WO2010007651A1 - 抗歯周病効果を有する組成物 - Google Patents
抗歯周病効果を有する組成物 Download PDFInfo
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- WO2010007651A1 WO2010007651A1 PCT/JP2008/003985 JP2008003985W WO2010007651A1 WO 2010007651 A1 WO2010007651 A1 WO 2010007651A1 JP 2008003985 W JP2008003985 W JP 2008003985W WO 2010007651 A1 WO2010007651 A1 WO 2010007651A1
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- nucleic acid
- acid compound
- adenine nucleic
- adenine
- adenosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/13—Nucleic acids or derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a drug, food or drink, or oral composition having an anti-periodontal disease effect.
- 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.
- 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.
- nonpatent literature 1 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 periodontal tissue, etc. are known (nonpatent literature 1).
- the periodontal pocket is a site where toothbrushes and the like are difficult to enter, and food is clogged and plaque is likely to accumulate. 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.
- periodontal disease 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.
- 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.
- Non-patent Document 2 discloses a cell growth factor (basic fibroblast growth factor: bFGF)
- Patent Document 1 it has been known to add adenosine and AMP in the oral composition, but the purpose of adding 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 Japanese Patent Document 1
- Patent Document 3 Japanese Patent Laid-Open No. 11-124322 JP 61-151113 A JP 62-418A Dental hygiene “Risk factor of periodontal disease (3) smoking”, Vol. 23 No. 4 Page. 321-334 (2003) Research Institute for Advanced Medical Technology “Periodical Disease Searching for New Treatment”, Chapter 2 Section 2 P56-64 “Periodontal Regeneration Therapy with Fibroblast Growth Factor (bFGF)” Card. Pract. , JST, Vol. 17, no. 3, Page. 315-317 (2006) Journal of Biological Chemistry, Vol. 278, No. 29, Page. 26788-26792 (2003)
- Periodontal tissue regeneration therapy using bFGF as described above uses bFGF itself, which is a physiologically active protein, as an active ingredient.
- bFGF itself, which is a physiologically active protein, as an active ingredient.
- 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.
- adenine nucleic acid compound or polyphosphate The purpose and effect at the time of blending the adenine nucleic acid compound or polyphosphate are as described above.
- 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.
- Non-patent Document 3 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 to have an effect of increasing blood flow.
- 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.
- 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.
- adenine nucleic acid compounds such as adenosine and adenosine 5′-monophosphate (AMP) induce and produce bFGF that promotes blood flow locally in periodontal tissue and strongly induces regeneration of periodontal tissue. I found out.
- adenine nucleic acid compounds such as adenosine and adenosine 5′-monophosphate (AMP) and polyphosphate are promoted as compounds that promote blood flow in periodontal tissue and induce and produce bFGF in periodontal tissue or alveolar bone.
- AMP adenosine 5′-monophosphate
- polyphosphate adenine nucleic acid compound
- 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.
- 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.
- 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.
- An anti-periodontal disease agent comprising an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid as active ingredients.
- An oral hygiene agent containing an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid as active ingredients.
- An adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid 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.
- 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).
- 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.
- adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP).
- AMP adenosine 5′-monophosphate
- ADP adenosine 5′-diphosphate
- ATP adenosine 5′-triphosphate
- 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.
- 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.
- the adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP).
- AMP adenosine, adenosine 5′-monophosphate
- ADP adenosine 5′-diphosphate
- ATP adenosine 5′-triphosphate
- 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.
- 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.
- 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.
- An oral hygiene method comprising administering an effective amount of an adenine nucleic acid compound or an adenine nucleic acid compound and polyphosphoric acid.
- 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
- adenine nucleic acid compound is adenosine, adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and / or adenosine 5′-triphosphate (ATP).
- AMP adenosine 5′-monophosphate
- ADP adenosine 5′-diphosphate
- ATP adenosine 5′-triphosphate
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- AMP adenosine 5′-monophosphate
- ADP adenosine 5′-diphosphate
- ATP adenosine 5′-triphosphate
- Adenosine and AMP are both recognized as natural components existing in the living body, and in particular, AMP is used as a food additive and is a highly safe and convenient compound.
- the active ingredient of the present invention may be an adenine nucleic acid compound alone or a mixture of a plurality of nucleic acid compounds with other nucleic acid compounds.
- 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.
- Such adenine nucleic acid compounds are not particularly limited in their origin, but those derived from natural products such as yeast, bacteria, seafood, animals, plants and the like are suitable.
- 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.
- examples of the polyphosphoric acid used in the present invention include polyphosphoric acid in which the polyphosphoric acid is linear or branched, or a salt thereof, cyclic metaphosphoric acid or a salt thereof, branched ultraphosphoric acid or a salt thereof.
- 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.
- the active ingredient of the present invention when used as food and drink, health food and drink, prepared powdered milk, etc., can be used 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.
- an agent for increasing blood flow and basic fibroblast growth factor, periodontal tissue or alveolar bone regeneration, anti-periodontal agent, oral hygiene agent, etc. 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.
- toothpastes such as toothpaste, liquid toothpaste, moisturized toothpaste, granular toothpaste, oral pasta, mouthwash, oral troche, etc., depending on the dosage form
- blending another additive as an arbitrary component.
- 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.
- various medicinal ingredients can also be blended with the various compositions described above.
- medicinal ingredients include, but are not limited to, anti-inflammatory agents, blood flow promoters, fluorides, bactericides, and the like.
- the compounding amount of the active ingredient ranges from 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.
- 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.
- the content of polyphosphoric acid is not particularly limited, but the blending concentration is preferably 0.01 to 10.0% by weight.
- the administration or ingestion method is not particularly limited, but a method of staying in the oral cavity in a timely manner is preferable.
- the dose or intake varies depending on the subject's age, body weight, degree of symptoms, administration or intake method, etc., but the amount of the adenine nucleic acid compound as an active ingredient is 1 mg to 500 g per person per day.
- An amount capable of exerting an anti-periodontal disease action may be appropriately selected from a range of about 1 mg to 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.
- an adenine nucleic acid compound of 0.01 mg / kg or more per day preferably about 0.1 mg / kg to 1 g / kg
- the anti-periodontal disease action can be obtained.
- Polyphosphoric acid is preferably ingested at a dose of 0.01 mg / kg or more per day, preferably 0.1 mg / kg to 0.5 g / kg.
- the active ingredient of the present invention is highly safe, even if it is ingested in a larger amount than the above range, it can be used in one direction.
- Example 1 Human gingival fibroblasts or human pulp cells were cultured in a plastic 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.
- bFGF is SDS-PAGE, Western blotting, ECL Advance Western Blotting Detection Kit, (RPN2135, Amersham) and ECL Plus Western blotting reagent pack, (PPN2124, software analysis using PJ2124, Amer BFGF was quantified. The effect of adenosine or AMP treatment was examined with the control group as 100%.
- 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.
- 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.
- 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 human dental pulp cells with adenosine.
- 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.
- 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.
- Example 2 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.
- Example 3 As an index of the 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.
- ERK phosphorylated extecellular signal-regulated kinases
- 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.
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Abstract
Description
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
(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。
<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。
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。
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。
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。
(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。
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。
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。
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。
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。
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。
<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。
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。
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。
<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。
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。
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。
Claims (28)
- 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。
- 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。
- 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。
- 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。
- 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。
- 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、請求項1~5のいずれか1項に記載の薬剤または飲食品。
- 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、請求項1~5のいずれか1項に記載の薬剤または飲食品。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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、請求項8~12のいずれか1項に記載のいずれか記載の使用。
- 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、請求項8~12のいずれか1項に記載の使用。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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、請求項15~19のいずれか1項に記載の化合物または組成物。
- 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、請求項15~19のいずれか1項に記載の化合物または組成物。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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、請求項22~26のいずれか1項に記載の方法。
- 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、請求項22~26のいずれか1項に記載の方法。
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