JP2016504279A - Oral care composition containing theaflavin extract - Google Patents

Abstract

To treat and alleviate bad breath of humans and animals and related oral hygiene problems such as gingivitis, caries, periodontal disease, elimination of dental sensitivity, and maintaining the balance of microorganisms in the oral cavity A composition for use in the oral cavity is provided. In the present invention, a composition comprising an effective amount of theaflavins for oral hygiene, an effective amount of a buffer, and about 40 to 99% by weight of one or more pharmaceutically acceptable water-soluble carriers. And the total water content of the composition is about 5-20%. Also disclosed are methods of producing the compositions of the present invention by extraction from black tea and methods of using the compositions of the present invention. [Selection figure] None

Description

  The present invention relates to an oral care composition containing polyphenols effective for imparting antibacterial and antibacterial protective functions to the oral cavity. Furthermore, the use of the composition of the present invention as a mouthwash can refresh breath, prevent bad breath, and prevent damage caused by dental materials such as caries (caries) gingivitis and periodontal disease. . In particular, the composition of the present invention comprises catechins and theaflavins from black tea extract and green tea extract in effective amounts.

  According to Chinese oral hygiene guidelines published by the Chinese Ministry of Health on September 7, 2009, the results of the National Oral Hygiene Survey show that caries (commonly known as caries) and periodontal disease (gingivitis and tooth Reported that two of the most common diseases (including peritonitis) threaten the oral hygiene of the population and are very difficult to treat and require a great deal of time and money ing.

  Caries present problems such as tissue hardening, discoloration, deformation, tissue change, and are caused by the acid associated with sugar fermentation by certain oral bacteria. The early stages of caries are generally not painful or uncomfortable. Caries are usually found on dental surfaces as black spots or white spots on the tooth surface. As the caries progresses further, caries are formed and pain is detected upon contact with sour or sweet foods, and pain is further felt by cold, heat and other stimuli. It becomes a state. If left untreated, dental caries further progresses, teeth are lost, serious chewing becomes difficult, and the overall health of each person is adversely affected.

  Periodontal disease occurs around dental support organs (cementum, alveolar bone, gingiva, periodontal ligament) with various diseases. Initially, there are gingiva that are red and swollen and tend to bleed when touched. If left untreated, gingival retraction, alveolar bone resorption, formation of periodontal pockets, loose tooth inclination and / or wobble may occur, with pus leakage from the periodontium and bad breath. In some cases, teeth may be lost. Periodontal disease is a major cause of adult loss of teeth. The bad smell of breath is said to be bad breath and does not threaten life, but it is embarrassing and inconvenient. Bad breath in public places is unacceptable to others and may not be acceptable to families. Although halitosis may occur when systemic diseases or infections occur, in many cases, bad breath is caused by the oral cavity, specifically proteins and peptides attached to the tooth surface and the back of the tongue Or the metabolism of amino acids and the presence of gram-negative anaerobic bacteria. As a result, an unpleasant odor is generated by the volatile sulfur compound (VSC).

Two kinds of sulfur-containing amino acids generated by protein degradation, namely cysteine and methionine, are hydrogen sulfide (H ₂ S) and methyl mercaptan (CH ₃ SH), dimethyl sulfide (Me ₂ S), and dimethyl disulfide ((CH ₃ )). ₂ S ₂ ), a thiol (—SH) -containing compound, which may function as one of the main causes of strong odor even at low concentrations. During the metabolic process, at least dozens of microorganisms produce hydrogen sulfide, methyl mercaptan, and fatty acids in the mouth. Such bacteria include Fusobacterium haemophilus, Wei ronococci (Veyronella), and Trepoma denticola, a spirochete that produces tartar. Due to the special structure of the lingual papillae, which significantly increases the surface area of the tongue, the removal of epithelial cell debris on the surface of the tongue, eating away, dead white blood cells and bacteria, subgingival plaque and adjacent dental plaque The surface roughness provides an ideal environment for anaerobic bacteria to survive and grow. In addition, there are a number of organic acids and compounds related to bad breath, such as butyric acid, propionic acid, methylindole (skatole), cadaverine, and indole.

  Clinical patients with periodontal disease often have bad breath problems. Soder and other researchers have found that patient plaque, calculus index, gingival index and probe depth, which are indicators of bad breath, are higher than those without bad breath problems . Yaegaki and Sanada measure the concentration of volatile sulfur compounds in exhaled breath after banning the use of food and other mouths. They find that hydrogen sulfide and methyl mercaptan concentrations correlate significantly higher with periodontal health. In particular, the concentrations of methyl mercaptan and hydrogen sulfide were 44.0 ng / 10 ml and 2.6 ng / 10 ml, respectively. In addition, they have found a high correlation with periodontal pockets and bleeding. According to the same study, it was found that the concentration of volatile sulfur compounds was reduced by about 50% in healthy periodontals. In another study, regardless of the concentration of volatile sulfur compounds in the breath, the depth of the probe pocket and the bleeding index were highly correlated with periodontal disease, halitosis, and inflammation of the tongue and gums. These oral diseases are primarily caused by the presence of bacteria that produce plaque and a foul-smelling substance. Therefore, the removal of plaque is fundamentally important for maintaining oral health not only in individuals but also in oral health care professionals. Use of a toothbrush, mouthwash, tooth and tongue cleaning reduces the number of bacteria in the mouth and effectively reduces the level of volatile sulfur in the mouth, thereby reducing bad breath. By using a toothbrush to remove plaque, litter, and food residue, the health of teeth and periodontal tissue can be protected while maintaining good oral health. However, even if the plaque is removed with a toothbrush, the plaque again accumulates on the tooth surface in a few hours. During night sleep, saliva secretion decreases and the self-cleaning function of the teeth decreases. Therefore, it is important to brush your teeth before going to bed at night.

  It is clear that rinsing with water can remove food residue in the mouth, but that alone is not sufficient to remove plaque. Since a commercially available mouth washing liquid supplies antibacterial and anti-inflammatory substances, it is effective in suppressing dental plaque, thereby maintaining the health condition in the mouth. For example, oral cleaning with fluoride is a typical method for preventing dental caries and is effective for application to portions where the amount of fluoride is low. Oral cleaning with chlorhexidine can sterilize bacteria present in saliva and adsorbed on the tooth surface, and is suitable for patients with periodontal disease. Oral cleaning using essential oil as the main active ingredient is suitable for daily use because it has a bactericidal action against many bacteria. Some mouthwashes are useful for recovering and gargle from stomatitis and cheilitis, and others are useful for preventing infection and promoting wound healing.

  Chewing sugarless gum also helps to stimulate saliva secretion, relieve acidity in the oral cavity, refresh your breath and clean your teeth. However, oral toothpastes, oral cleansing solutions, and other products contain chemicals such as antibiotics (triclosan, stannous fluoride, chlorhexidine, quaternary ammonium salts, eg, chlorophenol). These substances can kill odor-producing bacteria, but the effect is short and the improvement effect does not last for a long time. These substances can also have undesirable side effects such as taste changes.

  Tea cultivation and consumption has a long history. Tea contains various active ingredients such as polyphenols, theaflavins, theanine, caffeine. The research and use of these active ingredients has been mainly limited to the fields of food, beverages, pharmaceuticals, health foods and dietary supplements. Catechin-based polyphenols contained in tea can suppress the growth of anaerobic bacteria, thereby suppressing the generation of odor. Hayakawa et al., US Pat. No. 6,057,059, describes that the application of tea in the field of oral care can increase dental acid resistance with a composition comprising at least one tea polyphenol, fluoride and aluminum salt. ing. Patent Document 2 (October 9, 2002, 2010) by Procter & Gamble Co. (Chinese corporation) discloses an effective amount of polyphenols, buffering agents, about 40% to 99%, one or more. It is described that tea polyphenols can be used as the main component of an oral care composition comprising a water-soluble carrier and a total water content of about 5% to 20%.

  However, there are few reports on the use of theaflavins from black tea extracts for oral hygiene. As a result of research, green tea catechins inhibit the growth of anaerobic bacteria and reduce the production of sulfides, thereby causing malodors, plaque formation, caries, and teeth including gingivitis and periodontitis. It has been found to delay the onset of perinatal disease. However, unlike green tea catechins, theaflavins in black tea are the most important active substances. These are important polyphenolic catechins (catechin (C), epigallocatechin (GC), epicatechin (EC), 3′-epicatechin gallate formed by oxidation or fermentation of natural pigments that are aromatics. (ECG), epigallocatechin gallocatechin (EGC), and epigallocatechin gallate (EGCG) etc.). They are more complex tea polyphenolic pigments that contain a benzotropolone molecular structure backbone. In the tea fermentation process, theaflavins (theaflavins, TF) and thearvidins (thearubigins, thearbins, TR) are formed by the oxidation of tea catechins. Traditionally, this oxidation process is called fermentation. Theaflavins and thealubidins give a unique color and aroma to tea. These theaflavins are mainly theaflavin (TF1), theaflavin-3-gallate (TF2a), theaflavin-3'-gallate (TF2b), and theaflavin- 3,3′-digallate (TF3).

US Pat. No. 5,470,565 Chinese Patent Application No. 1373652

  The present invention is used in the oral cavity to treat and reduce bad breath and related oral hygiene issues such as gingivitis, caries, periodontal disease, elimination of dental hypersensitivity, maintaining microbial balance in the oral cavity It relates to a composition. More specifically, in the present invention, an effective amount of theaflavins for oral hygiene, an effective amount of a buffering agent, about 40 to 99% by mass of one or more pharmaceutically acceptable water-soluble carriers. In the composition comprising, the total moisture content of the oral composition is about 5-20%. The present invention further includes a method of obtaining the composition of the present invention by extracting black tea and a method of using the composition of the present invention. In particular, the compositions of the present invention are used by human or animal patients or for patients to mitigate bad breath and oral diseases by gargleing and / or washing the mouth with this composition.

The structural formula of the compound used in the composition of the present invention is shown.

  As used herein, an “effective (dose) amount” provides a detectable degree of control over the growth and reproduction of malodorous bacteria, thereby improving bad breath and / or plaque in the oral cavity. Means a dosage sufficient to inhibit the formation of.

  As used herein, “tea” means leaves of plants (Camellia sinensis (L.) O. Kuntze) that are classified as perennial evergreens of the camellia family, Chinese tea, that is, lobular Contains tea (Camellia sinensis var. Sinensis) and puer tea leaves (Camellia sinensis var. Assamica).

  As used herein, “theaflavins” include theaflavin, isotheaflavin, neotheaflavin, 3-gallate theaflavins, 3′-galatotheaflavins (theaflavin-3′-gallate), 3,3′-digallate Theaflavins (teaflavin-3,3'-digalate), epitheaflavic acid, 3'-epitheaflavic acid gallate (epitheaflavic acid-3'-gallate), tea retinoic acid (theaflavic acid), tea 3'-retinoic acid gallate (theaflavic acid-3'-gallate) and mixtures thereof, but are not limited thereto. The “theaflavins” of the present specification includes salts of the above substances.

  The compositions of the present invention can be in the form of toothpastes, dentifrices, oral sprays, chewing gums, or sustained release tablets.

  Unless otherwise noted, “dentifrice” in this description means an ointment, gel or liquid formulation.

  The oral (oral) composition is applied to the oral surface or oral cavity to achieve its oral health care objective, which reaches substantially all dental surfaces and / or oral tissues It means a composition that stays in place for a reasonable amount of time. The oral health care composition of the present invention can be effectively used for both humans and animals.

  As used herein, “water carrier” means any aqueous material that is safe and effective for application to the compositions of the present invention. These substances are abrasives, peroxide materials, alkali metal bicarbonates, thickeners, anticalculus agents, wetting agents, water, surfactants, titanium dioxide, antioxidants, metal ions, plant zinc, coloring Including agents, flavoring agents, xylitol, erythritol, sweeteners, herbs, preservatives, and mixtures thereof.

  The active ingredients of the composition of the present invention include tea polyphenol catechins (catechin (C), epigallocatechin (GC), epicatechin, hormone (EC), 3′-gallic acid, epicatechin (ECG), epi These are theaflavins produced from gallocatechin and gallocatechin (EGC) and 3-epi gallic catechin gallate gallate (EGCG)). The catechins are contained in black tea and are obtained by oxidation or fermentation of aromatic natural pigments belonging to the polyphenol hydroxide of tea having a benzotropolone structure, which is the most important active substance of black tea. During tea processing, tea catechins are oxidized to produce theaflavins (TF) and red tea pigment (thearubins, TR). Traditionally, these oxidation treatments are called fermentation. Theaflavins and thearvins give color and a characteristic aroma to black tea. Theaflavins include theaflavin (TF1), theaflavin-3-gallate (TF2a), theaflavin-3'-gallate (TF2b), and theaflavin-3,3 '. -Contains bis gallate (theaflavin-3,3'-digallate, TF3). Its chemical structure is shown in FIG. The active ingredient used in the composition of the present invention is extracted from black tea using the method described in US Pat. No. 8,282,970. The entire contents of the above U.S. patents are incorporated herein.

[Example 1]
Three samples of theaflavin TF1 were prepared at concentrations of 20% (TF20), 40% (TF40) and 60% (TF60). Here, all the concentrations are mass%. The following microorganisms, which are known to cause malodor from the mouth, were selected:
P. gingivalis; Aeromonas of Porphyromonas gingivalis; Black Prevotella (Black); Prevotella intermedia; Bacteroides forsythus; and Fusobacterium nucleatum.
Subgingival plaque and tongue coating were collected and inoculated into non-selective medium.

(Experimental procedure)
The tea extract is added to the medium and divided into the experimental group of sample 1 (TF20), the experimental group of sample 2 (T40), and the experimental group of sample 3 (T60), and the control medium does not contain the tea extract Also made. Microorganisms were added to the sample and the mixture was cultured under anaerobic or semi-anaerobic conditions. Colonies obtained from the culture were counted, and the degree of inhibition of the growth of microorganisms in each sample was determined (unit: ppm).

[Example 2]
(Effect of theaflavins on volatile sulfur compounds (VSC))
To each of the theaflavin extract samples TF20, TF40, and TF60 were added bacteria that produce bad breath: Porphyromonas gingivalis; Aeromonas; Prevoterra intermedia; and Fusobacterium nucleatum. Each tea extract medium was divided into experimental group 1 (TF20), experimental group 2 (TF40), and experimental group 3 (TF60). Each experimental group was divided into 0.2% and 1.0% dose groups. A positive control consisting of 0.2% chlorhexidine solution medium and a control without any extract were also prepared.

  Each experimental group, positive control group, and blank control group were inoculated with the above-mentioned bacteria, cultured at 37 ° C. for 7 hours under anaerobic conditions, and the level of volatile sulfur compounds (VSC) was measured with an exhalation meter (harness). Meter).

  The following formulations were made (all percentages below are% by weight and are values based on the total weight of the formulation):

Formulation 1:
Hydrogen phosphate dihydrate 45%; Silicon dioxide 2%; Glycerol 10%; Sorbitol 10%; Carboxymethyl cellulose; Gracilaria 0.3; Sodium lauryl sulfate 16.8%; Purified water 28.9%; Flavor 1%; sweetener.

Formulation 2:
Stannous fluoride 0.2%; calcium pyrophosphate 39%; glycerol 10%; sorbitol 20; stannous pyrophosphate, adhesives, flavors, and blowing agents 4.6%; purified water 25%.

Formulation 3:
Sodium monofluorophosphate 0.76%; insoluble sodium metaphosphate 42%; dicalcium phosphate dihydrate; aluminum hydroxide 1%; wetting agent; Irish moss extract 1%; titanium dioxide 0.4%; Benzene sodium 0.5%; N-lauroyl sarcosine sodium; flavor; purified water to make 100%.

Formulation 4:
N-lauroyl sarcosine sodium; sodium lauryl sulfate 0.5%; sodium alginate 0.9%; proteolytic enzyme (paste, 1500-2000 units per gram); purified water to make 100%.

Formulation 5:
Quaternary ammonium salt 0.5%; Nonionic surfactant 2%; Glycerol 22%; CMC 0.85%; Sodium pyrophosphate; Saccharin 0.2%; Sodium benzoate 0.5%; Precipitated calcium carbamate 5% DCP dihydrate 46.8%; flavoring 0.8%; purified water 21.1%.

Formulation 6:
Purified water to make potassium nitrate 10%; glycerol 25%; glycol cellulose ether 1.6%; polyoxymethylene sorbitan monolaurate; silica 24%; mint oil 1%; saccharin 0.2%;

Formulation 7:
Sodium chloride 15%; hydroxyethyl cellulose; colloidal silica 2.5%; glycerol 5%; ethylene oxide%; propylene oxide block copolymer 0.5%; calcium phosphite 30%; saccharin 0.3%; Purified water.

[Example 3]
(Prescription of mouthwash)
Composition:
Chlorhexidine 2 g; metronidazole 2 g; mint oil 0.5 ml; tween-80 (1 ml); saccharin sodium; distilled water to make 1000 ml.

Preparation method:
Chlorhexidine and metronidazole were dissolved in an appropriate amount of distilled water, mint oil and Tween 80 were added, thoroughly mixed and dissolved in heated distilled water, saccharin sodium was added, and the mixture was stirred and dissolved until completely dissolved. Distilled water was added to the filter and stirred well.

[Example 4]
Composition Aspect A Aspect B
Theaflavins (TF60) 10g 5g
Tween-80 1ml 1ml
Mint 0.5ml 0.5ml
Phosphate buffer solution 10ml 10ml
Essential oil 0.1ml 0.1ml
Coloring agent 100mg 100mg
Preservative 50mg 50mg
Deionized water 1000ml 1000ml

[Example 5]
(Chewing gum)
Composition Aspect C Aspect D
Theaflavins (TF60) 10g 5g
Tween-80 1ml 1ml
Mint 0.5ml 0.5ml
Phosphate buffer solution 10ml 10ml
Essential oil 0.1ml 0.1ml
Coloring agent 100mg 100mg
Preservative 50mg 50mg
Deionized water 1000ml 1000ml

[Example 6]
(Multilayer sustained release buccal tablets)
Composition Aspect E Aspect F
Theaflavins (TF60) 10g 5g
Tween-80 1ml 1ml
Mint 0.5ml 0.5ml
Phosphate buffer solution 10ml 10ml
Essential oil 0.1ml 0.1ml
Coloring agent 100mg 100mg
Preservative 50mg 50mg
Deionized water 1000ml 1000ml

[Example 7]
In this example, a halimeter was used to test the health-inhibiting effect of seven compositions on patients selected according to the following criteria for abnormality determination:
Halimeter value (concentration of volatile sulfur) ≧ 200 × 10 ³ ml / m ³ ;
No signs of ENT, digestive, respiratory and other systemic illnesses;
The exclusion of factors that cause abnormal health conditions in the mouth;
The absence of serious mucosal disease due to the use of antibiotics in the mouth before the experiment;
And low compliance.
Zhu Huanze examines the use of aromatic beverages, cosmetics, and mouthwashes within 24 hours before using the test composition; contains garlic, green onions, carrots and other sulfur-containing products prior to testing Check for high-dose food; between 7:00 am and 12:00 am, brush your teeth, check your breath before you rinse your mouth, and do not eat anything for 6 hours confirmed.

  125 patients were selected according to the above criteria, and each was randomly assigned to 5 groups. After brushing with toothpaste called 0.4% T20, 0.4% T40, 0.4% T60, deodorant Using a specific toothpaste and toothbrush. After brushing, the subject was isolated for 1 minute, and an expiration meter (halimeter) was placed about 4 cm toward the trachea. The detection process was performed by nasal breathing, and the peak of volatile sulfide concentration in the breath was recorded after 0, 1, 2, 3, 4, and 5 hours. The exhalation test records for each patient were taken after washing. A double reading was performed. SPSS statistical software was used to process and analyze the experimental results and was self-control by performing paired (t) tests between the two groups.

[Example 8]
N cases were confirmed for the breath of bad breath patients caused by mouths of male X cases and female X cases. The conditions for each patient are as follows:
18 years of age or older; overall healthy; non-smoker; at least 20 original teeth; no periodontal treatment within at least 6 months; No attachment, markedly inconvenient dental restoration, absence of dental caries and food fragments, and no mucosal disease; no antibiotics used for 2 weeks within 1 month, 3 consecutive days or more Not using antibiotics; for women, neither menstrual period, pregnancy, nor breastfeeding.
The patient signed an informed consent document.

(Experimental conditions and treatment)
Tobacco and alcohol were banned for two days before the test. Within one day before the test, intake of garlic, onion, green onion, daiko and other foods and the use of highly aromatic cosmetics were also prohibited. In the morning, subjects were examined without brushing their teeth, eating meals, and not using mouth washes, chewing gum, coffee or other beverages. The test was conducted in a well-ventilated and odorless room. All confirmation of the condition was performed by experienced olfactory engineers.

1) Use of mouth washing solution According to appropriate criteria, detection of abnormal breaths in patients with XX is randomly assigned to 5 groups, called 0.4% T20, 0.4% T40, 0.4% T60. Gargle with the washing solution and rinse in the mouth with 15 ml of distilled water for 1 minute. The subject was isolated for 1 minute, and about 4 cm was placed in the mouth with a breath meter (halimeter) facing the trachea. The detection process was performed by nasal breathing, and the peak of volatile sulfide concentration in the breath was recorded after 0, 1, 2, 3, 4, 5, and 6 hours. The exhalation test records for each patient employed post-wash values, each time value was detected in duplicate, and average values were obtained for each.

[Example 9]
(Chewing gum)
Exhalation abnormalities were detected using the appropriate criteria described above. The patients were randomly assigned to 5 groups and chewing gums called 0.4% T20, 0.4% T40, 0.4% T60 for 5 minutes. After chewing the gum, the subject's mouth was closed for 1 minute, and an expiration meter (halimeter) was placed about 4 cm toward the trachea. The detection process was performed by nasal breathing, and the peak of volatile sulfide concentration in the breath was recorded after 0, 1, 2, 3, 4, 5, and 6 hours. In the expiratory test record for each patient, the value after washing was adopted. A double reading was performed. SPSS statistical software was used to process and analyze the experimental results and was self-control by pairing (T) testing between the two groups.

  The subject was isolated for 1 minute, and the breath measuring device (halimeter) was placed about 4 cm in the mouth with the trachea facing. The detection process was performed by nasal breathing, and the peak of volatile sulfide concentration in the breath was recorded after 0, 1, 2, 3, 4, 5, and 6 hours. The exhalation test records for each patient employed post-wash values, each time value was detected in duplicate, and average values were obtained for each.

[Example 10]
(Multilayer sustained release buccal tablets)
Detection of abnormalities in exhalation of patients according to appropriate criteria was randomly assigned to 5 groups, and tablets were administered as 0.4% T20, 0.4% T40, 0.4% T60. The subject's mouth was closed for 1 minute, and an expiration meter (halimeter) was inserted about 4 cm toward the trachea. The detection process was performed by nasal breathing, and the peak of volatile sulfide concentration in the breath was recorded after 0, 1, 2, 3, 4, 5, and 6 hours. In the expiratory test record for each patient, the value after washing was adopted. A double reading was performed. SPSS statistical software was used to process and analyze experimental results and was self-control by pairing (t) testing between the two groups.

(Experimental result)
Theaflavins are effective against the growth of bacteria that produce bad breath (volatile sulfide concentration) in the mouth.

1. Experimental group Control: The gas concentration of volatile sulfur compounds (VSC) in an anaerobic box can be considered as the background concentration of VSC in the incubator environment.
Negative control: Same as the positive control and sample group strains, except that no substance that suppresses VSC is used.
Positive control: Chlorhexidine was used as a positive reference for inhibitory effect.
Theaflavins: Samples containing samples of theaflavins according to 20%, 40%, and 60% purity.
Actual value: Negative control, positive control and sample data minus control value is the data value.

2. Experimental strains used Bacteria that produce halitosis (standard strain of Fn and standard strain of Pg)

3. Results Inhibitory effect on VSC production by standard strain Fn

  Inhibitory effect on VSC production by standard strain Pg

Claims (3)

  A composition for use in the oral cavity to treat oral health problems in humans and animals, the amount of theaflavins effective for oral health, the amount of buffering agent effective for pH buffering, about 40 to 99% by weight And a total water content of about 5 to 20% by weight.   Extracting black tea with water to obtain an extract containing about 20 to 60% by mass of theaflavins, and then adding an effective amount of a buffer and a pharmaceutically acceptable water-soluble carrier to the extract. A method of producing a composition of   A method of treating halitosis comprising washing the oral cavity with the composition of claim 1.

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