JP2001172150A - Composition for oral cavity and medicinal composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To develop a composition for the oral cavity and a medicinal composition for external use with slight allergy, capable of exhibiting effective antimicrobial properties on at least carious causative bacteria or Staphyloccus aureus and utilizable as the composition for use in the oral cavity or the medicine for external use. SOLUTION: This composition for the oral cavity or medicinal composition for external use is characterized as comprising an ingredient derived from amber, hinokitiol or a plant essential oil containing the hinokitiol and xylitol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention has antibacterial activity against cariogenic bacteria and Pseudomonas aeruginosa, prevents dental caries, and treats inflammation such as stomatitis and gingivitis, and trauma such as abrasions and cuts. The present invention relates to an oral and topical drug composition having an effective antibacterial property.

[0002]

2. Description of the Related Art Troubles in the oral cavity are mainly caused by dental caries and inflammation caused by stomatitis or gingivitis. Of these, dental caries is caused by the oral bacteria such as Streptococcus mutans in the dental plaque.
Is caused by demineralization of the teeth.
In addition, stomatitis and gingivitis are caused by infiltration and deterioration of Staphylococcus aureus due to invasion of oral tissues for some reason.

[0003] For these, oral compositions and external preparations mainly containing a bactericide such as triclosan, antibiotics, and cetylpyridinium chloride have been used. However, these have safety concerns, and not only are they not allowed to be added to foods, but they also contain specified ingredients specified in Article 61, Paragraph 4 of the Pharmaceutical Affairs Law as allergens, There is a problem that there are many cases where the symptoms worsen after use.

[0004] Xylitol is considered effective in terms of dental caries, and is widely used in commercial products. However, when the ratio of xylitol to total carbohydrates is as low as 60% or less, the effect of suppressing cariogenic bacteria is sufficient. It is hard to say that it is powerless against S. pyogenes, which causes stomatitis and gingivitis. For the stomatitis and gingivitis, there are Chinese herbal ointments and the like, but satisfactory antibacterial activity has not always been obtained.

[0005]

SUMMARY OF THE INVENTION In these respects, there are few allergies, and it shows an effective antibacterial property at least against cariogenic bacteria and Staphylococcus aureus, and can be used as an oral composition or an external medicine. There is a need for the development of drug compositions.

[0006]

The composition for oral and topical use of the present invention is characterized by "containing an amber-derived component, hinokitiol or a plant essential oil containing hinokitiol and xylitol as active ingredients".

An antibacterial composition comprising a combination of amber-derived components, hinokitiols, and xylitol exhibits strong antibacterial activity against both the major cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus, and also exhibits hinokitiol. Can also reduce the slight irritancy that it has. Therefore, when the antibacterial composition of the present invention is used as a composition for oral cavity, it exerts an excellent inhibitory effect on cariogenic bacteria and S. pyogenes, and when used as an external preparation, it is excellent against S. pyogenes. Demonstrate the suppression effect. As the amber-derived component, a component extracted from amber by a method described below is used as an active ingredient.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail with reference to embodiments. Oral and external medicine compositions according to the present invention,
It contains (A) an amber-derived component, (B) one or more plant essential oils selected from hinokitiol or hinokitiol-containing plant essential oils, and (C) xylitol.

[0009] In fossil amber amber as a raw material derived from the component mainly Pinus plant resins (mainly C ₄₀ H ₆₄ 0 _4), comprising a succinic acid representative of organic minerals. It is amorphous, transparent or translucent, has a shape of a lump or a drop, has a shell-like cross section, and is brittle. It has a fat-gloss yellow (= amber) color and may take on a white or red color. The composition varies slightly depending on the amber source used.

The amber-derived component used in the present invention is formed, for example, by the following method. (a1) Oil amber while stirring amber in a nitrogen stream
(= Oil bath) heated or amber to 28kHz, 1
A molten composition obtained by heating and melting while applying an ultrasonic wave or electromagnetic wave of 00 W, (a2) a cooled composition obtained by cooling the molten composition, and (a3) a composition obtained by melting the amber. The residual component obtained by extracting and removing the organic solvent-soluble component, (a
4) While stirring the amber in a stream of nitrogen,
(In an oil bath) (for example, at 280 ° C.), then cooled to (for example, 50 ° C. or lower), refluxed with anhydrous ethanol (for example, 3 hours), and the soluble component was extracted in the ethanol layer. Was washed with ethanol, melted again by heating, and then cooled.The composition obtained by cooling, (a5) anhydrous ethanol was added to amber, and the mixture was refluxed for several hours (for example, 5 hours).
A low-boiling liquid obtained by steam distillation of the filtrate, (a6) amber is heated in an oil bather (= oil bath) while stirring in a nitrogen stream (for example, at 280 ° C.), and thereafter (for example, 50 ° C.)
The mixture was cooled to below), refluxed with anhydrous ethanol (for example, 3 hours), the extracted ethanol layer was concentrated under reduced pressure, and the low-boiling liquid obtained by steam distillation was obtained. (B) Amber was obtained by dry distillation. Amber vinegar, or amber obtained by heating amber in an autoclave or the like, that is, a `` water-soluble extract '' or `` aqueous extract '', the dried fraction of amber (i.e., amber vinegar) is an aoxic state of amber. For example, it is obtained by heating at 120 ° C. to 900 ° C. (for example, 450 ° C.) under nitrogen filling and cooling the evaporated components.

The “water-based extract” is prepared by (b1) placing amber in an autoclave, heating continuously with pressurized steam (for example, at 180 ° C.) for 1 week, returning to normal pressure after cooling, cooling the steam to form water droplets. Then, the accumulated aqueous layer is separated, and the obtained aqueous layer is concentrated under reduced pressure until it becomes viscous. Alternatively, (b2) put amber in an autoclave, heat n-butanol and water continuously for 1 week with pressurized steam (for example, 180 ° C) of a mixed solvent of 4: 1, return to normal pressure after cooling, and return to normal pressure. Is cooled to form water droplets, the pooled aqueous layer is separated, and it is concentrated by heating until it becomes viscous. (b3) Water is added to amber (for example, 300 mesh pass) powder, and the mixture is extracted under pressure in a pressure cooker at 105 ° C. for 15 days, and the resulting liquid is concentrated until it becomes viscous.

These amber-derived compositions have a heat melting temperature generally in the range of 120 to 380 ° C., depending on the place where the amber is produced.

Hinokitiol is β-thyaprisin and has a molecular formula of C ₁₀ H ₁₂ O ₂ and a molecular weight of 164.20, and is commercially available as a raw material for cosmetics. Essential oils such as cypress oil containing hinokitiol, asunaro oil-Taiwan hinoki oil, and hinoki oil may be used. When using essential oils, it is not limited to only one type, and two or more types may be appropriately mixed.

Xylitol is a sugar alcohol (pentacarbon) having a molecular formula of C ₅ H ₁₂ O ₅ and a molecular weight of 152.15.
Streptococcus mutans, which is not metabolized by Streptococcus mutans, which is the main causative bacterium of caries, which is commercially available as a food ingredient or a cosmetic ingredient as a sweetener, is killed by continuing to eat xylitol.

In the present invention, the amount of the amber-derived component relative to the whole composition is 0.00001% to 20%, preferably 0.0001% to 10%, more preferably 0.001% to 5%.
%. Hinokitiol is present in an amount of 0.00001% to 10%, preferably 0.0001% to 3%, more preferably 0.001% to 1%.
%, Or in the case of using essential oils, it may be converted in terms of the content of hinokitiol, which is 1/2 of these. Xylitol is 0.001% to 50%, preferably 0.01% to 30%, more preferably 0.1% to 20%.

According to the present invention, the composition for oral and topical use obtained by using hinokitiol and xylitol in combination with the amber-derived component according to the present invention includes, for the oral cavity, toothpastes such as toothpaste and powder toothpaste, mouthwashes, and oral patches. Drugs, lipsticks, chewable tablets, candy, chewing gum and the like can be mentioned. For external use, they can be applied to ointments, patches, cataplasms, creams, gels, serums, lotions, hair tonics and the like.

Further, if necessary, appropriate components such as glycerin, other saccharides, fats and oils, surfactants and the like can be blended. For example, in the case of toothpaste, it is a fragrance, a thickener, a surfactant, an abrasive, a sweetener, another herbal extract, or the like.

Hereinafter, the present invention will be described specifically with reference to examples. Of course, the present invention is not limited to the following embodiments. `` Example Al-3 '' 1 kg of Dominican amber 450 under nitrogen filling
10 g of about 45 g of distillate (amber dry distillate) obtained by heating to dry distillation to ℃
And 3 g of xylitol and 0.005 g of hinokitiol in each of the bases to be described later, in which the above component composition was blended in (base recipe-1). In Examples (Al) and (base recipe-2). Examples (A-2), (base formulation-
Example (A-3) blended in 3) was obtained. [Example Bl-3] 100 g of Lithuanian amber was heated and melted at 250 ° C by applying ultrasonic waves of 28 kHz and 100 W while stirring in a nitrogen stream, cooled to 180 ° C, and dissolved by adding 200 kg of squalane. Then, cooled (amber composition-containing oils and fats) 0.4 g and xylitol 3 g, hinokitiol 0.005 g
Was blended in each base described below, and blended with the above component composition in (base recipe-1)
(Bl), those blended in (base formulation-2) Example (B-2),
Example (B-3) blended in (Base formulation-3). [Example Cl-3] 1 kg of Mexican amber was placed in an autoclave, heated to 180 ° C. with pressurized steam, and continuously heated for one week.
After cooling, the pressure was returned to normal pressure, the water vapor was cooled to form water droplets, and the 100 ml liquid obtained by separating the accumulated aqueous layer was further concentrated under reduced pressure to about 20 g (amber water extract) 0.3 g. And 3 g of xylitol and 0.005 g of hinokitiol in each of the bases described below, in which the above composition was blended in (base formulation-1) .Example (Cl), (base formulation
Example (C-2) blended in -2) and Example (C-3) blended in (base formulation-3). `` Example D '' The hinokitiol of Example (A-1) was converted to Hiba essential oil 0.
Replaced with 5g.

Base formulation-1 (applied to Examples A, B, C, D) Toothpaste (target product) Silica 19.0 g Condensed glycerin 30.0 g Kirayasaponin 2.0 g Carrageenan 1.5 g Japanese peppermint leaf oil 1.0 g Purified water balance 100.0 g Base formulation-2 (used in Examples A, B, C) Tablets (target product) Natural crystalline cellulose 25.0 g Silicon dioxide 25.0 g Natural lemon oil 0.2 g L-ascorbic acid 0.1 g Lactose Residual total 100.0 g Base formulation -3 (Used in Examples A, B, and C) Essence-like topical drug (target product) Cosmetics Seaweed extract 20.0 g Cosmetics Aloe extract 30.0 g Fermented hyaluronic acid 0.6 g Purified water Residual total 100.0 g Antibacterial activity test: Streptococcus mutans bacteria and Staphylococcus aureus are added to each of the culture media at a concentration of 10% in Examples and Comparative Examples, and cultured at 37 ° C. for 2 days. If no growth was observed (-), if growth was observed (+)
Displayed. "Comparative Example-1" ... only base formula-1 "Comparative Example-2" ... only base formula-2 "Comparative Example-3" ... only base formula-3 "Comparative Example-4" -A product obtained by removing xylitol and hinokitiol from Example (A-1) (that is, only an amber dry distillation solution as an active ingredient). "Comparative Example-5": A product obtained by removing xylitol and hinokitiol from Example (B-1) (that is, as an active ingredient, only an oil-and-fat agent containing an amber component). "Comparative Example-6": Example (C-1) excluding xylitol and hinokitiol (that is, only an amber water extract as an active ingredient). “Comparative Example-7”: A product obtained by removing the amber dry distillation solution and xylitol from Example (A-1) (that is, only hinokitiol was used as the active ingredient). "Comparative Example-8": The hinokitiol of Comparative Example-7 was made 0.05%. "Comparative Example 9": A quadrupled amount of the amber dry distillation solution of Comparative Example-4. “Comparative Example-10”: The amount of the amber-derived component (amber composition-containing oil and fat agent) of Comparative Example-5 was quadrupled. “Comparative Example-11”: A quadrupled amount of the amber water extract of Comparative Example-6. “Comparative Example-12”: xylitol in the base formulation of Comparative Example-1
3g only. "Comparative Example-13": a composition in which xylitol in Example (A-1) was replaced with sorbitol.

[0020]

【table 1】

From Table 1, the embodiment (A-1, A-2, A-3, B-1, B-2, B-3,
In all of C-1, C-2, C-3, D), antibacterial activity is observed in both Streptococcus mutans bacteria and Staphylococcus aureus. On the other hand, the product of Comparative Example-12 containing only xylitol and the product of Comparative Example-7 containing only hinokitiol did not show any antibacterial activity. In addition, in the case of only amber-derived components (in this case, amber distillate, amber composition-containing fats and oils, and amber aqueous extract), it is effective for Staphylococcus aureus, but not effective for Streptococcus mutans bacteria This is apparent from Comparative Examples 4, 5, and 6. Comparative Example-13
Replaces xylitol with sorbitol, but sorbitol does not have any antibacterial activity against any bacteria even in the presence of amber-derived components and hinokitiol. This is because sorbitol does not produce a synergistic effect of the three components,
This indicates that xylitol is an essential component for producing a unique synergistic effect of the three components. That is, from this fact, the amber-derived component (in the above example, the amber dry distillation solution, the amber composition-containing oil and fat agent, and the amber aqueous extract,
A unique synergistic effect was observed between xylitol and hinokitiol (including the residual component of 3)), which proved to be a useful antibacterial composition against the two bacteria. Example D also revealed that an effect could be obtained by using hiba oil instead of hinokitiol.

From Comparative Examples 8, 9, 10, and 11, it was found that antibacterial mosquitoes against the above-mentioned two bacteria could be obtained by increasing the concentration of amber-derived substances and hinokitiol by 4 times or 10 times. However, there are problems with cost, irritation of hinokitiol, problems with allergies, etc., and browning due to hinokitiol, so-called "burn", which is not preferable in commercialization.

To make a comprehensive judgment from these results,
(1) In the case of a practical concentration of 50 to 100 ppm, of course, 5 p
pm or less of the minimum inhibitory concentration (M
(IC) The following low-concentration hinokitiol, which no longer exhibits antibacterial activity, (2) Amber-derived components at concentrations that do not exhibit antibacterial activity against Streptococcus mutans bacteria alone, and (3) against two bacteria In a three-component blended system containing xylitol, which has no antibacterial activity, the excellent antibacterial activity against the two bacteria was exhibited at a low concentration due to the synergistic action of these three components. This is also useful in terms of cost.

Since the product of the present invention contains hinokitiol as an active ingredient, which may cause allergic reactions to the user, it is necessary to prevent the user from causing allergic effects when used for oral and topical use. is important. Then, the allergenicity is examined next. Example (A-4): A mixture of the hinokitiol of Example (A-3) at 5 ppm. Example (A-5): A compound obtained by mixing the hinokitiol of Example (A-3) at 20 ppm. Example (A-6): A compound obtained by mixing the hinokitiol of Example (A-3) at 50 ppm. Example (A-7): 100 ppm of hinokitiol of Example (A-3)
What was blended to become. "Comparative Example-14": a composition in which Hinokitiol in Comparative Example-3 (base formulation-3) was blended at 5 ppm. “Comparative Example-15”: A compound obtained by mixing hinokitiol in Comparative Example-3 (base formulation-3) to 20 ppm. “Comparative Example-16”: A compound obtained by mixing hinokitiol in Comparative Example-3 (base formulation-3) at 50 ppm. “Comparative Example-17”: a compound obtained by mixing hinokitiol in Comparative Example-3 (base formulation-3) to 100 ppm.

"Skin patch test" Five adult men with allergies in particular to hinokitiol were selected, and each Example and each Comparative Example were applied for 24 hours or applied using a bandage of Japanese Pharmacopoeia and removed for 24 hours. Later, the condition of the skin was investigated. Depends on the condition of the skin; skin in a healthy state with no change ... 0 slight redness ... 1 obvious redness ... ·········· 2 Evaluation with erythema, edema and papules · · · 3 with perceptional changes such as itching · · · 4 with pathological changes such as blisters · · · · 5 The score indicates the total evaluation of five adult men.

[0026]

[Table 2]

From Table 2, it can be seen that a person who is easily sensitized to hinokitiol has allergic symptoms even at 5 to 10 ppm (Comparative Example 14) which does not exhibit antibacterial activity, and cannot be used as an external preparation. Even worse, when the concentration reached a practical concentration of 50 to 100 ppm (Comparative Examples 16 and 17), considerably severe redness, itching (raised), etc. were recognized, 18 points,
A high score of 21 points. In particular, 100 ppm (Comparative Example 17)
Then, everyone is accompanied by perceptual changes such as itching. On the other hand, in Examples (A-4 to 7), the scores of 5 or more were reduced at all the concentrations, indicating that they had antiallergic properties.

Furthermore, 5 ppm which is not practically practical (Example A
It shows antibacterial activity even at a low concentration of -4), and is used for allergic and atopic skin diseases, which have been increasing in recent years due to a score of only 5 points with no perceptual change and a slight redness. It turned out to be a possible therapeutic agent and proved to be a very useful oral and topical composition.

[0029]

The composition for oral and topical use of the present invention comprises an amber-derived component which does not exhibit antibacterial activity against Streptococcus mutans bacteria alone, a low-concentration hinokitiol,
By combining the three components of xylitol, which has no antibacterial activity, without causing allergies, the synergistic action of these three components can be used to prevent Staphylococcus aureus, a pyogenous bacterium, and Streptococcus mutans, a cariogenic bacterium. It shows excellent antibacterial activity and is useful as a medicine for preventing caries, inflammation in the oral cavity and also for skin.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 35/78 A61K 35/78 W A61P 1/02 A61P 1/02 17/00 101 17/00 101 (72 Inventor Noichi Sawaguchi 1-31-15 Yoyogi, Shibuya-ku, Tokyo, Japan Inside the Advanced Utilization Research Center for Crude Drugs (72) Inventor Kazuo Nakao 1-31-15, Yoyogi, Shibuya-ku, Tokyo Inside the Advanced Utilization Research Center for Crude Drugs ( 72) Inventor Hitoshi Kuromaru 1-31-15 Yoyogi, Shibuya-ku, Tokyo, Japan Inside the Advanced Utilization of Crude Drugs Company (72) Inventor Hirofumi Haba 1-31-15, Yoyogi, Shibuya-ku, Tokyo F Terms (reference) 4C083 AA111 AB172 AC122 AC131 AD212 AD262 AD332 AD352 AD551 AD642 CC02 CC41 DD15 DD22 DD27 EE10 EE32 EE33 4C087 AA01 AA02 AA04 BA07 MA02 M A17 MA28 MA35 MA47 MA57 MA63 NA06 NA14 ZA67 ZA89 ZB35 4C088 AB03 MA08 MA17 MA28 MA35 MA47 NA06 NA14 ZA67 ZA89 ZB35 4C206 AA01 AA02 CA05 CB25 MA03 MA37 MA48 MA55 MA67 MA77 MA83 NA06 NA14 ZA67 ZA89 ZB35

Claims (8)

[Claims] 1. An oral and topical composition comprising an amber-derived component, hinokitiol or a plant essential oil containing hinokitiol and xylitol as active ingredients. 2. The content of the amber-derived component is 0.00001% to 20%, the content of hinokitiol is 0.00001% to 10%, and the content of xylitol is 0.0% to the whole composition.
The oral and external medicine composition according to claim 1, wherein the composition is from 01% to 50%. 3. A composition for oral and topical use wherein the component derived from amber according to claim 1 or 2 is a dried product of amber. 4. A composition for oral and topical use wherein the component derived from amber according to claim 1 or 2 is an aqueous extract of amber. 5. A composition for oral and topical use, wherein the component derived from amber according to claim 1 or 2 is an extract of amber. 6. A composition for oral and topical use wherein the component derived from amber according to claim 1 or 2 is a residue obtained by extracting amber with an organic solvent. 7. The amber-derived component according to claim 1 or 2, wherein the amber powder is a low-boiling liquid obtained by refluxing an amber powder together with an organic solvent, filtering a reflux liquid, and steam-distilling the filtrate. Oral and topical drug compositions. 8. A composition for oral and topical use, wherein the component derived from amber according to claim 1 or 2 is a melt of amber.