JP7604777B2 - Oral Composition - Google Patents

Description

The present invention relates to an oral composition that promotes absorption of allantoin or its derivatives into the oral mucosa, such as the gums, has excellent absorbency, is pleasant to eat, and is suitable for preventing or suppressing periodontal diseases, such as gingivitis.

As a water-soluble active ingredient blended in an oral composition, for example, allantoin or a derivative thereof is known to have a tissue repairing effect by activating cell functions, and to be useful in preventing or suppressing periodontal diseases such as gingivitis. In order for this water-soluble active ingredient to act efficiently, it is important that it is absorbed and penetrated into the oral mucosa such as the gingiva.
However, unlike the skin, the oral cavity is constantly supplied with saliva and is wet, and oral compositions are often rinsed with water after application to the oral cavity, creating an environment in which it is difficult for water-soluble ingredients to be absorbed and penetrated into the wet mucosal surface of the gingiva or its interior. For this reason, it is difficult to sufficiently promote the absorption of water-soluble active ingredients into the oral mucosal surface of the gingiva or its interior, and in particular, it has been an issue to improve the absorption promotion effect of allantoin or its derivatives, which are unstable and easily decomposed, into the oral mucosa.

Patent Document 1 (JP 2015-205826 A) proposes incorporating specific fatty acids or esters into an oral composition to improve the absorption of water-soluble active ingredients into oral tissues. However, there are issues with the feel of use, and it has been proposed that the addition of specific fragrance ingredients would be effective in resolving the lack of refreshing feeling (Patent Document 2; JP 2016-222582 A).
Water-insoluble vitamin E or its derivatives, which have a peripheral circulation promoting effect (blood circulation promoting effect) in gingival tissue, are also widely used in oral compositions such as dentifrice compositions as an active ingredient for preventing or suppressing periodontal diseases such as gingivitis, and nonionic surfactants contribute to the stable formulation of these, and polyoxyethylene (20) hydrogenated castor oil and the like are widely used due to their good usability. In Patent Document 3 (JP Patent Publication 2017-214297 A), an oil-soluble specific fatty acid or ester is blended to promote absorption of a water-soluble active ingredient in the oral cavity, and a polyoxyethylene alkyl ether, an inorganic acid, or an alkali metal salt of an organic acid is further blended together with water-insoluble tocopherol or its derivative, thereby ensuring the storage stability of tocopherol or its derivative and simultaneously blending it, and suppressing the oily odor caused by the specific fatty acid or ester to improve the usability.
As described above, the specific fatty acids or esters mentioned above can cause problems with the feel when used depending on the formulation, and there has been a demand for the development of a new technology for promoting absorption of water-soluble active ingredients into the oral mucosa.

JP 2015-205826 A JP 2016-222582 A JP 2017-214297 A JP 2009-149537 A JP 2018-43933 A

The present invention has been made in consideration of the above circumstances, and aims to provide an oral composition that has excellent absorbability of allantoin or its derivatives into the oral mucosa, has a good taste, and is easy to use.

The present inventors conducted extensive research to achieve the above object, and discovered that when polyoxyethylene hydrogenated castor oil having an average number of moles of ethylene oxide added of a specific value or less and vitamin E or a derivative thereof are combined in an oral composition containing allantoin or a derivative thereof, the absorption of component (A) into the oral mucosa is promoted, the bitterness is suppressed, and the composition has a good taste and feel when used, and the composition can be stably combined even after storage. That is, according to the present invention, an oral composition containing (A) allantoin or a derivative thereof, (B) polyoxyethylene hydrogenated castor oil having an average number of moles of ethylene oxide added of 5 to 10 moles, and (C) vitamin E or a derivative thereof has excellent absorption of component (A) into the oral mucosa, a good taste and feel when used, and good storage stability of component (A), leading to the invention.

In the present invention, by combining the (A) component with the (B) component, the absorption of the (A) component into the oral mucosa was promoted, and the (A) component was effectively absorbed and penetrated. This absorption promotion effect was not obtained when polyoxyethylene hydrogenated castor oil with an average added mole number of ethylene oxide of 20 moles was used instead of the (B) component, and was an effect specific to the (B) component. Furthermore, when the (C) component was further added, it was unexpected that the bitterness caused by the combined use of the (A) and (B) components was suppressed and reduced by the (C) component, and thus the absorption of the (A) component into the oral mucosa was improved while maintaining good taste.
Therefore, the oral cavity composition of the present invention ensures a pleasant taste when used, promotes the absorption of component (A) into the oral mucosa, and allows component (A) to be absorbed into the oral mucosa at a high rate. In addition, the storage stability of component (A) is ensured, and the composition can be stably blended even after storage at high temperature (50°C), and the pH of the composition can be set to 6.4 or less, at which component (A) is relatively stable.
In addition, Patent Documents 4 and 5 (JP 2009-149537 A and JP 2018-43933 A) disclose the improvement of oral mucosa permeability of ascorbic acid phosphate salts by polyoxyethylene hydrogenated castor oil having an average added mole number of ethylene oxide of 5 to 10, and are effective when the pH of the oral composition is 6.5 or higher. In contrast, the present invention relates to allantoin or its derivatives, which are unstable and easily decomposed, particularly in the basic range, and improves oral mucosa absorbability of component (A) and suppresses bitterness by components (B) and (C), and the above-mentioned action and effect are excellent even when the pH of the oral composition is set to 6.4 or lower, and are rather remarkable at the above pH value or lower.

Accordingly, the present invention provides the following oral compositions.
(A) allantoin or a derivative thereof,
An oral composition comprising (B) polyoxyethylene hydrogenated castor oil having an average added mole number of ethylene oxide of 5 to 10 moles, and (C) vitamin E or a derivative thereof.

According to the present invention, it is possible to provide an oral composition that has excellent absorbability of component (A) into the oral mucosa, has a good taste, and also has storage stability of component (A). The oral composition of the present invention can efficiently exert its medicinal effect by absorbing and penetrating component (A) into the oral mucosa such as the gums, and is useful for preventing or suppressing periodontal diseases such as gingivitis.

The present invention will be described in further detail below. The oral composition of the present invention contains (A) allantoin or a derivative thereof, (B) a specific polyoxyethylene hydrogenated castor oil, and (C) vitamin E or a derivative thereof.

(A) Allantoin or its derivatives have a gum tissue repairing effect and are active ingredients for preventing or suppressing periodontal disease.
Examples of allantoin or a derivative thereof include allantoin, allantoin chlorohydroxyaluminum, and allantoin dihydroxyaluminum, and one or more of these can be used.

The amount of (A) allantoin or its derivative is preferably 0.01 to 0.5% (mass%, the same applies below) of the entire composition, and more preferably 0.05 to 0.2%. When the amount is within the above range, the absorbability of component (A) into the oral mucosa is sufficiently promoted and excellent, and the bitterness is sufficiently suppressed. In addition, the storage stability of component (A) can be sufficiently obtained.

Component (B) is polyoxyethylene hydrogenated castor oil having an average added mole number of ethylene oxide (hereinafter sometimes abbreviated as EO) of 5 to 10 moles, and acts as an absorption promoter for component (A) into the oral mucosa.
The EO of the polyoxyethylene hydrogenated castor oil is 5 to 10 mol, preferably 5 to 7 mol. It is important for the EO to be within the above range in order to promote the absorption of the component (A) into the oral mucosa, and if the EO exceeds 10 mol, the effect of promoting the absorption of the component (A) into the oral mucosa is inferior.

The amount of component (B) in the composition is preferably 0.1-3% of the total composition, and more preferably 0.2-2%. When the amount is 0.1% or more, absorption of component (A) into the oral mucosa is promoted, and absorbency is sufficiently excellent. When the amount is 3% or less, absorbency is sufficiently excellent, and the bitterness is not too strong, and the bitterness can be sufficiently suppressed.

(C) Vitamin E or a derivative thereof acts as a bitterness suppressor in a combined system of components (A) and (B).
Examples of vitamin E or a derivative thereof that can be used include tocopherols such as d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol; esters thereof, for example, esters with organic acids such as acetic acid, nicotinic acid, succinic acid, and linoleic acid, particularly organic acids having 1 to 20 carbon atoms, and salts thereof. Specific examples of vitamin E derivatives include tocopherol acetate such as d-α-tocopherol acetate and dl-α-tocopherol acetate, tocopherol nicotinate such as d-α-tocopherol nicotinate and dl-α-tocopherol nicotinate, tocopherol succinate such as d-α-tocopherol succinate and dl-α-tocopherol succinate, tocopherol linolenate such as d-α-tocopherol linolenate and dl-α-tocopherol linolenate, and tocopherol calcium succinate. These may be used alone or in combination of two or more.

The amount of (C) vitamin E or a derivative thereof is preferably 0.01-3% of the total composition, more preferably 0.05-2%. If the amount is 0.01% or more, the bitterness is sufficiently suppressed and the taste is good. If the amount is 3% or less, the effect of component (B) is maintained and the absorption-promoting effect of component (A) into the oral mucosa is sufficiently excellent.

Furthermore, (A)/(B), which indicates the ratio of the amount of component (A) to the amount of component (B), is preferably 0.005 to 5, more preferably 0.05 to 1, as a mass ratio. When the mass ratio of (A)/(B) is 0.005 or more, the absorption of component (A) into the oral mucosa is further promoted, resulting in better absorbency, and when it is 5 or less, the bitterness is sufficiently suppressed.

The ratio (A)/(C) of the amount of component (A) to component (C) is preferably 0.01 to 10, more preferably 0.05 to 2, as a mass ratio. When the mass ratio (A)/(C) is within the above range, the absorbability of component (A) into the oral mucosa is sufficiently excellent, and the bitterness is further suppressed and reduced. When it is less than 0.01, the absorbability of component (A) into the oral mucosa may decrease, and when it exceeds 10, the bitterness may not be sufficiently suppressed.

The ratio (B)/(C) of the amounts of the components (B) and (C) is preferably 0.2 to 60 by mass, more preferably 0.2 to 40, and particularly preferably 0.4 to 20, from the viewpoint of suppressing bitterness. If the mass ratio of (B)/(C) is 60 or less, the bitterness is sufficiently suppressed.

In terms of the present action and effect, particularly suppression of bitterness and storage stability of component (A), the oral cavity composition of the present invention preferably has a pH (25° C.) of 4 to 6.4, more preferably 5 to 6. When the pH is 6.4 or lower, the storage stability of component (A) over time is sufficiently ensured, and when the pH is 4 or higher, the bitterness is sufficiently suppressed.
A pH adjuster can also be added. Examples of the pH adjuster include citric acid, citric acid or a salt thereof such as sodium citrate, malic acid or a salt thereof, phosphoric acid or a salt thereof, alkali metal hydroxides such as sodium hydroxide, and bicarbonates.

The oral composition of the present invention can be prepared in the form of a paste, liquid, or the like, into a dentifrice composition such as a toothpaste, liquid dentifrice, or lubricant dentifrice, a mouthwash composition, or even a mouth spray, and is particularly suitable as a dentifrice composition or a mouthwash composition, and especially as a dentifrice composition.

In addition to the above-mentioned components, the oral composition of the present invention may contain known additives (pharmacologically acceptable carriers) and active ingredients that can be used in oral compositions, provided that the effects of the present invention are not impaired. Examples of such additives include abrasives, thickening agents, binders, surfactants, sweeteners, preservatives, colorants, fragrances, and solvents. These components can be mixed with water to prepare the composition. The amounts shown below are based on the total amount of the composition.

Examples of abrasives include silica-based abrasives such as anhydrous silicic acid, silica gel, aluminosilicate, and zirconosilicate; calcium phosphate-based abrasives such as anhydrous or dihydrated calcium phosphate dibasic and calcium phosphate tribasic; calcium pyrophosphate, aluminum hydroxide, aluminum oxide, calcium carbonate, and synthetic resin-based abrasives. The amount of abrasive to be used should be 2-50%, and preferably 10-40%.

Thickening agents include sugar alcohols such as sorbitol, xylitol, erythritol, and reduced starch saccharification products, and polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol. The amount of thickening agent used is usually 5 to 50%.

Examples of binders include alginic acid or its derivatives such as sodium alginate and propylene glycol alginate, gums such as xanthan gum, cellulose derivatives such as sodium carboxymethylcellulose and hydroxyethylcellulose, organic binders such as sodium polyacrylate, polyvinyl alcohol, and polyvinylpyrrolidone, and inorganic binders such as thickening silica. The amount of binder used is usually 0.1 to 10%.

As the optional surfactant, an anionic surfactant, a nonionic surfactant other than the component (B), a cationic surfactant, or an amphoteric surfactant can be blended.
Examples of the anionic surfactant include alkyl sulfates such as sodium lauryl sulfate, acyltaurates such as sodium lauroylmethyltaurate, acyl sarcosinates, and acyl amino acid salts. The amount of the anionic surfactant, particularly sodium lauryl sulfate, is preferably 0.001 to 10%, more preferably 0.01 to 5%, from the viewpoint of exerting the effects of the present invention.
The nonionic surfactant may not be blended (0% blending amount) other than the component (B), but may be blended within a range that does not impair the effects of the present invention, in which case the blending amount is preferably 0.5% or less, more preferably 0.2% or less. Examples of the optional nonionic surfactant include sugar fatty acid esters, sugar alcohol fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene higher alcohol ethers.
Examples of the cationic surfactant include alkyl ammonium type surfactants and quaternary ammonium salts such as alkyl benzyl ammonium salts. Examples of the amphoteric surfactant include betaine type surfactants such as alkyl betaines and fatty acid amidopropyl betaines, and alkyl imidazole type surfactants such as 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolium betaine.
The amount of the optional surfactant is 0.01 to 10%, particularly 0.1 to 5%.

Examples of sweeteners include sodium saccharin, aspartame, stevioside, stevia extract, and paramethoxycinnamic aldehyde.
Examples of the preservative include paraoxybenzoic acid esters such as methylparaben, ethylparaben, and butylparaben, and benzoic acid or a salt thereof.
Colorants include Blue No. 1, Yellow No. 4, titanium dioxide, and the like.

Fragrances include peppermint oil, spearmint oil, anise oil, eucalyptus oil, wintergreen oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil, lime oil, lavender oil, rosemary oil, laurel oil, chamomile oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, grapefruit oil, sweet ginger oil, Natural fragrances such as yuzu oil, iris concrete, absolute peppermint, absolute rose, orange flower, and processed fragrances (front distillation, back distillation, liquid-liquid extraction, essences, powdered fragrances, etc.) of these natural fragrances, as well as menthol, carvone, anethole, cineole, methyl salicylate, cinnamic aldehyde, eugenol, 3-l-menthoxypropane-1,2-diol, thymol, linalool, linalyl acetate, limonene, Single flavors such as menthone, menthyl acetate, N-substituted-paramenthan-3-carboxamide, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allyl cyclohexane propionate, methyl anthranilate, ethyl methylphenyl glycidate, vanillin, undecalactone, hexanal, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cyclotene, furfural, trimethylpyrazine, ethyl lactate, and ethyl thioacetate, as well as blended flavors such as strawberry flavor, apple flavor, banana flavor, pineapple flavor, grape flavor, mango flavor, butter flavor, milk flavor, fruit mix flavor, and tropical fruit flavor, and other known flavor materials used in oral compositions can be used in combination, and the flavors are not limited to those described in the examples.
The amount of the fragrance to be blended is not particularly limited, but the above-mentioned fragrance materials are preferably used in an amount of 0.000001 to 1% in the composition, and fragrances using the above-mentioned fragrance materials are preferably used in an amount of 0.1 to 2% in the composition.

The active ingredient may be any ingredient other than component (A) and component (C), such as nonionic bactericides, cationic bactericides, enzymes such as dextranase, fluorine-containing compounds such as sodium fluoride and sodium monofluorophosphate, water-soluble phosphate compounds, sodium chloride, potassium nitrate, aluminum lactate, plant extracts, anti-tartar agents, and anti-plaque agents. The amount of active ingredient to be blended is an effective amount within a range that does not interfere with the effects of the present invention.

The present invention will be specifically explained below with examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, % indicates mass % unless otherwise specified.

[Examples and Comparative Examples]
Oral compositions (toothpastes) having the compositions shown in Tables 1 to 5 were prepared by conventional methods and evaluated by the following methods. The results are also shown in the tables. In the tables, the figures in parentheses for polyoxyethylene hydrogenated castor oil are the average number of moles of ethylene oxide added.

(1) Method for evaluating absorbability of allantoin or its derivatives A human three-dimensional epidermal model (LabCyte EPI-MODEL 24, manufactured by J-TEC Co., Ltd.) was cultured overnight in the attached medium. The cup in which the epidermal model was cultured was transferred to a 24-well plate to which PBS (phosphate buffered saline) was added, and 50 μL of a solution obtained by diluting the oral composition three-fold with artificial saliva was injected onto the surface of the epidermal model and allowed to stand for 3 minutes. After leaving the surface, 50 μL of water was added to the surface of the epidermal model, and washing was repeated twice by pipetting. The washing solution was discarded, and 50 μL of water was added to the surface of the epidermal model. After incubation for 6 hours (37° C., 5% CO ₂ ), the epidermal model was removed and removed. Allantoin or its derivatives permeated into the PBS were quantified by absolute calibration curve method using HPLC under the following test conditions, and the amount absorbed into the epidermal model was determined.
(Equipment used)
Pump: Shimadzu Corporation LC-20AD
・Sample introduction part: Shimadzu Corporation SIL-20AC
・Detector: Shimadzu Corporation SPD-20A
・Column thermostat: Shimadzu Corporation CTO-20AC
・Eluent flow rate: 1mL/min
(Test conditions)
Detector: ultraviolet spectrophotometer (measurement wavelength: 210 nm)
Column: Inertsil _NH2 (diameter 4.6 mm x length 250 mm, particle size 5 μm)
Column temperature: 35°C
Eluent: Acetonitrile/phosphate buffer solution mixture (4:1)
The absorption rate (%) was calculated assuming that the amount of allantoin or its derivative absorbed in the oral composition of Comparative Example 1 was 100%, and the absorbency of allantoin or its derivative (absorbability of component (A)) was determined from the obtained absorption rate using the following evaluation criteria to evaluate the absorbency into the oral mucosa.
Evaluation criteria: ◎: More than 150% ○: More than 100% but not exceeding 150% ×: Less than 100%

(2) Evaluation method for usability (absence of bitterness) Nine subject monitors squeezed 1 g of the oral composition filled in a typical laminated tube container out of the container, placed it on a toothbrush, and cleaned the inside of the mouth in the usual manner. The taste (bitterness) was judged according to the following rating scale.
Rating criteria: 4 points: no bitterness felt; 3 points: almost no bitterness felt; 2 points: bitterness felt, but tolerable; 1 point: bitterness felt to an unacceptable extent. The average of the ratings from the nine panelists was calculated and the usability (absence of bitterness) was evaluated according to the following rating criteria.
Evaluation criteria:
◎: 3.5 points or more ○: 3.0 points or more and less than 3.5 points ●: 2.0 points or more and less than 3.0 points ×: Less than 2.0 points

(3) Method for evaluating the storage stability of allantoin or its derivatives over time Oral compositions filled in a general laminated tube container were stored for 2 weeks in a thermostatic chamber at 50° C. or −5° C. After leaving them to reach room temperature, 1.5 g of the oral composition was extruded from the container and separated, 20 mL of 80% ethanol was added, the mixture was shaken for 15 minutes, and centrifuged (3,000 rpm, 10 minutes). The amount of allantoin or its derivatives in the supernatant was quantified by absolute calibration curve method using HPLC under the following test conditions, and the contents of allantoin or its derivatives in the samples stored at 50° C. and −5° C. were calculated.
(Equipment used)
Pump: Shimadzu Corporation LC-20AD
・Sample introduction section: Shimadzu Corporation SIL-20AC
・Detector: Shimadzu Corporation SPD-20A
・Column thermostat: Shimadzu Corporation CTO-20AC
・Eluent flow rate: 1mL/min
(Test conditions)
Detector: ultraviolet spectrophotometer (measurement wavelength: 273 nm)
Column: Inertsil _NH2 (diameter 4.6 mm x length 250 mm, particle size 5 μm)
Column temperature: 35°C
Eluent: Acetonitrile/phosphate buffer solution mixture (4:1)
The residual rate (%) of allantoin or a derivative thereof was calculated from the content ratio of the product stored at 50°C when the content of allantoin or a derivative thereof in the product stored at -5°C was taken as 100%, and the storage stability over time of allantoin or a derivative thereof (storage stability of component (A)) was evaluated according to the following evaluation criteria.
Evaluation criteria: ⊚: The remaining rate of allantoin or its derivatives is 95% or more; ◯: The remaining rate of allantoin or its derivatives is 90% or more but less than 95%; ×: The remaining rate of allantoin or its derivatives is less than 90%.

＊；（Ｂ）成分を含まない比較例１は、苦味が発現しなかった。

*: In Comparative Example 1, which did not contain the component (B), no bitterness was observed.

Claims (5)

(A) allantoin or a derivative thereof,
(B) polyoxyethylene hydrogenated castor oil having an average added mole number of ethylene oxide of 5 to 10 moles, and (C) vitamin E or a derivative thereof,
An oral composition having a mass ratio of (A)/(B) of 0.01 to 5 and a mass ratio of (A)/(C) of 0.03 to 2, a content of component (A) of 0.01 to 0.2 mass%, and a pH of the composition at 25°C of 4 to 6.4. 2. The oral composition according to claim 1 , wherein the mass ratio of (A)/(B) is 0.05 to 5. The oral composition according to claim 1 or 2, wherein the mass ratio of (B)/(C) is 0.2 to 60. The oral composition according to any one of claims 1 to 3, wherein the content of component (B) is 0.1 to 3 mass %, and the content of component (C) is 0.01 to 3 mass %. The oral composition according to any one of claims 1 to 4, which is a dentifrice composition.