JP2010047512A - Oral composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral composition for maintaining hygienic condition in the oral cavity and for ameliorating the environment in the oral cavity, and to provide a microbicidal composition for the oral cavity, especially having excellent microbicidal effects and proliferation-inhibiting effects of bacteria or the like, and providing mild action to a human body. <P>SOLUTION: The oral composition contains a sesquiterpene derivative originated from a natural, cultivated, or cultured biomass of Phellinus linteus of Mucronoporaceae. Especially, the sesquiterpene derivative is γ-ionylidene derivative and/or a drimane derivative in the oral composition. The oral composition can be used as a therapeutic or preventive agent of periodontal disease or a related disease thereof, or in a shape of dentifrice, mouthwash, troche, and the like. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a composition for oral cavity that has an excellent bactericidal effect and suppressive effect on the growth of pathogenic bacteria and has a mild effect on the human body.

  If the oral hygiene condition deteriorates, oral diseases such as periodontal disease such as caries, gingivitis, and alveolar pyorrhea are caused. Periodontal disease, in particular, is considered to have the potential to affect most adults, and the morbidity rate is steadily increasing as the population ages. Symptoms of periodontal disease include bleeding from the gingiva, unpleasant halitosis, and loss of teeth, but recent research has shown that periodontal disease is not just a local disease in the oral cavity. It has been reported that it affects various organs of the disease, and the relationship between periodontal disease and many adult diseases is also attracting attention.

The periodontal pathogens are the cause of periodontal disease, currently, Porphyromonas gingivalis (Porphyromonas gingivalis), Tannerella (Bacteroides) Forushichia (Tannerella (Bacteroides) forsythia), Toreponema-Denchikora (Treponema denticola), Prevotella・Intermedia ( Prevotella intermedia ), Campylobacter rectus , Fusobacterium nucleatum , Actinobacillus actinomycetemcomitans , Actinomyces viscos These are anaerobic bacteria that grow in plaque and calculus in the periodontal pocket (between teeth and gums). Therefore, periodontal disease can be prevented by removing plaque and calculus and maintaining the oral cavity in a hygienic state in which these bacteria are difficult to propagate.

Aspiration pneumonia, which is common in elderly people, is caused by S. aureus, Pseudomonas aeruginosa and Candida bacteria including MRSA (methicillin resistant Staphylococcus aureus ). In the oral cavity where hygiene has deteriorated, such as when washing is impossible, the above-mentioned bacteria proliferate remarkably, and it is said that it develops by aspiration into the lower respiratory tract unconsciously. Therefore, prevention of these diseases that cause death of the elderly can be expected by keeping the oral cavity hygienic.

  Conventionally, as a method for maintaining the hygiene state in the oral cavity, oral cleaning such as tooth brushing and gargle is generally used. However, in view of the fact that many adults develop periodontal disease, it cannot be said that sufficient oral cleaning is performed. In particular, brushing the tooth surface is not easy to brush to completely remove plaque in the periodontal pocket, and it is difficult to remove water-insoluble substances by gargle using only water. . Therefore, the cleaning agent (for example, dentifrice, gargle) used at that time does not only require a refreshing feeling, but also a bactericidal effect such as periodontal disease bacteria attached to the periodontal pocket, a growth inhibitory effect, and There is a strong demand for an extremely safe thing for the human body because it is excellent in sustainability of the suppression effect and is frequently used on a daily basis.

  Currently, hinokitiol, triclosan, and the like are used as bactericides for periodontal diseases. However, it has been pointed out that exposure to triclosan may affect the nervous system and cause autism, and that sewage treatment recovers less than about 50% of the triclosan in the wastewater. This is a situation where the development of chemicals is required.

  Oral hygiene management is also important in dental treatment. For example, oral implant treatment is widely performed as a state-of-the-art medical treatment, but the presence or absence of fungi in the tissues surrounding the implant body greatly affects the prognosis of the implant operation. Therefore, infection protection is indispensable. For example, sterilization with ethanol or the like is not preferable from the viewpoint of implant fixation because it causes protein degeneration in surrounding tissues. At present, antibiotics are generally administered in addition to mouthwash, but antibiotics have problems in terms of induction of resistant bacteria, replacement of bacteria, etc., and antibacterial equivalent to or higher than antibiotics. A safe oral composition having an effect is desired.

  The object of the present invention is to maintain oral hygiene and other oral compositions for improving the oral environment, particularly bactericidal compositions with excellent bactericidal effects and bacteria-inhibiting effects, and mild action on the human body. To provide things.

The present inventors have made continued various studies on compounds showing growth inhibitory activity against periodontal disease pathogenic bacterium, natural Phellinus igniarius family Meshimakobu (Phellinus linteus), the sesquiterpene derivatives from cultivated or cultured cells, It has been found that it exhibits strong antibacterial activity equivalent to or better than hinokitiol and triclosan currently used as a bactericidal agent for periodontal diseases, and has completed the present invention.

  Furthermore, the present inventors have isolated various components including novel compounds from the essential oil derived from Messima cob, and as a result of investigating the growth inhibitory activity against periodontal disease pathogenic bacteria for each component, the present inventors have found a compound particularly excellent in antibacterial activity. It was.

That is, the present invention relates to the following oral compositions and novel compounds.
1. Phellinus igniarius family Meshimakobu (Phellinus linteus) natural, oral composition characterized by containing sesquiterpene derivatives from cultivated or cultured cells.
2. 2. The composition for oral cavity according to 1 above, wherein the sesquiterpene derivative is a γ-ionylidene derivative and / or a doriman derivative.
3. The composition for oral cavity according to 2 above, wherein the γ-ionylidene derivative is a compound represented by the following general formula (I):

(Wherein R ₁ represents COOH or CH ₂ OH, R ₂ and R ₃ represent H, OH or CH ₃ , respectively, R ₄ and R ₅ represent H or OH, or together represent an epoxy. Forming a group,... May be a double bond).
4). A composition for oral cavity comprising one or more of compounds (1) to (5) and (8) represented by the following structural formula.

5. An oral composition comprising the compound (1) and / or the compound (2).

6). 6. The composition for oral cavity according to any one of 1 to 5 above, which is a toothpaste, liquid toothpaste, dental gel, mouthwash, mouthwash, candy, troche or chewing gum additive component.
7). The composition for oral cavity according to any one of 1 to 5 above, which is a therapeutic agent or preventive agent for periodontal disease and related diseases.

8). 8. The composition for oral cavity according to 7 above, which is a preventive agent for aspiration pneumonia.
9. 6. The composition for oral cavity according to any one of 1 to 5 above, which is a bactericide after implant treatment.
10. Γ-ionylidene derivative which is compound (3), compound (5), compound (6) or compound (7) represented by the following structural formula:

It included in the oral compositions of the present invention, sesquiterpene derivatives from Phellinus igniarius family Meshimakobu (Phellinus linteus) cells have strong growth inhibitory activity against periodontal disease pathogenic bacterium. Moreover, because the raw material, Meshimakobu, is derived from natural products and is also used as an edible material, even if the composition of the present invention is regularly used as a dentifrice or mouthwash, etc., even if part of it is absorbed into the body, There are no harmful effects on the body. Therefore, it is effective for preventing and treating periodontal diseases and the like by keeping the oral cavity in a hygienic state in which periodontal disease bacteria and the like are difficult to propagate by using as a safe composition for oral cavity. Further, by using the composition of the present invention as an intraoral rinse, it is effective for oral hygiene management after head and neck surgery and oral care for the elderly. Moreover, since the composition for oral cavity of this invention contains the sesquiterpene derivative which is an essential oil component, it also has a function as a fragrance | flavor.

Sesquiterpene derivative used in the oral compositions of the present invention is a component derived from bacteria of Phellinus igniarius family Meshimakobu (Phellinus linteus), as the cells, natural, cultivated or cultured cells can be used. For the culture, the mycelium isolated from the fruit body is plated in a medium such as PDA (Potate Dextrose Agar) medium, MYS (Malt Yeast Sucrose) medium Melin-Norklans medium, Norrklans's C medium, Hamada medium, Ota medium, liquid shaking culture, What is necessary is just to carry out about several hours-several months by culture methods, such as liquid stationary culture and aeration stirring culture.

  The sesquiterpene derivatives to be included in the oral composition include various sesquiterpene derivatives obtained by using essential oil obtained by steam distillation of mesimacob cells or by appropriately extracting from mesimacob cells with a solvent. You may use the extract to do. Alternatively, one or more of isolated compounds obtained by further separating and purifying the extract may be used. Moreover, since various sesquiterpene derivatives derived from Meshimakobu were identified and their structures were determined as described below, these compounds can also be produced by chemical synthesis and used.

In order to isolate various compounds from the extract of Mesima Kobu, reverse phase column chromatography, normal phase column chromatography, high performance liquid chromatography, thin layer chromatography, gas chromatography, distillation, distribution, precipitation, recrystallization, etc. These methods can be performed by appropriately combining or repeating the methods. In the present invention, as shown in Reference Example 1 below, were cultured hyphae isolated from Phellinus linteus fruiting body, from CHCl3 fraction of AcOEt extracts and culture mycelium MeOH extract of culture filtrate, the new compound 18 Twenty-two sesquiterpene derivatives including seeds, caffeic acid (3,4-dihydrocinnamic acid), three 1,4-benzodioxane dicarboxylic acid derivatives including one new compound, and ergosterol were isolated. The 22 sesquiterpene derivatives that are essential oil components are classified according to their structure into 7 types of γ-ionylidene type derivatives, 14 types of bisabolane type derivatives, and 1 type of drimane type derivatives. The structural formulas of 22 sesquiterpene derivatives isolated in the present invention are as follows.

  Nineteen of the above sesquiterpene compounds (compounds (1) to (9) and (11) to (20)) were tested for antibacterial activity against periodontal disease-causing bacteria, and all compounds other than compound (12) were tested. Activity was observed. Among them, compounds (1) to (5), which are ionylidene type derivatives, and compound (8), which is a Doriman type derivative, exhibit strong antibacterial activity. Especially, compounds (1) and (2) are currently used for toothpaste and dental rinse. As strong as triclosan. Compounds (5) and (8) showed the same activity as hinokitiol. Triclosan has become less used due to the problem of residual in the environment, and γ-ionylidene derivatives, especially compounds (1) and (2), are expected as novel anti-periodontitis fungicides that replace triclosan.

Among the sesquiterpene compounds, the compounds (3), (5), (6), (7) and (9) to (22) are novel compounds isolated and identified for the first time by the present inventors. is there.
The composition for oral cavity of the present invention contains various sesquiterpene compounds derived from mesimacob cells, and contains an extract of a culture filtrate obtained by culturing mesimacob cells and / or an extract of cultured mycelium. Or the composition containing any 1 or more types of the isolated sesquiterpene compound may be sufficient. The composition of the present invention is preferably one or more of compounds (1) to (5) which are ionylidene-type derivatives and / or doriman-type derivatives, and more preferably compounds (8) which are ionylidene-type derivatives. Containing.

  The content of the sesquiterpene derivative in the oral composition varies depending on the type, use, form, application method, number of uses, etc. of the derivative, but is usually 0.0001 to 10% by weight, preferably 0.001 to the total amount of the composition. It is 1% by weight, particularly preferably 0.01 to 0.5% by weight.

  In addition to the above essential oil, the oral composition of the present invention contains commonly used oral bases and additives, toothpaste, liquid dentifrice, dental gel, mouthwash, mouthwash, wrinkle, It can be in the form of a troche or chewing gum. Examples of the base that can be blended include dental calcium hydrogen phosphate, aluminum oxide, sorbite liquid, and the like. Examples of the additive include a binder, a wetting agent, a foaming agent, a surfactant, a solvent, a solubilizing agent, a preservative, a sweetener, and a coloring agent, and components commonly used in this field can be used. Moreover, you may add the component which has another antimicrobial property in the range which does not impair the effect of the composition of this invention.

  In the oral composition of the present invention, the essential oil as an active ingredient has strong growth inhibitory activity against oral bacteria, particularly periodontal disease pathogenic bacteria. It can be used for prevention and treatment of periodontal disease-related diseases. Furthermore, the composition of the present invention can maintain good oral hygiene and improve the oral environment as a dentifrice or mouthwash. The composition of the present invention is also useful as a dental bactericidal agent for oral use, and can be used, for example, as a bactericidal agent after implant treatment.

Example 1
Phellinus linteus culture
Mycelia isolated from Phellinus linteus fruiting bodies were precultured in PDA medium (Potato Dextrose Agar 39g, DW 1L). The periphery of the cultured mycelium is punched out with a cork borer with a diameter of 10 mm, MYS medium (Malt ext. 30g, Yeast ext. 5g, sucrose 10g, DW 1L) is transplanted to each disk in a 125mL / 500mL flask and shaken for 35 days. Culture (25 ° C, dark, 63 rpm) was performed.

Extraction
100 MYS media were divided into culture filtrate (11L) and cultured mycelium (fresh weight. 990.55g). The culture filtrate was concentrated to 6.05 L and extracted four times with 8.5 L of EtOAc to give an EtOAc fraction (M EtOAc, 14.18 g). Culture mycelium was extracted with MeOH, water was added to the MeOH extract obtained, 3 times with CHCl ₃ 2L, further extracted 4 times with EtOAc 1.2 L, respectively CHCl ₃ fractions (My CHCl3, 20.99g) And EtOAc fractions (My EtOAc, 0.9557 g) were obtained.

Isolation of Compound The EtOAc fraction of the culture filtrate was fractionated into Fr. 1-10 by normal phase column chromatography as shown in FIG. The obtained fraction was repeatedly purified by column chromatography and HPLC, and a total of 17 kinds including 13 kinds of new compounds (5, 6, 9 to 11, 13 17, 21, 22, 26) were isolated. Moreover, the novel compound 12 was obtained from the EtOAc fraction of the culture filtrate cultured in the static field.

The CHCl ₃ fraction of the cultured mycelium was fractionated into Fr. 1-10 by normal phase column chromatography as shown in FIG. The obtained fraction was repeatedly purified by HPLC, and a total of 9 kinds including 5 kinds of new compounds (3, 7, 18, 19, 20) were isolated.
Table 1 shows the yield of the isolated compound.

Compound identification The isolated compounds (1) to (26) were analyzed by optical rotation, IR, UV, FABMS, HRFABMS, ¹ H-NMR, ¹³ C-NMR, etc. It was determined.

Compound (1) : (-)-trans-g-monocyclofarnesol
Colorless oil
[a] _D ²² -6.76 ° (c = 0.10, MeOH)
IR (KBr) n _max cm ^-1 : 3421, 2927, 2855, 1643.
UV (MeOH) l _max nm (log e): 204 (4.06).
FABMS (positive) m / z: 222 [M] ⁺ , 245 [M + Na] ⁺ .
HRFABMS (positive) m / z: Calcd for C ₁₅ H ₂₆ O [M] ⁺ , 222.1984; Found 222.1979.
¹ H-NMR (CDCl ₃ ) d:
0.82 (3H, s, 13-H ₃ ), 0.90 (3H, s, 12-H ₃ ), 1.20 (1H, ddd, J = 12.5, 9.5, 5.0Hz, 2-Ha), 1.44 (1H, m, 2-Hb), 1.48 (1H, m, 7-Ha), 1.50 (2H, m, 3-H ₂ ), 1.56 (1H, m, 7-Hb), 1.66 (3H, d, J = 1.0Hz, _{15-H 3), 1.68 (} 1H, dd, J = 11.5, 3.5Hz, 6-H), 1.77 (1H, ddd, J = 13.5, 10.5, 6.0Hz, 8-Ha), 1.96 (1H, m, 8-Hb), 2.00 (2H, m, 4-H ₂ ), 4.12 (2H, d, J = 7.0Hz, 11- H ₂ ), 4.53 (1H, d, J = 2.5Hz, 14-Ha), 4.75 (1H, ddd, J = 2.5, 1.0, 1.0Hz, 14-Hb), 5.39 (1H, tq, J = 7.0, 1.0Hz, 10-H)
¹³ C-NMR (CDCl ₃ ) d: See Table 2

Compound (2) : Phellidene A
Colorless oil
[a] _D ²³ -16.8 ° (c = 0.12, MeOH).
IR (KBr) n _max cm ^-1 : 3335, 2931, 1644.
EIMS m / z: 224 [M] ⁺ .
HREIMS m / z: Calcd for C ₁₅ H ₂₈ O [M] ⁺ , 224.2140; Found 224.2146.
¹ H-NMR (CDCl ₃ ) d:
0.82 (3H, s, 13-H ₃ ), 0.88 (3H, d, J = 6.0Hz, 15-H ₃ ), 0.90 (3H, s, 12-H ₃ ), 1.10 (2H, m, 8-H ₂ ), 1.19 (1H, m, 2-Ha), 1.38 (1H, m, 10-Ha), 1.40 (2H, m, 7-H ₂ ), 1.48 (1H, m, 2-Hb), 1.52 ( 2H, m, 3-H ₂ ), 1.54 (1H, m, 9-H), 1.55 (1H, m, 10-Hb), 1.67 (1H, dd, J = 10.0, 5.0Hz, 6-H), 1.99 (2H, m, 4-H ₂ ), 3.63 (1H, dd, J = 10.0, 6.0Hz, 11-Ha), 3.69 (1H, dd, J = 10.0, 6.0Hz, 11-Hb), 4.52 ( 1H, d, J = 3.0Hz, 14-Ha), 4.73 (1H, d, J = 3.0Hz, 14-Hb)
¹³ C-NMR (CDCl ₃ ) d: See Table 2

Compound (3) :
Colorless oil
[a] _D + 18.8 °
IR (KBr) n _max cm ^-1 : 3380, 1645.
FABMS m / z: 241 [M] ⁺ , 263 [M + Na] ⁺ .
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 3

Compound (4) :
Colorless powder
[a] _D + 11.7 °
IR (KBr) n _max cm ^-1 : 3420, 1680, 1645, 1625, 1600.
EIMS m / z: 234 [M] ⁺
NMR: see Table 4
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 5

Compound (5)
Colorless oil
[a] _D + 3.4 °
IR (KBr) n _max cm ^-1 : 3420, 1710, 1645.
FABMS m / z: 239 [M + H] ⁺
NMR: see Table 4
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 6

Compound (6)
Colorless oil
[a] _D + 13.7 °
IR (KBr) n _max cm ^-1 : 3415, 1694, 1647.
FABMS m / z: 253 [M] ⁺ , 275 [M + Na] ⁺ .
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 7

Compound (7)
Colorless powder
[a] _D + 4.6 °
IR (KBr) n _max cm ^-1 : 3400, 1696, 1650, 1640.
FABMS m / z: 251 [M] ⁺ , 273 [M + Na] ⁺ .
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 8

Compound (8)
Colorless solid
[a] _D -5.1 °
FABMS m / z: 239 [M] ⁺ , 261 [M + Na] ⁺ .
EIMS m / z: 238 [M] ^+
1 H- ¹³ C Long-Range Correlation by HMBC: See Table 9

Compound (9)
Colorless columnar crystals
[a] _D -69.7 °
IR (KBr) n _max cm ^-1 : 3400, 1690, 1625.
FABMS m / z: 283 [M + H] ⁺ , 305 [M + Na] ⁺ .
NMR: See Table 10
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 11

Compound (10)
Colorless needle crystal
[a] _D -186 °
^{_{IR (KBr) n max cm -1}} : 3423, 1766, 1666.
FABMS m / z: 265 [M] ⁺
NMR: See Table 10
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 12

Compound (11)
Colorless solid
[a] _D + 49.5 °
IR (KBr) n _max cm ^-1 : 3420, 1744, 1650, 1657, 1644.
FABMS m / z: 289 [M + Na] ^+
1 H- ¹³ C Long-Range Correlation by HMBC: See Table 13

Compound (12)
Colorless solid
[a] _D + 35.9 °
IR (KBr) n _max cm ^-1 : 3441, 1742, 1693, 1650.
FABMS m / z: 319 [M + Na] ^+
1 H- ¹³ C Long-Range Correlation by HMBC: See Table 14

Compound (13)
Colorless solid
[a] _D + 6.8 °
IR (KBr) n _max cm ^-1 : 3396, 1768, 1643.
FABMS m / z: 283 [M + H] ⁺ , 305 [M + Na] ⁺ .
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 15

Compound (14)
Colorless needle crystal
[a] _D -73.6 °
IR (KBr) n _max cm ^-1 : 3190, 1715, 1660.
FABMS m / z: 289 [M + Na] ⁺
NMR: See Table 16

Compound (15)
Colorless solid
[a] _D -60.3 °
IR (KBr) n _max cm ^-1 : 3415, 1693, 1634.
FABMS m / z: 305 [M + Na] ⁺
NMR: See Table 16
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 17

Compound (16)
Colorless solid
[a] _D -19.1 °
IR (KBr) n _max cm ^-1 : 3385, 1680, 1640.
FABMS m / z: 291 [M + Na] +
NMR: See Table 18
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 19

Compound (17)
Colorless oil
[a] _D -58.9 °
IR (KBr) n _max cm ^-1 : 3433, 1689, 1658.
FABMS m / z: 305 [M + Na] ⁺
NMR: See Table 18
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 20

Compound (18)
Colorless oil
[a] _D -14.5 °
IR (KBr) n _max cm ^-1 : 3458, 1691, 1648.
FABMS m / z: 251 [M + H] ⁺ , 273 [M + Na] ⁺ .
NMR: See Table 18
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 21

Compound (19)
Colorless oil
[a] _D = 124 °
IR (KBr) n _max cm ^-1 : 3395
FABMS m / z: 261 [M + Na] ⁺
NMR: See Table 22
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 23

Compound (20)
Colorless solid
[a] _D -117 °
IR (KBr) n _max cm ^-1 : 3379
FABMS m / z: 261 [M + Na] ⁺
NMR: See Table 22
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 24

Compound (21)
Yellow oil
[a] _D -0.9 °
IR (KBr) n _max cm ^-1 : 3421, 1711, 1690, 1630, 1601, 1447.
FABMS m / z: 453 [M + Na] +
NMR: See Table 25
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 26

Compound (22)
Yellow oil
[a] _D -23.8 °
IR (KBr) n _max cm ^-1 : 3432, 1744, 1631, 1600, 1454.
FABMS m / z: 467 [M + Na] ⁺
NMR: See Table 25
¹ H- ¹³ C Long-Range Correlation by HMBC: See Table 27

  From the above results, it is found that the compounds (1) to (22) have the above structural formula, and the compounds (23) to (26) are compounds represented by the following structural formula.

(Test Example 1)
Determination of minimum inhibitory concentration (MIC) of sesquiterpenes against Porphyromonas gingivalis
(1) Test bacteria Porphyromonas gingivalis and its culture
Porphyromonas gingivalis ATCC33277 (provided by Prof. Kikuchi, Faculty of Dentistry, Meikai University) was inoculated into Muller Hinton S sheep blood agar (Eiken Chemical Co., Ltd.), and within AnaeroPack Jar (Mitsubishi Gas Chemical Co., Ltd.), AnaeroPack Kenki (Mitsubishi Gas) Was pre-cultured at 37 ° C. under anaerobic conditions in the dark for 4 days.
Bacteria obtained by culturing were scraped off, dissolved in a phosphate buffer solution, and diluted 10 times, and the inoculated bacterial solution was adjusted as shown in Table 28.

(2) Preparation and MIC measurement of test compound Mini test tubes using test GAM bouillon broth (Nissui Pharmaceutical Co., Ltd.) with test compounds, hinokitiol and triclosan as controls, dissolved in DMSO and starting at the concentrations shown in Table 28 It was distributed to 10 bottles so that each was diluted 1-fold. Inoculate 10 μL of the bacterial solution adjusted with phosphate buffer into a test tube containing the diluted test compound, and cultivate in AnaeroPack jar with AnaeroPack KENKI under anaerobic culture conditions at 37 ° C for 72 hours in the dark. Went.

The minimum concentration at which no gross growth was observed was defined as MIC (Table 28).
The concentration of the inoculum for each compound is also as shown in Table 28.

(3) Results As a result of measuring the minimum inhibitory concentration (MIC) against Porphyromonas gingivalis , one of the causative agents of periodontal disease, for 19 sesquiterpene derivatives (1-9, 11-20) isolated from Meshimakobu, Activity was observed with compounds other than 12 (Table 28).

  The γ-Ionylidene derivative showed activity at a MIC value of 3.3 to 310 mg / mL. Among them, Compound 1 and Compound 2 showed strong activities of 5.9 and 3.3 mg / mL, respectively. (-)-Dimendiol was active at a MIC value of 18.4 mg / mL. Bisabolane derivatives, with the exception of compound 12, showed activity at MIC values of 149 to 705 mg / mL.

Compound 1 and Compound 2 in the γ-Ionylidene derivative show stronger activity than hinokitiol (MIC value 25.0 mg / mL) which is also used clinically, and clinically used triclosan (MIC value 3.13). mg / mL). Compounds 5 and 8 showed the same activity as hinokitiol.
(Prescription Example 1)
The following ingredients were mixed to prepare a dentifrice.

(Ingredient) (%)
Antibacterial agent: (-)-trans-γ-monocyclofarnesol 0.02%
Base: Dental calcium hydrogen phosphate, aluminum oxide 50%
Wetting agent: Glycerin 20%
Foaming agent: 1% sodium urarate sulfate
Adhesive: 1% sodium carboxymethylcellulose
Preservatives: Sodium benzoate, paraoxybenzoate 1%
Purified water remaining <br/> 100% total

(Prescription example 2)
The following ingredients were mixed to prepare a mouthwash.
(Ingredient) (%)
Antibacterial agent: Feridene A 0.02%
Base: 0.5% sorbite solution
Solvent: Ethanol 5%
Preservative: Benzoic acid 0.1%
Sodium benzoate 0.1%
Solubilizer:
Polyoxyethylene polyoxypropylene glycol 2.5%
Sweetener: Xylitol 1.5%
Licorice extract trace color: Green No. 3 0.1%
Purified water remaining <br/> 100% total

The figure which shows isolation | separation operation of the AcOEt fraction of a culture filtrate. It shows a CHCl ₃ fraction separation of the culture mycelium.

Claims (10)

Phellinus igniarius family Meshimakobu (Phellinus linteus) natural, oral composition characterized by containing sesquiterpene derivatives from cultivated or cultured cells.   The composition for oral cavity according to claim 1, wherein the sesquiterpene derivative is a γ-ionylidene derivative and / or a doriman derivative. The composition for oral cavity according to claim 2, wherein the γ-ionylidene derivative is a compound represented by the following general formula (I):

Wherein R ₁ represents COOH or CH ₂ OH, R ₂ and R ₃ each represent H, OH or CH ₃ , and R ₄ and R ₅ each represent H or OH or together An epoxy group is formed, and... May be a double bond). A composition for oral cavity comprising one or more of compounds (1) to (5) and (8) represented by the following structural formula.

An oral composition comprising the compound (1) and / or the compound (2).

  The composition for oral cavity of any one of Claims 1-5 which is a toothpaste, a liquid toothpaste, a dental gel, a mouthwash, a mouthwash, a candy, a troche, or a chewing gum addition component.   The composition for oral cavity in any one of Claims 1-5 which is a therapeutic agent or preventive agent of a periodontal disease and its related disease.   The composition for oral cavity according to claim 7, which is a preventive agent for aspiration pneumonia.   The composition for oral cavity according to any one of claims 1 to 5, which is a bactericidal agent after implant treatment. Γ-ionylidene derivative which is compound (3), compound (5), compound (6) or compound (7) represented by the following structural formula:

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