WO2010150944A1 - Composition for the management and improvement of oral health - Google Patents
Composition for the management and improvement of oral health Download PDFInfo
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- WO2010150944A1 WO2010150944A1 PCT/KR2009/005480 KR2009005480W WO2010150944A1 WO 2010150944 A1 WO2010150944 A1 WO 2010150944A1 KR 2009005480 W KR2009005480 W KR 2009005480W WO 2010150944 A1 WO2010150944 A1 WO 2010150944A1
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- composition
- dibenzo
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- management
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Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Definitions
- the present invention relates to a composition for the management and improvement of oral health. More particularly, the present invention relates to the composition comprising dibenzo--p-dioxin derivatives for providing effective maintenance and improvement of oral health by inhibiting the formation of microbial biofilms and eliminating the biofilms effectively.
- Oral health which indicates an ideal state and functioning of oral tissues is crucial to the quality of life in every human being.
- Major problems to oral health include dental caries, gum diseases, periodontal diseases and halitosis.
- the root causes of all those oral disorders are known to be the biofilms generated by oral pathogenic germs (Allaker 2008) which are also called dental plaques.
- Such germs unless they are strongly bound to the oral surface and exist in protective layers, can be easily eliminated by antibacterial action of saliva, during beverage drinking or tooth-brushing, but they are capable of specific binding to the oral surface and efficient formation of tough biofilms for better chance of their survival.
- bioflim Once a bioflim is formed by them, it is so tough and resistant to mechanical or chemical stimuli that it can hardly be removed by normal brushing or cleansing, and requiring highly toxic or large quantity of bactericidal agents even for a temporary inhibition.
- Biofilms if untreated, grow thicker and thicker to form tartars which provide ideal habitats for numerous kinds of other bacteria, leading to many kinds of oral disorders.
- dental scaling has been recommended, and its effect has also been confirmed.
- only a small population is sufficiently treated with dental scaling due to the inconvenience, fear and cost associated with visiting dentists. Consequently, majority of untreated population depends only on tooth brushing for elimination of biofilms or dental calculus and is exposed to many oral disorders.
- the object of the present invention is to overcome the limitations of the prior arts and to provide both safe and effective composition that can be used to maintain and improve oral health. More specifically, the object of the present invention is to effectively prevent oral unpleasantness at low concentration, and to provide an improvement in dental caries and gum diseases, by providing the composition that effectively inhibits the formation of microbial biofilms and eliminates the biofilms.
- the present invention provides the composition comprising dibenzo-p-dioxin derivatives for effective maintenance and improvement of oral health.
- the dibenzo-p-dioxin derivatives according to the present invention may be two or more compounds selected from the group consisting of the following Formula 1 through Formula 4.
- each R is H, C1- C5 alkyl, C2- C5 alkenyl, phenyl, C7-C12 phenyl alkyl, C2-C20 alkanoyl, C3-C20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl.
- the present invention enables long-lasting freshness and cleanliness of one's oral cavity by effectively inhibiting the formation of biofilms and eliminating the biofilms which cause dental caries, tartars, halitosis (bad breath) and gum diseases. Moreover, the present invention provides effective maintenance and improvement of oral health by preventing dental caries and gum diseases, and improving them. Furthermore, the present invention provides safe composition comprising natural substances for the management and improvement of oral health that can be universally used regardless of age.
- FIG. 1 is a graph that illustrates the results of prevention and treatment effects of periodontal disease using chewing gums comprising the composition 7 by comparing with a placebo group.
- PLA Plaque accumulation
- GI Gingival Index
- BOP Bleeding on probing
- PD Periodontal probing depth
- CAL Clinical attachment level
- FIG. 2 is a graph that illustrates the longer-lasting effect of tooth-brushing using toothpastes comprising the composition 5 by comparing with the placebo group.
- Strains of Streptococcus living underneath the biofilms produce lactic acid using sugar molecules present in the oral cavity to erode the enamel layer of the teeth, leading to dental caries.
- Strains including P. gingivalis that inhabit the untreated biofilms or tartar developed around gingiva produce stimulatory substances to induce various inflammatory responses.
- Biofilms formed by anaerobic bacteria inhabiting underneath the tongue break down proteins remaining in oral cavity to release sulfur- and amine-containing chemicals to cause bad breath.
- An ideal substance for toothpastes or mouth washes that can be safely and easily used for effective maintenance and improvement of oral health should have following features: (1) antibacterial activity at low concentrations; (2) long-lasting anti-inflammation; (3) non-stimulating nature; (4) long-term safety; (5) absence of unpleasantness and the like. Since synthetic bactericidal chemicals have serious side effects such as induction of chemical resistance, discoloration, toxicity, loss of tasting sense, etc, the present inventors searched for plant-derived natural substances which are able to inhibit the formation of biofilms and eliminate the biofilms for a longer period of time and to be more effective at low concentrations than previously known natural substances.
- biofilms occurs via two phases consisting of an initial attachment of bacteria to the oral surface and the following co-adhesion phase where vast inter-bacterial adhesion occurs.
- the first phase occurs during the first week, when almost exclusively the strains of Streptococcus are attached to the oral surface.
- the second phase which occurs through the next several weeks involves over 700 strains of bacteria.
- P. gingivalis is known to be a major strain involved in this phase.
- specific proteins mediating adhesion are known to be critically involved in the formation of biofilms.
- the present inventors searched for more effective compounds or composition for the management and improvement of oral health that exert their antibacterial effects on the two-dimensional oral surface rather than simply on the three-dimensional solutions. More specifically, the present inventors searched for potent natural antibacterial substances (work in solutions as conventional antibacterial agents do) that can strongly bind to specific adhesion-mediating proteins present on the oral surface, so that such substances not only inactivate the bacterial adhesion spot in oral cavity but also arrange the antibacterial substances two-dimensionally on the oral surface to prevent the formation of biofilms in oral cavity and enhance long-lasting effect.
- the present inventors searched for: (1) natural substances both with potent antibacterial effect against the strains of Streptococcus and strong binding affinity with bacterial adhesion spot present on the oral surface; (2) natural substances both with potent antibacterial effect against the strains of P. gingivalis and strong binding affinity with the proteins mediating interbacterial adhesion mostly during the second phase of biofilm formation.
- Such substances can not only inhibit the accumulation of biofilms but also eliminate biofilms effectively by arranging the substances two-dimensionally and enhance actual concentration of antibacterial substances.
- the present invention differs from prior arts in that the substances of the present invention not only bind to the specific spot to which the bacteria can adhere but also exert antibacterial effect on two-dimensional oral surface, whereas conventional bactericidal substances interact with the strains of Streptococcus, P. gingivalis and antibacterial agent only in three-dimensional solutions.
- One advantage of the present invention provides an unprecedented control over biofilms by combination of specific inactivation of the originating sites for bioflim growth and the establishment of antibacterial effect on the very sites.
- Another advantage of the present invention is that such specific antibacterial action occurring on the two-dimensional oral surface enables more effective inhibition of the formation of biofilms or plaque and elimination of biofilms at lower concentrations, realizing both economy and safety.
- the present invention can provide a variety of compositions by combining substances with high binding affinity and those with potent antibacterial effects.
- the inventors has completed the present invention by finding that such substances and compositions comprising dibenzo-p-dioxin derivatives have excellent effects in inhibition of the formation of microbial films and elimination of biofilms at low concentrations, and by verifying their benefits in management and improvement of oral health using test products containing the same.
- the present invention relates to the composition for the management and improvement of oral health comprising dibenzo-p-dioxin derivatives as active ingredients.
- such dibenzo-p-dioxin derivatives according to the present invention may be two or more compounds selected from the group consisting of the following Formula 1 through Formula 4:
- each R is H, C 1- C 5 alkyl, C 2 - C 5 alkenyl, phenyl, C 7 -C 12 phenyl alkyl, C 2 -C 20 alkanoyl, C 3 -C 20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl.
- each R is H, methyl, ethenyl, benzyl, acetyl, oleoyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
- each R is H.
- composition for the management and improvement of oral health may preferably comprise 3-70 wt% of the dibenzo-p-dioxin derivative of the Formula 1, 1-75 wt% of the dibenzo-p-dioxin derivative of the Formula 2, 2-60 wt% of the dibenzo-p-dioxin derivative of the Formula 3 and 2-60 wt% of the dibenzo-p-dioxin derivative of the Formula 4, and more preferably may comprise 15-60 wt% of the dibenzo-p-dioxin derivative of the Formula 1, 6-50 wt% of the dibenzo-p-dioxin derivative of the Formula 2, 15-50 wt% of the dibenzo-p-dioxin derivative of the Formula 3 and 12-50 wt% of the dibenzo-p-dioxin derivative of the Formula 4.
- the dibenzo-p-dioxin derivatives according to the Formula 1 through the Formula 4 of the present invention possess various benefits for the management and improvement of oral health. More specific benefits of such compounds can be described as follows.
- the compound according to the Formula 1 of the present invention is especially potent in antibacterial effects against cariogenic bacteria which are involved in the initial steps of biofilm formation. Therefore, the presence of the compound within the above-mentioned range according to the Formula 1 in the composition according to the present invention enhances especially the inhibitory effect against initial biofilm formation and antibacterial effect against cariogenic bacteria.
- the compound according to the Formula 2 of the present invention is especially potent in anti-inflammatory effect in periodontal cells (i.e., inhibition activity of TNF- ⁇ and IL-1 ⁇ ). Therefore, the presence of the compound within the above-mentioned range according to the Formula 2 in the composition of the present invention enhances especially the inhibitory effect and improving effect against periodontitis.
- the compound according to the Formula 3 of the present invention is especially potent in antibacterial effects not only against cariogenic bacteria which are involved in initial biofilm formation, but also against periodontitis-causing bacteria which are involved in the second phase of the biofilm formation. Therefore, the presence of the compound within the above-mentioned range according to the Formula 3 in the composition of the present invention enhances especially inhibitory effect against biofilm formation, and the antibacterial effects against both cariogenic and periodontitis-causing bacteria.
- the compound according to the formula 4 of the present invention is especially potent in inhibition of bacteria from adhering to the oral surface during the initial attachment of the bacteria. Therefore, the presence of the compound within the above-mentioned range according to the Formula 4 in the composition according to the present invention especially enhances the inhibitory effect against biofilm formation.
- composition according to the present invention are especially effective in inhibition of biofilm formation.
- composition according to the present invention may additionally comprises one or more dibenzo-p-dioxin derivatives selected from the group of compounds according to the Formula 5 through the Formula 10:
- each R is H, C 1 - C 5 alkyl, C 2 - C 5 alkenyl, phenyl, C 7 -C 12 phenyl alkyl, C 2 -C 20 alkanoyl, C 3 -C 20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl.
- each R is H, methyl, ethenyl, benzyl, acetyl, oleoyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
- each R is H.
- composition according to the present invention may comprise 0.1-50 wt% of one or more of the dibenzo-p-dioxin derivatives selected from the group of compounds according to the Formula 5 through the Formula 10.
- composition according to the present invention that additionally comprises one or more of the dibenzo-p-dioxin derivatives selected from the group of compounds according to the Formula 5 through the Formula 10 represents more preferable activity, when the composition comprises the compound according to the Formula 7.
- the compound according to the Formula 7 of the present invention is especially potent in antibacterial effect not only against the cariogenic bacteria involved in the initial phase of the biofilms formation but also against the periodontitis-causing bacteria involved in the second phase of the biofilms formation. Therefore, the presence of such compounds in the composition according to the present invention especially enhances both the inhibitory effect against biofilm formation and the antibacterial effect against cariogenic and periodontitis-causing bacteria.
- composition according to the present invention is especially effective in elimination of biofilms when such compositions comprise the compounds according to the Formula 1, the Formula 3 and the Formula 7.
- composition according to the present invention that comprises all compounds according to the Formula 1 through the Formula 10 may preferably comprise 3 ⁇ 50 wt% of the compound of the Formula 1, 1-15 wt% of the compound of the Formula 2, 2-40 wt% of the compound of the Formula 3 and 2-30 wt% of the compound of the Formula 4, 0.1 ⁇ 10 wt% of the compound of the Formula 5, 0.1 ⁇ 10 wt% of the compound of the Formula 6, 2 ⁇ 40 wt% of the compound of the Formula 7, 0.1 ⁇ 10 wt% of the compound of the Formula 8, 0.1 ⁇ 6 wt% of the compound of the Formula 9 and 0.1 ⁇ 20 wt% of the compound of the Formula 10.
- composition of the present invention can be prepared in any suitable category of products including pharmaceuticals and dietary supplements.
- the pharmaceutical products comprising the composition of the present invention can be prepared in any suitable dosage form, including a tablet, a troche, a capsule, an elixir, a suspension, a syrup, a wafer and the like.
- the dietary supplements comprising the composition of the present invention can be prepared in any suitable dosage form, including a tablet, a powder, a capsule, a suspension, a syrup, a beverage, food (i.e., a bar, bread) a toothpaste, a gum and a candy and the like.
- the desirable daily usage of the composition of the present invention may preferably be 0.01-100mg.
- the composition of the present invention may preferably be used for the inhibition of oral biofilms formation, elimination of oral biofilms, prevention of dental caries, prevention of tartar formation, prevention and improvement of gum diseases, and elimination of bad breath.
- the dibenzo-p-dioxin derivatives of the present invention may be prepared by any conventional skills including synthesis using commercial reagents, and extracts and separation from natural resources, especially from seaweeds.
- Example 1-2 Separation of the dibenzo-p-dioxin derivatives from purified polyphenol mixture
- the polyphenol mixture obtained from the Example 1 was filtered using 0.2 ⁇ m of membrane filter and loaded into HPLC (column: HP ODS Hypersil; eluent: 15-70% of aqueous methanol, linear gradient; elution time: 30 min; flow rate: 1.0ml/min) .
- each R is H.
- the inhibition activity against the adhesion step which is crucial in the formation of biofilms has been evaluated in the dibenzo-p-dioxin derivatives of the present invention together with other well-known antibacterial compounds.
- the inhibition activity was assessed by measuring the binding activity to the immobilized proline-rich protein 1 using ELISA method at the same concentration. The more details of the example are described as follows.
- PRP1(Proline-rich protein 1) was separated and purified from human saliva collected from three healthy male donors using the method of Ramasubbu et al (Ramasubbu, N., M. S. Reddy, E. J. Bergey, G. G. Haraszthy, S.-D. Soni, and M. J. Levine. 1991. Large-scale purification and characterization of the major phosphoproteins and mucins of human submandibular-sublingual saliva. Biochem. J. 280:341-352).
- PBST solution phosphate buffer containing 0.1% Tween 20
- the detection of the bound antibody was performed at 405nm using AP-conjugated Goat anti-rabbit IgG (H+L) (Anaspec,USA) as a second antibody and p-nitrophenyl phosphate as a chromogenic substrate.
- Bovine serum albumin was used as a negative control. Quantification was performed using the following equation.
- Binding activity to PRP1 (%) 100 ⁇ (Absorbance of negative control -Absorbance of sample)/Absorbance of negative control
- Example 3-1 Antibacterial activity of the compositions in solution against periodontal bacteria involved in initial stage of biofilm formation
- Biofilm formation can be more effectively inhibited by the substances which not only have strong binding affinity with bacterial adhesion proteins on the oral surface so that prevent initial attachment of bacteria to the oral surface, but also provide antibacterial activity. Therefore, the potent active ingredients were searched by measuring antibacterial activity independently from inhibition of adhesion step.
- Antibacterial activity of the dibenzo-p-dioxin derivatives of the Example 2 and positive controls against multi-species bacteria strain contained Streptococcus mutans (ATCC25275), S.sanguis (ATCC 10556, American type culture Collection, Rockwille, MD, USA), Actinomyces viscosus (KCCM 12074, Korea Culture enter of Microorganisms, Seoul, Korea) was determined. All bacteria were cultured aerobically at 37°C for 24 hrs in BHI (brain heart infusion broth, DIFCO laboratories, Ditroit, MI, USA). Antibacterial activities of each sample were determined by measurement of MIC (Minimum inhibitory concentration) using culture medium micro-dilution method.
- MIC Minimum inhibitory concentration
- Example 3-2 Anti-bacterial activity against periodontal bacteria associated with the second stage of development of biofilm
- Antibacterial activities were determined by measurement of MIC (Minimum inhibitory concentration) using culture medium micro-dilution method.
- MIC Minimum inhibitory concentration
- 2-fold serial dilutions were progressively prepared with BHI medium and final concentration of the compositions ranged from 0.25 to 125 ⁇ g/ml.
- the 96-well polystyrene microplate were inoculated with 20 ⁇ l per well of multi-species bacterial cell suspension at a final concentration of 1X10 6 CFU/ml. After incubation at 37°C for 24 hrs, the absorbance was measured at 596nm to assess the bacteria growth in each well.
- the MIC endpoint was defined as the lowest concentration of the test agent that produced at least 90% reduction of absorbance in comparison with the untreated cell. All experiments were performed in triplicate and the average values were calculated. The MICs of each sample are shown as Table 2.
- Chlorhexidine gluconate showed the strongest anti-bacterial effect. And the compounds of the Formula 3 and the Formula 7 showed the strongest anti-bacterial activity among the natural substances.
- Example 4 Inhibition activity of periodontal inflammation caused by P. gingivalis -LPS
- Periodontal disease comprises a group of infections that leads to inflammation of the gingival tissues and destruction of periodontal tissues.
- Porphyromonas gingivalis is now regarded to be one of the most important of these bacteria.
- P. gingivalis is known to be able to induce high level of several cytokines such as lipopolysaccharide ( P. gingivalis -LPS) and proteinases that lead to periodontal tissue destruction.
- P. gingivalis -LPS (LPS generated by P. gingivalis ) stimulates the production of proinflammatory cytokines such as interleukin-1 (IL-1 ⁇ ) and tumor necrosis factor alpha (TNF- ⁇ ) that caused many periodontal disease. Therefore, we investigated the protective effects of the compositions on periodontal disease through inhibition of proinflammatory cytokines induced by P. gingivalis -LPS.
- IL-1 ⁇ interleukin-1
- TNF- ⁇ tumor necrosis factor alpha
- P. gingivalis (A7A1-28) was cultured in brain heart infusion broth, which contained 5 mg of hemin and 0.5 mg of vitamin K/ml at 37°C in an anaerobic chamber (90% N 2 , 5% H 2 , and 5% CO 2 ) for 24hrs.
- LPS extraction was achieved by the hot phenol-water method.
- the bacterial cell pellet was suspended in distilled water, and then an equal volume of 90% phenol was added dropwise at 60 and stirred constantly for 20 min.
- the aqueous phase was separated by centrifugation at 7,000rpm for 15 min at 4C.
- the aqueous phase was pooled and dialyzed against deionized water for 3 days at 4°C.
- the dialyzed LPS preparation was then centrifuged at 40,000 rpm for 1.5 h at 4°C.
- the precipitate was suspended with 30 ml of pyrogen-free water, dialyzed against distilled water for 3 days, lyophilized, and stored at 4°C.
- the mouse macrophage cell line RAW 264.7 were maintained in the DMEM medium supplemented 4.5 g/l of glucose, 10% serum, and 1% antibiotic at 37°C for 24 hours. After the cell was plated and incubated for 48 hours, the cells were treated with 50 ⁇ g/ml of compounds of the Formula 1 to the Formula 10, or positive controls and incubated at 37°C for 3 days. The cells were then treated with lysis buffer (0.1M potassium phosphate buffer solution, pH 7.8, 1% Triton X-100/1mM DTT/2mM EDTA). The amounts of interleukin-1 (IL-1 ⁇ ) and tumor necrosis factor alpha (TNF- ⁇ ) released to the culture media were analyzed by using an ELISA (Enzyme-linked innumosorbent assay). The results are shown in Table 3.
- the compound of the Formula 2 showed the strongest activity against proinflammatory cytokines.
- Example 3 and 4 demonstrated that dibenzo-p-dioxin derivatives had inhibition effects against biofilm formation.
- the compositions 1- 10 were prepared from these dibenzo-p-dioxin derivatives and described in Table 4.
- compositions of the Example 5 and positive controls against formation of biofilm were assessed. Each sample was dissolved in 100% DMSO, and then diluted to concentrations of 0.5-40 ⁇ l/ml using 1% sterile mucin. The artificial saliva, 1% type III mucin (mucin from porcine stomach, Sigma-Aldrich), was diluted with adherence buffer and autoclaved at 121°C for 15 min.
- Multi-species inocula was prepared using Streptococcus mutans ATCC25275, S.sanguis ATCC 10556 (American type culture Collection, Rockwille, MD, USA), Actinomyces viscosus KCCM 12074 (Korea Culture center of Microorganisms, Seoul, Korea). In details, the cultured bacteria cell was harvested by centrifugation (4500rpm, 5min), washed with PBS (phosphate-buffered saline, pH7.2).
- PBS phosphate-buffered saline, pH7.2
- the cell was resuspended in adherence buffer (10mM KPO 4 , 50mM KCl, 1mM CaCl 2 , 0.1mM MgCl 2 , pH7.0) and adjusted to a concentration of 1x10 6 CFU/ml.
- Multi-species inocular contained same concentration of each bacteria strain.
- Preventive effects of the compositions against biofilm formation were assessed by the modified method of Rukayadi and Hwang. In details, 0.5-50 ⁇ g/ml of samples were placed in 96-well polystyrene microplates, then incubated and shaken at room temperature for 3 h, followed by air-drying overnight.
- the untreated cell was used as a control and IC 50 was determined.
- Biofilm cells were treated with 0.5 ⁇ 50 ⁇ g/ml of the compositions or positive controls and incubated for 1 h. Biofilm cells were stained with 0.4% crystal violet solution for 30 min, rinsed thoroughly with distilled water. The stained cells were dissolved in 200 ⁇ l of 95% ethanol and the amount of remaining crystal violet stain was determined using microplate reader at 596nm. The percentage of elimination of oral biofilm was calculated using the following equation and the results were shown in Table 6.
- Example 8 Prevention and treatment of periodontal disease by the composition
- composition 7 for the prevention and treatment of periodontal disease was clinically investigated as following Table 7.
- the test group comprising the composition 7 showed excellent effects on preventing periodontal disease and improving periodontal status as compared with the placebo group.
- the composition 6 showed excellent effects on preventing and improving gingivitis.
- the effect of the present invention on everyday life was evaluated in terms of its effect on the generation of bad breath or oral unpleasantness. It was evaluated according to the method described in Table 11 using toothpaste containing a composition according to the present invention.
- One of the control toothpastes comprised the Ecklonia cava extract which is known to be effective in removing bad breath.
- the other control paste comprised of chlorhexidine which is known to be a strong antiseptic chemical and popularly used in dental-care products.
- the use of the toothpaste comprising the composition 5 according to the present invention showed a substantially longer-lasting effect in inhibition of oral unpleasantness in comparison with the uses of the toothpaste comprising Ecklonia cava extract or chlorhexidine as an active ingredient.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a composition comprising dibenzo-p-dioxin derivatives as active ingredients for the management and improvement of oral health. The composition enables long-lasting freshness and cleanliness of one's oral cavity by effectively inhibiting the formation of biofilms and eliminating the biofilms which cause dental caries, tartars, halitosis (bad breath) and gum diseases. Moreover, the present invention provides effective maintenance and improvement of oral health by preventing dental caries and gum diseases, and improving them.
Description
The present invention relates to a composition for the management and improvement of oral health. More particularly, the present invention relates to the composition comprising dibenzo--p-dioxin derivatives for providing effective maintenance and improvement of oral health by inhibiting the formation of microbial biofilms and eliminating the biofilms effectively.
Oral health which indicates an ideal state and functioning of oral tissues is crucial to the quality of life in every human being. Major problems to oral health include dental caries, gum diseases, periodontal diseases and halitosis. The root causes of all those oral disorders are known to be the biofilms generated by oral pathogenic germs (Allaker 2008) which are also called dental plaques. Such germs, unless they are strongly bound to the oral surface and exist in protective layers, can be easily eliminated by antibacterial action of saliva, during beverage drinking or tooth-brushing, but they are capable of specific binding to the oral surface and efficient formation of tough biofilms for better chance of their survival. Once a bioflim is formed by them, it is so tough and resistant to mechanical or chemical stimuli that it can hardly be removed by normal brushing or cleansing, and requiring highly toxic or large quantity of bactericidal agents even for a temporary inhibition. Biofilms, if untreated, grow thicker and thicker to form tartars which provide ideal habitats for numerous kinds of other bacteria, leading to many kinds of oral disorders. As a representative method to remove biofilms and tartars, dental scaling has been recommended, and its effect has also been confirmed. However, only a small population is sufficiently treated with dental scaling due to the inconvenience, fear and cost associated with visiting dentists. Consequently, majority of untreated population depends only on tooth brushing for elimination of biofilms or dental calculus and is exposed to many oral disorders. In order to solve such problems, many mouth washing products containing bactericidal chemicals such as chlorhexidine, cetylpyridinium chloride and triclosan which kill cariogenic and periodontitis-causing germs have been commercialized. However, long-term use of such synthetic bactericidal chemicals causes damage to non-pathogenic bacteria as well as oral mucosa, giving rise to side effects such as induction of chemical resistance by pathogenic bacteria, discoloration of teeth and loss of tasting sense. Especially, a popularly used bactericidal agent, chlorhexidine has been reported to induce shocks and may be very dangerous when one has an injury in the oral cavity. Recently, to avoid such toxicity and side effects of synthetic chemicals, the use of plant-derived antibacterial agents such as thymol, eucalyptol, menthol, EGCG and xylitol is increasing. However, the effectiveness in inhibition and elimination of biofilms is too limited to provide satisfactory management and improvement of oral health.
Therefore the object of the present invention is to overcome the limitations of the prior arts and to provide both safe and effective composition that can be used to maintain and improve oral health. More specifically, the object of the present invention is to effectively prevent oral unpleasantness at low concentration, and to provide an improvement in dental caries and gum diseases, by providing the composition that effectively inhibits the formation of microbial biofilms and eliminates the biofilms.
The present invention provides the composition comprising dibenzo-p-dioxin derivatives for effective maintenance and improvement of oral health.
The dibenzo-p-dioxin derivatives according to the present invention may be two or more compounds selected from the group consisting of the following Formula 1 through Formula 4.
[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
wherein each R is H, C1- C5 alkyl, C2- C5 alkenyl, phenyl, C7-C12 phenyl alkyl, C2-C20 alkanoyl, C3-C20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl.
The present invention enables long-lasting freshness and cleanliness of one's oral cavity by effectively inhibiting the formation of biofilms and eliminating the biofilms which cause dental caries, tartars, halitosis (bad breath) and gum diseases. Moreover, the present invention provides effective maintenance and improvement of oral health by preventing dental caries and gum diseases, and improving them. Furthermore, the present invention provides safe composition comprising natural substances for the management and improvement of oral health that can be universally used regardless of age.
FIG. 1 is a graph that illustrates the results of prevention and treatment effects of periodontal disease using chewing gums comprising the composition 7 by comparing with a placebo group.
PLA: Plaque accumulation, GI: Gingival Index, BOP: Bleeding on probing,
PD: Periodontal probing depth, CAL: Clinical attachment level
FIG. 2 is a graph that illustrates the longer-lasting effect of tooth-brushing using toothpastes comprising the composition 5 by comparing with the placebo group.
Hereinafter, the present invention will be described in detail.
Strains of Streptococcus living underneath the biofilms (or dental plaques) produce lactic acid using sugar molecules present in the oral cavity to erode the enamel layer of the teeth, leading to dental caries. Strains including P. gingivalis that inhabit the untreated biofilms or tartar developed around gingiva produce stimulatory substances to induce various inflammatory responses. Biofilms formed by anaerobic bacteria inhabiting underneath the tongue break down proteins remaining in oral cavity to release sulfur- and amine-containing chemicals to cause bad breath.
An ideal substance for toothpastes or mouth washes that can be safely and easily used for effective maintenance and improvement of oral health should have following features: (1) antibacterial activity at low concentrations; (2) long-lasting anti-inflammation; (3) non-stimulating nature; (4) long-term safety; (5) absence of unpleasantness and the like. Since synthetic bactericidal chemicals have serious side effects such as induction of chemical resistance, discoloration, toxicity, loss of tasting sense, etc, the present inventors searched for plant-derived natural substances which are able to inhibit the formation of biofilms and eliminate the biofilms for a longer period of time and to be more effective at low concentrations than previously known natural substances.
According to a scientific literature (Rosan et al, Microbes and Infection 2000, 2:1599-1607), the formation of biofilms occurs via two phases consisting of an initial attachment of bacteria to the oral surface and the following co-adhesion phase where vast inter-bacterial adhesion occurs. The first phase occurs during the first week, when almost exclusively the strains of Streptococcus are attached to the oral surface. The second phase which occurs through the next several weeks involves over 700 strains of bacteria. However, P. gingivalis is known to be a major strain involved in this phase. During both phases of adhesion, specific proteins mediating adhesion are known to be critically involved in the formation of biofilms. Since conventional bactericidal substances were not made to block the adhesion process, but to simply attack the bacteria present in the three-dimensional solution, their effect is limited and do not generally last long. Consequently, high concentrated or highly toxic bactericidal substances are required for better and longer effect, and it leads to side effects such as accumulation of toxicity in tissues exposed to them, loss of tasting sense, increase of resistance to such chemicals by bacteria. In other words, as the products made of conventional substances, it is impossible to prevent and eliminate the formation of biofilms sufficiently with ordinary use (daily 1-2 times of brushing or rinsing with mouth wash etc.). Furthermore, it is difficult to maintain oral health effectively, safely and improve it due to the side effects. Recognizing the importance of adhesion processes in the formation of biofilms, the present inventors searched for more effective compounds or composition for the management and improvement of oral health that exert their antibacterial effects on the two-dimensional oral surface rather than simply on the three-dimensional solutions. More specifically, the present inventors searched for potent natural antibacterial substances (work in solutions as conventional antibacterial agents do) that can strongly bind to specific adhesion-mediating proteins present on the oral surface, so that such substances not only inactivate the bacterial adhesion spot in oral cavity but also arrange the antibacterial substances two-dimensionally on the oral surface to prevent the formation of biofilms in oral cavity and enhance long-lasting effect. The more specifically, the present inventors searched for: (1) natural substances both with potent antibacterial effect against the strains of Streptococcus and strong binding affinity with bacterial adhesion spot present on the oral surface; (2) natural substances both with potent antibacterial effect against the strains of P. gingivalis and strong binding affinity with the proteins mediating interbacterial adhesion mostly during the second phase of biofilm formation.
Such substances can not only inhibit the accumulation of biofilms but also eliminate biofilms effectively by arranging the substances two-dimensionally and enhance actual concentration of antibacterial substances.
Therefore, the present invention differs from prior arts in that the substances of the present invention not only bind to the specific spot to which the bacteria can adhere but also exert antibacterial effect on two-dimensional oral surface, whereas conventional bactericidal substances interact with the strains of Streptococcus, P. gingivalis and antibacterial agent only in three-dimensional solutions. One advantage of the present invention provides an unprecedented control over biofilms by combination of specific inactivation of the originating sites for bioflim growth and the establishment of antibacterial effect on the very sites. Another advantage of the present invention is that such specific antibacterial action occurring on the two-dimensional oral surface enables more effective inhibition of the formation of biofilms or plaque and elimination of biofilms at lower concentrations, realizing both economy and safety. Furthermore, the present invention can provide a variety of compositions by combining substances with high binding affinity and those with potent antibacterial effects.
During the search for such substances to realize the purpose of the present invention, the present inventors have become aware that proline-rich peptides existing on the oral surface and bacterial membrane are crucially involved in the adhesion processes that oral bacteria adhere to oral surface and other bacteria during biofilm formation through US patent 5013542 (Method to inhibit adhesion of disease-causing microorganisms to teeth) and a literature (Rosan et al, Microbes and Infection 2000, 2:1599-1607). Based on this information, the present inventors searched for natural potent antibacterial substances that has strong binding affinity toward proline-rich peptides at the same time, and discovered that natural substances and compositions comprising dibenzo-p-dioxin derivatives possess such properties. The inventors has completed the present invention by finding that such substances and compositions comprising dibenzo-p-dioxin derivatives have excellent effects in inhibition of the formation of microbial films and elimination of biofilms at low concentrations, and by verifying their benefits in management and improvement of oral health using test products containing the same.
The present invention relates to the composition for the management and improvement of oral health comprising dibenzo-p-dioxin derivatives as active ingredients.
Preferably, such dibenzo-p-dioxin derivatives according to the present invention may be two or more compounds selected from the group consisting of the following Formula 1 through Formula 4:
[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
wherein each R is H, C1- C5 alkyl, C2- C5 alkenyl, phenyl, C7-C12 phenyl alkyl, C2-C20 alkanoyl, C3-C20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl.
Preferably wherein each R is H, methyl, ethenyl, benzyl, acetyl, oleoyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
More preferably each R is H.
The composition for the management and improvement of oral health according to the present invention may preferably comprise 3-70 wt% of the dibenzo-p-dioxin derivative of the Formula 1, 1-75 wt% of the dibenzo-p-dioxin derivative of the Formula 2, 2-60 wt% of the dibenzo-p-dioxin derivative of the Formula 3 and 2-60 wt% of the dibenzo-p-dioxin derivative of the Formula 4, and more preferably may comprise 15-60 wt% of the dibenzo-p-dioxin derivative of the Formula 1, 6-50 wt% of the dibenzo-p-dioxin derivative of the Formula 2, 15-50 wt% of the dibenzo-p-dioxin derivative of the Formula 3 and 12-50 wt% of the dibenzo-p-dioxin derivative of the Formula 4.
The dibenzo-p-dioxin derivatives according to the Formula 1 through the Formula 4 of the present invention possess various benefits for the management and improvement of oral health. More specific benefits of such compounds can be described as follows.
The compound according to the Formula 1 of the present invention is especially potent in antibacterial effects against cariogenic bacteria which are involved in the initial steps of biofilm formation. Therefore, the presence of the compound within the above-mentioned range according to the Formula 1 in the composition according to the present invention enhances especially the inhibitory effect against initial biofilm formation and antibacterial effect against cariogenic bacteria.
The compound according to the Formula 2 of the present invention is especially potent in anti-inflammatory effect in periodontal cells (i.e., inhibition activity of TNF-α and IL-1β). Therefore, the presence of the compound within the above-mentioned range according to the Formula 2 in the composition of the present invention enhances especially the inhibitory effect and improving effect against periodontitis.
The compound according to the Formula 3 of the present invention is especially potent in antibacterial effects not only against cariogenic bacteria which are involved in initial biofilm formation, but also against periodontitis-causing bacteria which are involved in the second phase of the biofilm formation. Therefore, the presence of the compound within the above-mentioned range according to the Formula 3 in the composition of the present invention enhances especially inhibitory effect against biofilm formation, and the antibacterial effects against both cariogenic and periodontitis-causing bacteria.
The compound according to the formula 4 of the present invention is especially potent in inhibition of bacteria from adhering to the oral surface during the initial attachment of the bacteria. Therefore, the presence of the compound within the above-mentioned range according to the Formula 4 in the composition according to the present invention especially enhances the inhibitory effect against biofilm formation.
When the two or more compounds selected from the group of compounds according to the Formula 1 through the Formula 4 are those of the Formula 1, 3, or 4, the composition according to the present invention are especially effective in inhibition of biofilm formation.
The composition according to the present invention may additionally comprises one or more dibenzo-p-dioxin derivatives selected from the group of compounds according to the Formula 5 through the Formula 10:
[Formula 5]
[Formula 6]
[Formula 7]
[Formula 8]
[Formula 9]
[Formula 10]
wherein each R is H, C1- C5 alkyl, C2- C5 alkenyl, phenyl, C7-C12 phenyl alkyl, C2-C20 alkanoyl, C3-C20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl.
Preferably wherein each R is H, methyl, ethenyl, benzyl, acetyl, oleoyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
More preferably each R is H.
The composition according to the present invention may comprise 0.1-50 wt% of one or more of the dibenzo-p-dioxin derivatives selected from the group of compounds according to the Formula 5 through the Formula 10.
The composition according to the present invention that additionally comprises one or more of the dibenzo-p-dioxin derivatives selected from the group of compounds according to the Formula 5 through the Formula 10 represents more preferable activity, when the composition comprises the compound according to the Formula 7.
The compound according to the Formula 7 of the present invention is especially potent in antibacterial effect not only against the cariogenic bacteria involved in the initial phase of the biofilms formation but also against the periodontitis-causing bacteria involved in the second phase of the biofilms formation. Therefore, the presence of such compounds in the composition according to the present invention especially enhances both the inhibitory effect against biofilm formation and the antibacterial effect against cariogenic and periodontitis-causing bacteria.
The composition according to the present invention is especially effective in elimination of biofilms when such compositions comprise the compounds according to the Formula 1, the Formula 3 and the Formula 7.
The composition according to the present invention that comprises all compounds according to the Formula 1 through the Formula 10 may preferably comprise 3~50 wt% of the compound of the Formula 1, 1-15 wt% of the compound of the Formula 2, 2-40 wt% of the compound of the Formula 3 and 2-30 wt% of the compound of the Formula 4, 0.1~10 wt% of the compound of the Formula 5, 0.1~10 wt% of the compound of the Formula 6, 2~40 wt% of the compound of the Formula 7, 0.1~10 wt% of the compound of the Formula 8, 0.1~6 wt% of the compound of the Formula 9 and 0.1~20 wt% of the compound of the Formula 10.
The composition of the present invention can be prepared in any suitable category of products including pharmaceuticals and dietary supplements.
The pharmaceutical products comprising the composition of the present invention can be prepared in any suitable dosage form, including a tablet, a troche, a capsule, an elixir, a suspension, a syrup, a wafer and the like. The dietary supplements comprising the composition of the present invention can be prepared in any suitable dosage form, including a tablet, a powder, a capsule, a suspension, a syrup, a beverage, food (i.e., a bar, bread) a toothpaste, a gum and a candy and the like.
The desirable daily usage of the composition of the present invention may preferably be 0.01-100mg. The composition of the present invention may preferably be used for the inhibition of oral biofilms formation, elimination of oral biofilms, prevention of dental caries, prevention of tartar formation, prevention and improvement of gum diseases, and elimination of bad breath.
Hereinafter, the present invention will be described with reference to the following Examples, but not be construed to limit the present invention.
The following Examples can be moderately modified and changed within the scope of the present invention by person skilled in the art.
The dibenzo-p-dioxin derivatives of the present invention may be prepared by any conventional skills including synthesis using commercial reagents, and extracts and separation from natural resources, especially from seaweeds.
Example 1. Preparation of the dibenzo-p-dioxin derivatives
Example 1-1. Preparation of polyphenol mixture from Eisenia arborea
After fresh Eisenia arborea (1Kg) was extruded to remove fibers, 95% ethyl alcohol (4L) was added and stirred for 30 min at room temperature. The extract solution was filtered and dried to obtain 58 g of brown powder. The brown powder was dissolved with 20 times of distilled water at 50°C, and then PVPP (Polyvinylpyrrolidone) resin (10 times of dry powder) was added and stirred for 1 hr at 50℃. The PVPP resin was filtered and washed with distilled water more than 5 times of the PVPP resin. 95% ethyl alcohol was added to the washed PVPP resin and stirred for 30 min at room temperature. The solution was filtered and dried to obtain 8g of dark brown powder. Total polyphenol content, measured by Folin's reagent, was 95.6%.
Example 1-2. Separation of the dibenzo-p-dioxin derivatives from purified polyphenol mixture
The polyphenol mixture obtained from the Example 1 was filtered using 0.2 μm of membrane filter and loaded into HPLC (column: HP ODS Hypersil; eluent: 15-70% of aqueous methanol, linear gradient; elution time: 30 min; flow rate: 1.0ml/min) .
10 active substances were separated from the mixture and the compounds were independently confirmed to be the dibenzo-p-dioxin derivatives of the Formula 1 to the Formula 10.
[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
[Formula 6]
[Formula 7]
[Formula 8]
[Formula 9]
[Formula 10]
Wherein each R is H.
Example 2. Binding/inactivation affinity of the compositions with proline-rich peptide
The inhibition activity against the adhesion step which is crucial in the formation of biofilms has been evaluated in the dibenzo-p-dioxin derivatives of the present invention together with other well-known antibacterial compounds. The inhibition activity was assessed by measuring the binding activity to the immobilized proline-rich protein 1 using ELISA method at the same concentration. The more details of the example are described as follows.
PRP1(Proline-rich protein 1) was separated and purified from human saliva collected from three healthy male donors using the method of Ramasubbu et al (Ramasubbu, N., M. S. Reddy, E. J. Bergey, G. G. Haraszthy, S.-D. Soni, and M. J. Levine. 1991. Large-scale purification and characterization of the major phosphoproteins and mucins of human submandibular-sublingual saliva. Biochem. J. 280:341-352). Purified PRP1 (2 mmol/ml, phosphate buffer, pH 7.4) was treated to the 96-well plates (activated with 2% glutaraldehyde in phosphate buffer, pH 7.4) and incubated overnight at 4℃ and immobilized. Subsequently the resulting plates were washed three times with a phosphate buffer containing 0.1% Tween 20 (PBST solution), and then with a casein solution. After one hour at room temperature, the plates were washed again three times with PBST solution. 100 μg/mL each of dibenzo-p-dioxin derivative according to the Formula 1 through the Formula 10 (R=H) and other known compounds was treated to the respective well. The plates were incubated for three hours at room temperature and washed three times with the PBST solution and then with the casein solution. Rabbit Anti-Human PRAP1 Polyclonal Antibody (Abcam, England) was dilute by 1:10,000 and added to each well. After overnight incubation at 4℃, unbound antibody was removed by washing with PBST solution three times.
The detection of the bound antibody was performed at 405nm using AP-conjugated Goat anti-rabbit IgG (H+L) (Anaspec,USA) as a second antibody and p-nitrophenyl phosphate as a chromogenic substrate. Bovine serum albumin was used as a negative control. Quantification was performed using the following equation.
Binding activity to PRP1 (%) = 100 × (Absorbance of negative control -Absorbance of sample)/Absorbance of negative control
As the result, the dibenzo-p-dioxin derivative according to the Formula 4 (R=H) showed the highest activity.
Table 1 
Example 3. Antibacterial activity of the compositions in solution
Example 3-1. Antibacterial activity of the compositions in solution against periodontal bacteria involved in initial stage of biofilm formation
Biofilm formation can be more effectively inhibited by the substances which not only have strong binding affinity with bacterial adhesion proteins on the oral surface so that prevent initial attachment of bacteria to the oral surface, but also provide antibacterial activity. Therefore, the potent active ingredients were searched by measuring antibacterial activity independently from inhibition of adhesion step.
Antibacterial activity of the dibenzo-p-dioxin derivatives of the Example 2 and positive controls against multi-species bacteria strain contained Streptococcus mutans (ATCC25275), S.sanguis(ATCC 10556, American type culture Collection, Rockwille, MD, USA), Actinomyces viscosus (KCCM 12074, Korea Culture enter of Microorganisms, Seoul, Korea) was determined. All bacteria were cultured aerobically at 37℃ for 24 hrs in BHI (brain heart infusion broth, DIFCO laboratories, Ditroit, MI, USA). Antibacterial activities of each sample were determined by measurement of MIC (Minimum inhibitory concentration) using culture medium micro-dilution method. In details, after stock solutions of each sample at a concentration of 1,000μg/ml were progressively prepared in 10%-DMSO, 2-fold serial dilutions were prepared with BHI medium and final concentration of each sample ranged from 0.25 to 125μg/ml. The 96-well polystyrene plate was inoculated with 20μl per well of multi-species bacterial cell suspension at a final concentration of 1x106 CFU/ml. After incubation at 37℃ for 24 hrs, the absorbance was measured at 596nm to assess the bacteria growth in each well. The MIC endpoint was defined as the lowest concentration of the test agent that produced at least 90% reduction of absorbance in comparison with the untreated cell. All experiments were performed in triplicate and the average values were calculated. The MICs of each sample are shown as Table 2.
Example 3-2. Anti-bacterial activity against periodontal bacteria associated with the second stage of development of biofilm
Antibacterial activity of the dibenzo-p-dioxin derivatives (compound 1 to 10) against Porphyromonas gingivalis (ATCC 53978), Porphyromonas endodontalis (ATCC 35406), Prevotella intermedia (ATCC 25611) was determined using the compounds of the Example 2. All bacteria were cultured in an anaerobic chamber (90% N2, 5% CO2, 5% H2) at 37℃ for 24 hrs in 30 g/L tripticase soy broth containing 5 g/L yeast extract, 0.5 g/L L-cysteine, 5 μg/ml hemin and 0.2 μg/ml vitamin K1. Antibacterial activities were determined by measurement of MIC (Minimum inhibitory concentration) using culture medium micro-dilution method. In details, after a stock solution of the compositions at a concentration of 1,000μg/ml was prepared in 10%-DMSO, 2-fold serial dilutions were progressively prepared with BHI medium and final concentration of the compositions ranged from 0.25 to 125μg/ml. The 96-well polystyrene microplate were inoculated with 20μl per well of multi-species bacterial cell suspension at a final concentration of 1X106 CFU/ml. After incubation at 37℃ for 24 hrs, the absorbance was measured at 596nm to assess the bacteria growth in each well. The MIC endpoint was defined as the lowest concentration of the test agent that produced at least 90% reduction of absorbance in comparison with the untreated cell. All experiments were performed in triplicate and the average values were calculated. The MICs of each sample are shown as Table 2.
Table 2 
Chlorhexidine gluconate showed the strongest anti-bacterial effect. And the compounds of the Formula 3 and the Formula 7 showed the strongest anti-bacterial activity among the natural substances.
Example 4. Inhibition activity of periodontal inflammation caused by P. gingivalis-LPS
Periodontal disease comprises a group of infections that leads to inflammation of the gingival tissues and destruction of periodontal tissues. Among many different species of bacteria associated with periodontal disease, Porphyromonas
gingivalis is now regarded to be one of the most important of these bacteria. P. gingivalis is known to be able to induce high level of several cytokines such as lipopolysaccharide (P. gingivalis-LPS) and proteinases that lead to periodontal tissue destruction.
P. gingivalis-LPS (LPS generated by P. gingivalis) stimulates the production of proinflammatory cytokines such as interleukin-1 (IL-1β) and tumor necrosis factor alpha (TNF-α) that caused many periodontal disease. Therefore, we investigated the protective effects of the compositions on periodontal disease through inhibition of proinflammatory cytokines induced by P. gingivalis-LPS.
P. gingivalis (A7A1-28) was cultured in brain heart infusion broth, which contained 5 mg of hemin and 0.5 mg of vitamin K/ml at 37℃ in an anaerobic chamber (90% N2, 5% H2, and 5% CO2) for 24hrs. LPS extraction was achieved by the hot phenol-water method. In details, the bacterial cell pellet was suspended in distilled water, and then an equal volume of 90% phenol was added dropwise at 60 and stirred constantly for 20 min. The aqueous phase was separated by centrifugation at 7,000rpm for 15 min at 4C. The aqueous phase was pooled and dialyzed against deionized water for 3 days at 4°C. The dialyzed LPS preparation was then centrifuged at 40,000 rpm for 1.5 h at 4°C. The precipitate was suspended with 30 ml of pyrogen-free water, dialyzed against distilled water for 3 days, lyophilized, and stored at 4°C.
The mouse macrophage cell line RAW 264.7 were maintained in the DMEM medium supplemented 4.5 g/l of glucose, 10% serum, and 1% antibiotic at 37°C for 24 hours. After the cell was plated and incubated for 48 hours, the cells were treated with 50 μg/ml of compounds of the Formula 1 to the Formula 10, or positive controls and incubated at 37℃ for 3 days. The cells were then treated with lysis buffer (0.1M potassium phosphate buffer solution, pH 7.8, 1% Triton X-100/1mM DTT/2mM EDTA). The amounts of interleukin-1 (IL-1β) and tumor necrosis factor alpha (TNF-α) released to the culture media were analyzed by using an ELISA (Enzyme-linked innumosorbent assay). The results are shown in Table 3.
Table 3 
As shown in Table 3, the compound of the Formula 2 showed the strongest activity against proinflammatory cytokines.
Example 5. Preparation of the compositions 1-12
Example 3 and 4 demonstrated that dibenzo-p-dioxin derivatives had inhibition effects against biofilm formation. The compositions 1- 10 were prepared from these dibenzo-p-dioxin derivatives and described in Table 4.
Table 4 
Example 6. Preventive effects of the compositions against biofilm formation
Inhibitory effects of the compositions of the Example 5 and positive controls against formation of biofilm were assessed. Each sample was dissolved in 100% DMSO, and then diluted to concentrations of 0.5-40μl/ml using 1% sterile mucin. The artificial saliva, 1% type III mucin (mucin from porcine stomach, Sigma-Aldrich), was diluted with adherence buffer and autoclaved at 121℃ for 15 min.
Multi-species inocula was prepared using Streptococcus mutans ATCC25275, S.sanguis ATCC 10556 (American type culture Collection, Rockwille, MD, USA), Actinomyces viscosus KCCM 12074 (Korea Culture center of Microorganisms, Seoul, Korea). In details, the cultured bacteria cell was harvested by centrifugation (4500rpm, 5min), washed with PBS (phosphate-buffered saline, pH7.2). The cell was resuspended in adherence buffer (10mM KPO4, 50mM KCl, 1mM CaCl2, 0.1mM MgCl2, pH7.0) and adjusted to a concentration of 1x106 CFU/ml. Multi-species inocular contained same concentration of each bacteria strain. Preventive effects of the compositions against biofilm formation were assessed by the modified method of Rukayadi and Hwang. In details, 0.5-50μg/ml of samples were placed in 96-well polystyrene microplates, then incubated and shaken at room temperature for 3 h, followed by air-drying overnight. After the coating treatment, 20μl of multi-species inocula were added to the wells in a total volume of 200μl per well (final concentration of cells 1x105 CFU/ml) and incubated at 37℃ for 24 hrs. The culture supernatants from each well were then decanted, and planktonic cells were removed by washing with 200μl of 50mM PBS. Biofilm cells were stained with 0.4% crystal violet solution for 30 min, rinsed thoroughly with distilled water. The stained cells were dissolved in 200μl of 95% ethanol and the amount of remaining crystal violet stain was determined using microplate reader at 596nm. The percentage of inhibition effect was calculated using the following equation and the results were shown in Table 5.
Prevention of biofilm formation (%) = (1-OD596 of the sample/OD596 of the untreated control) X 100
The untreated cell was used as a control and IC50 was determined.
Table 5 
Example 7. Elimination effects of biofilm by the compositions
Elimination of established oral biofilms is so important as much as inhibition of biofilm formation in oral health. Therefore, elimination effects of the compositions of the Example 5 and positive controls on established oral biofilms were assessed. Artificial multi-species oral biofilms were prepared in polystyrene 96-well microplate by the method of Stepanovic. Each plate was conditioned with 200μl of mucin as artificial saliva, incubated, and shaken gently at room temperature for 3h. Then excess mucin was removed and the plate was air-dried overnight. Multi-species oral biofilms were grown using 20μl of multi-species inoculums in BHI medium supplemented with 3% sucrose (BHIS) at 37℃ for 24 hrs. The culture supernatants from each well were then decanted, and planktonic cells were removed by washing with 200μl of 50mM PBS. Biofilm cells were treated with 0.5~50μg/ml of the compositions or positive controls and incubated for 1 h. Biofilm cells were stained with 0.4% crystal violet solution for 30 min, rinsed thoroughly with distilled water. The stained cells were dissolved in 200μl of 95% ethanol and the amount of remaining crystal violet stain was determined using microplate reader at 596nm. The percentage of elimination of oral biofilm was calculated using the following equation and the results were shown in Table 6.
Elimination of established oral biofilm (%) = (1-OD596 of the sample/OD596 of the untreated control) X 100
Table 6 
Example 8. Prevention and treatment of periodontal disease by the composition
The efficacy of the composition 7 for the prevention and treatment of periodontal disease was clinically investigated as following Table 7.
Table 7 
The proportion of compounds contained in test and placebo gum is presented in Table 8.
Table 8 
As shown in Fig. 1, the test group comprising the composition 7 showed excellent effects on preventing periodontal disease and improving periodontal status as compared with the placebo group.
Example 9. Prevention effects of dental caries by the composition
The efficacy of the composition 6 for the prevention of dental caries and anti-bacterial effect was clinically investigated as following Table 8.
Table 9 
As shown in Table 10, the composition 6 showed excellent effects on preventing and improving gingivitis.
Table 10 
Example 10. Evaluation of the effect on oral unpleasantness
The effect of the present invention on everyday life was evaluated in terms of its effect on the generation of bad breath or oral unpleasantness. It was evaluated according to the method described in Table 11 using toothpaste containing a composition according to the present invention. One of the control toothpastes comprised the Ecklonia cava extract which is known to be effective in removing bad breath. The other control paste comprised of chlorhexidine which is known to be a strong antiseptic chemical and popularly used in dental-care products.
Table 11 
As a result, the use of the toothpaste comprising the composition 5 according to the present invention showed a substantially longer-lasting effect in inhibition of oral unpleasantness in comparison with the uses of the toothpaste comprising Ecklonia cava extract or chlorhexidine as an active ingredient.
Claims (11)
- A composition for the management and improvement of oral health, wherein the composition comprises dibenzo-p-dioxin derivative as active ingredients.
- The composition for the management and improvement of oral health according to claim 1, wherein two or more of the dibenzo-p-dioxin derivatives are selected from the group consisting of the following Formula 1, 2, 3 and 4[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
wherein each R is H, C1- C5 alkyl, C2- C5 alkenyl, phenyl, C7-C12 phenyl alkyl, C2-C20 alkanoyl, C3-C20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl. - The composition for the management and improvement of oral health according to claim 2, wherein each R is H, methyl, ethenyl, benzyl, acetyl, oleoyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
- The composition for the management and improvement of oral health according to claim 2, wherein the composition comprises two or more of the dibenzo- p-dioxin derivatives selected from the group consisting of 3-70 wt% of the dibenzo- p-dioxin derivative of the Formula 1, 1-75 wt% of the dibenzo- p-dioxin derivative of the Formula 2, 2-60 wt% of the dibenzo- p-dioxin derivative of the Formula 3 and 2-60 wt% of the dibenzo-dioxin derivative of the Formula 4.
- The composition for the management and improvement of oral health according to claim 2, wherein two or more of the dibenzo-p-dioxin derivatives selected from the group consisting of the Formula 1, 2, 3 and 4 are the dibenzo-p-dioxin derivatives of formula 1, 3 and 4.
- The composition for the management and improvement of oral health according to claim 2, wherein the composition additionally comprises one or more of the dibenzo-p-dioxin derivatives selected from the group consisting of the Formula 5, 6, 7, 8, 9 and 10.[Formula 5]
[Formula 6]
[Formula 7]
[Formula 8]
[Formula 9]
[Formula 10]
wherein each R is H, C1- C5 alkyl, C2- C5 alkenyl, phenyl, C7-C12 phenyl alkyl, C2-C20 alkanoyl, C3-C20 alkenoyl, hydroxyphenyl, dihydroxyphenyl, or trihydroxyphenyl. - The composition for the management and improvement of oral health according to claim 6, wherein one or more of the dibenzo-p-dioxin derivatives selected from the group consisting of the Formula 5, 6, 7, 8, 9 and 10 are the dibenzo-p-dioxin derivative of the Formula 7.
- The composition for the management and improvement of oral health according to claim 7, wherein two or more of the dibenzo-p-dioxin derivatives selected from the group consisting of the Formula 1, 2, 3 and 4 are the dibenzo-p-dioxin derivatives of the Formula 1 and 3.
- The composition for the management and improvement of oral health according to claim 6, wherein each R of the Formula 5, 6, 7, 8, 9 and 10 is H, methyl, ethenyl, benzyl, acetyl, oleoyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
- The composition for the management and improvement of oral health according to claim 6, wherein the composition comprises 0.1-50wt% of one or more of the dibenzo-p-dioxin derivatives selected from the group consisting of the Formula 5, 6, 7, 8, 9 and 10.
- The composition for the management and improvement of oral health according to claim 1, wherein the composition is used for the inhibition of oral biofilms formation, elimination of oral biofilms, prevention of dental caries, prevention of tartar formation, prevention and improvement of gum diseases, and elimination of bad breath.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012517361A JP5457554B2 (en) | 2009-06-24 | 2009-09-25 | Oral health maintenance and improvement composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020090056654A KR101144221B1 (en) | 2009-06-24 | 2009-06-24 | Composition for the management and improvement of oral health |
| KR10-2009-0056654 | 2009-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2010150944A1 true WO2010150944A1 (en) | 2010-12-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2009/005480 WO2010150944A1 (en) | 2009-06-24 | 2009-09-25 | Composition for the management and improvement of oral health |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP5457554B2 (en) |
| KR (1) | KR101144221B1 (en) |
| WO (1) | WO2010150944A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109276466A (en) * | 2017-07-21 | 2019-01-29 | 博塔医疗株式会社 | It is effective component for preventing white hair and promoting the composition and product of dark hair using brown algae polyphenols |
| CN111018874A (en) * | 2019-11-25 | 2020-04-17 | 武汉华星光电半导体显示技术有限公司 | Hole transport material, preparation method thereof and organic light emitting diode device |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20000065613A (en) * | 1999-04-07 | 2000-11-15 | 김선봉 | Composition for removing bad odor and preventing tooth decay comprising ecklonia cava extract |
| JP2003277203A (en) * | 2002-03-25 | 2003-10-02 | Kumamoto Prefecture | Antibacterial agent based on phlorotannins |
| KR20080005711A (en) * | 2006-07-10 | 2008-01-15 | 부경대학교 산학협력단 | Composition containing phlorotannin for inhibition of matrix metalloproteinase activities |
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| JP2691902B2 (en) * | 1988-01-19 | 1997-12-17 | 日本製粉株式会社 | Glucosyltransferase inhibitor and caries preventive oral composition |
| JPH0948715A (en) * | 1995-08-04 | 1997-02-18 | Lion Corp | Composition for oral cavity |
| JP4189620B2 (en) * | 2000-03-01 | 2008-12-03 | ライオン株式会社 | Oral composition for periodontal disease prevention and treatment |
| KR100879558B1 (en) * | 2007-07-31 | 2009-01-22 | 라이브켐 주식회사 | Compositions for skin protection and improvement of skin diseases containing the dibenzo-p-dioxine derivatives |
-
2009
- 2009-06-24 KR KR1020090056654A patent/KR101144221B1/en active IP Right Grant
- 2009-09-25 WO PCT/KR2009/005480 patent/WO2010150944A1/en active Application Filing
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20000065613A (en) * | 1999-04-07 | 2000-11-15 | 김선봉 | Composition for removing bad odor and preventing tooth decay comprising ecklonia cava extract |
| JP2003277203A (en) * | 2002-03-25 | 2003-10-02 | Kumamoto Prefecture | Antibacterial agent based on phlorotannins |
| KR20080005711A (en) * | 2006-07-10 | 2008-01-15 | 부경대학교 산학협력단 | Composition containing phlorotannin for inhibition of matrix metalloproteinase activities |
Non-Patent Citations (1)
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| KIM M. M. ET AL: "Inhibitory effect of phloroglucinol on chronic inflammation", JOURNAL OF BIOTECHNOLOGY, vol. 136S, 2008, pages S577 - S578, XP026831246 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109276466A (en) * | 2017-07-21 | 2019-01-29 | 博塔医疗株式会社 | It is effective component for preventing white hair and promoting the composition and product of dark hair using brown algae polyphenols |
| CN111018874A (en) * | 2019-11-25 | 2020-04-17 | 武汉华星光电半导体显示技术有限公司 | Hole transport material, preparation method thereof and organic light emitting diode device |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2012531404A (en) | 2012-12-10 |
| KR101144221B1 (en) | 2012-05-10 |
| JP5457554B2 (en) | 2014-04-02 |
| KR20100138227A (en) | 2010-12-31 |
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