤（２５％ＡＭＰ＋３％カルボキシメチルセルロース（ＣＭＣ）／０．１％安息香酸Ｎａ）またはプラセボ（３％ＣＭＣ／０．１％安息香酸Ｎａ）を３７℃としたものを約０．８ｍＬ塗布し、口腔前庭歯肉の血流量変化を測定した。血流量の測定は以下の方法にて行なった。Example 2
<Method>
Oral vestibular gingiva of 5 subjects with healthy oral condition (4 males, 1 female, 25-30 years old), AMP preparation (25% AMP + 3% carboxymethylcellulose (CMC) /0.1% Na benzoate) or placebo About 0.8 mL of 37% (3% CMC / 0.1% Na benzoate) was applied, and changes in blood flow in the oral vestibular gingiva were measured. The blood flow was measured by the following method.
（口腔前庭歯肉の血流量変化測定方法）
無侵襲酸素モニターＯＭ−２２０（島津製作所製）を用いて近赤外光の透過量によりヘモグロビン量（血流量）を測定し、その血流量により血行促進効果を評価した。口腔前庭歯肉に製剤を塗布しやすいように口角鉤を装着し、その口角鉤に発光部プローブを固定し、口腔前庭に近赤外線を照射した。受光部センサーは口腔外のオトガイ部に密着させて固定した。製剤を塗布する約１分前から測定を開始し、総血流量が±０．０５ｍＭｃｍ（ミリモルセンチメートル）の振れがない安定した状態になった後、製剤を塗布し、サンプリング間隔は１秒で約５分間計測した。(Measurement of blood flow change in oral vestibular gingiva)
Using a non-invasive oxygen monitor OM-220 (manufactured by Shimadzu Corporation), the hemoglobin amount (blood flow rate) was measured based on the amount of transmitted near infrared light, and the blood circulation promoting effect was evaluated based on the blood flow rate. A mouth mustache was attached so that the preparation could be easily applied to the oral vestibular gingiva, a light emitting probe was fixed to the mouth mustache, and near-infrared rays were irradiated to the mouth vestibule. The light receiving part sensor was fixed in close contact with the chin part outside the oral cavity. Measurement was started about 1 minute before application of the preparation, and after the total blood flow became stable with no fluctuation of ± 0.05 mMcm (mmol centimeter), the preparation was applied and the sampling interval was 1 second. It was measured for about 5 minutes.
＜結果＞
それぞれの被験者において１秒毎の総血液量の増減について、最初の１分間の総血液量の平均増加量と全体（５分間）の総血液量の平均増加量を算出した。両群のｔ−ｔｅｓｔを行った結果、１分間の平均増加量はＡＭＰ群とプラセボ群との間に５％の有意差（＊）が認められ（図７）、５分間の平均増加量はＡＭＰ群とプラセボ群との間に１％の有意差（＊＊）が認められ（図８）、ＡＭＰを処置することにより口腔前庭歯肉の血流量が速やかに、且つ持続的に増加することが確認された。<Result>
For each subject, the average increase in total blood volume for the first minute and the average increase in total blood volume for the entire (5 minutes) were calculated for the increase or decrease in total blood volume per second. As a result of performing t-test of both groups, the average increase amount for 1 minute was found to be 5% significant difference (*) between the AMP group and the placebo group (FIG. 7). A significant difference (**) of 1% is observed between the AMP group and the placebo group (FIG. 8), and the blood flow rate of the oral vestibular gingiva may increase rapidly and continuously by treating AMP. confirmed.
実施例３
＜方法＞
ｂＦＧＦの作用発現の指標として、リン酸化されたｅｘｔｅａｃｅｌｌｕｌａｒ ｓｉｇｎａｌ−ｒｅｇｕｌａｔｅｄ ｋｉｎａｓｅｓ（ＥＲＫ）を測定した。ＥＲＫのリン酸化はｂＦＧＦのシグナル伝達機構のうち重要な因子であり、ｂＦＧＦの歯周組織再生効果の指標となるとされている。Example 3
<Method>
As an index of expression of bFGF action, phosphorylated extecellular signal-regulated kinases (ERK) were measured. ERK phosphorylation is an important factor in the signal transduction mechanism of bFGF, and is considered to be an index of the periodontal tissue regeneration effect of bFGF.
すなわち、ヒト歯髄細胞（ＨＤＰ−２株）を９６穴プレートに播種してセミコンフルエントにしたあと、１）０．２ｍＭ ＡＭＰ単独溶液、２）１ｍＭ ポリリン酸単独溶液、３）０．２ｍＭ ＡＭＰ＋１ｍＭ ポリリン酸混合溶液で一定時間（３０分間、１２０分間、２４時間）処理し、ＣＡＳＡ Ｃｅｌｌｕｌａｒ Ａｃｔｉｖａｔｉｏｎ ｏｆ Ｓｉｇｎａｌｉｎｇ ＥＬＩＳＡ ｋｉｔ（ＳｕｐｅｒＡｒｒａｙ Ｂｉｏｓｃｉｅｎｃｅ Ｃｏｒｐｏｒａｔｉｏｎ社製）でリン酸化ＥＲＫおよびトータルのＥＲＫをそれぞれ定量した。細胞数はアロマーブルーで染色してその色の濃さで算出し、それぞれのｗｅｌｌで補正した。
測定値をもとに、リン酸化ＥＲＫ／ｔｏｔａｌ ＥＲＫの比率を計算し、薬物処置初期、すなわち各薬剤処理１０分間後の値を１００とした場合の各処理群の３０分後、１２０分後、２４時間後の相対値（％）を求めた。That is, after seeding human dental pulp cells (HDP-2 strain) in a 96-well plate to make it semi-confluent, 1) 0.2 mM AMP alone solution, 2) 1 mM polyphosphate alone solution, 3) 0.2 mM AMP + 1 mM polyphosphate The mixture solution was treated for a certain period of time (30 minutes, 120 minutes, 24 hours), and phosphorylated ERK and total ERK were respectively quantified using CASA Cellular Activation of Signaling ELISA kit (SuperArray Bioscience Corporation). The number of cells was stained with aroma blue, calculated by the intensity of the color, and corrected for each well.
Based on the measured value, the ratio of phosphorylated ERK / total ERK was calculated, and after 30 minutes and 120 minutes of each treatment group when the initial value of the drug treatment, that is, 10 minutes after each drug treatment was taken as 100, The relative value (%) after 24 hours was determined.
＜結果＞
表１に示すように、処理後３０分経過した時点であっても、ＡＭＰ単独処理群およびＡＭＰとポリリン酸の併用処理群ではＥＲＫのリン酸化活性はほとんど低下することなく、ｂＦＧＦによる細胞の活性化が強く誘導されていることが明らかとなった。さらに、ＡＭＰ又はポリリン酸の単独処理群では２４時間後にＥＲＫのリン酸化活性の減少が認められたが、ＡＭＰとポリリン酸の併用処理群ではその減少は抑制され、併用処理によってｂＦＧＦによる細胞の活性化が単独処理より長時間持続することが明らかになった。<Result>
As shown in Table 1, even when 30 minutes have elapsed after the treatment, the phosphorylation activity of ERK hardly decreased in the AMP single treatment group and the combined treatment group of AMP and polyphosphate, and the cell activity by bFGF It became clear that the conversion was strongly induced. Furthermore, in the AMP or polyphosphate single treatment group, a decrease in ERK phosphorylation activity was observed after 24 hours, but in the AMP and polyphosphate combination treatment group, the decrease was suppressed. It became clear that crystallization lasted longer than single treatment.
Claims (28)
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| JP4799957B2 (en) * | 2005-08-23 | 2011-10-26 | 興和株式会社 | Pharmaceutical composition for the treatment of stomatitis |
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| WO2008087862A1 (en) * | 2007-01-18 | 2008-07-24 | Regenetiss Inc. | Agent against periodontal disease |
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