JP6734090B2 - Oral composition - Google Patents

Description

The present invention relates to an oral composition. More specifically, the present invention relates to an oral composition in which destabilization of hinokitiol and ε-aminocaproic acid and/or its salt is suppressed.

Periodontal disease is an oral disease that also leads to tooth loss, and various bacteria in oral plaque are involved in its development. Periodontal disease is accompanied by swelling and bleeding of the gums and significantly impairs the quality of life (QOL) of patients, so that prevention and treatment thereof are important in daily life. For prevention or treatment of oral diseases such as periodontal disease, it is known that plaque control by cleaning the oral cavity using oral compositions such as dentifrice, gargle and mouthwash is effective.

Hinokitiol is known to have a bactericidal action and a tissue astringent action, and has conventionally been associated with gingivitis or alveolar bleeding, redness, swelling, tingling, pain, itching, mouth stickiness, bad breath, etc. It is used by being mixed with oral compositions such as ointments and dentifrices for the purpose of alleviating various symptoms of pyorrhea and treating stomatitis. However, hinokitiol is known to have poor storage stability, and various studies have been made to improve the stability, such as by adding edetic acid (see Patent Document 1, for example).

On the other hand, anti-plasmin agents such as ε-aminocaproic acid and tranexamic acid are known to be able to suppress inflammation and bleeding in the oral cavity by the action of antagonizing plasmin, which inhibits blood coagulation. Oral compositions have also been reported (see, for example, Patent Document 2).

In addition, it is known that astringents such as aluminum lactate can suppress inflammation and bleeding in the oral cavity by tightening the tissue and enhancing the protective function against physical or chemical stimuli from the outside world. A combined oral composition has also been reported (see, for example, Patent Document 3).

An oral composition containing an antiplasmin agent or an astringent agent is effective in suppressing inflammation and bleeding in the oral cavity, but with the recent increase in consumers' health consciousness, inflammation and bleeding in the oral cavity are further suppressed. It is desired to develop an oral composition that can be effectively suppressed.

JP 2002-20253A JP, 2002-20250, A International Publication No. 2009/34919

In the composition for the oral cavity, when hinokitiol, an antiplasmin agent and an astringent are used in combination, not only a bactericidal effect in the oral cavity can be obtained, but also an effect of suppressing inflammation and bleeding in the oral cavity can be effectively obtained, and periodontal disease It is expected that the preventive or therapeutic effect on oral diseases such as Therefore, the present inventor conducted a study to develop an oral composition containing hinokitiol, an antiplasmin agent and an astringent, and in the oral composition, hinokitiol, ε-aminocaproic acid and/or an antiplasmin agent. When the salt and aluminum lactate as an astringent are used together, hinokitiol is stabilized by aluminum lactate. However, if these three components are simply combined without considering the formulation composition, ε-aminocaproic acid and/or a salt thereof is obtained. Was destabilized by aluminum lactate, and a new problem that ε-aminocaproic acid and/or its salt was decomposed with time was faced.

Then, this invention makes it a subject to provide the composition for oral cavity which is excellent in the storage stability of hinokitiol and (epsilon)-aminocaproic acid and/or its salt, and is excellent in the bactericidal effect and the effect of suppressing inflammation and bleeding.

The present inventors have conducted extensive studies to solve the above problems, and in the oral composition, (A) hinokitiol, (B) ε-aminocaproic acid and / or its salt, and (C) aluminum lactate is contained. Furthermore, 250 to 2500 parts by weight of (C) aluminum lactate per 100 parts by weight of (A) hinokitiol, and (B) aluminum lactate (C) per 100 parts by weight of ε-aminocaproic acid and/or its salt. It has been found that the storage stability of both hinokitiol and ε-aminocaproic acid and/or its salt is excellent by setting the ratio to be 25 to 250 parts by weight. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following modes.
Item 1. (A) Hinokitiol, (B) ε-aminocaproic acid and/or a salt thereof, and (C) containing aluminum lactate,
250 to 2500 parts by weight of the component (C) is contained with respect to 100 parts by weight of the component (A), and
25 to 250 parts by weight of the component (C) is contained with respect to 100 parts by weight of the component (B).
A composition for oral cavity, comprising:
Item 2. Item 2. The oral composition according to Item 1, which is a liquid dentifrice, a toothpaste, a moisturizing dentifrice, or a mouthwash.

According to the composition for oral cavity of the present invention, destabilization of hinokitiol can be suppressed, and also destabilization of ε-aminocaproic acid and/or a salt thereof which occurs in the coexistence with aluminum lactate can be suppressed, which is excellent. It can have excellent storage stability. Further, the oral composition of the present invention has an excellent bactericidal effect by stabilizing hinokitiol, and further has ε-aminocaproic acid and/or a salt thereof having an antiplasmin action, and aluminum lactate having an astringent action. Since it contains, the action of suppressing inflammation and bleeding in the oral cavity is enhanced, and it is expected that the preventive or therapeutic effect of oral diseases such as periodontal disease is improved.

1. Oral Composition The oral composition of the present invention comprises hinokitiol (hereinafter sometimes referred to simply as component (A)), ε-aminocaproic acid and/or a salt thereof (hereinafter simply referred to as component (B)). In some cases), and aluminum lactate (hereinafter sometimes simply referred to as “component (C)”), and contains 250 to 2500 parts by weight of component (C) per 100 parts by weight of component (A). , 25 to 250 parts by weight of the component (C) per 100 parts by weight of the component (B). Hereinafter, the oral composition of the present invention will be described in detail.

In the composition for oral cavity of the present invention, as the hinokitiol, a natural product-derived one or a chemically synthesized one may be used. The hinokitiol used in the present invention may be a refined product or a crude refined product, for example, a hinokitiol-containing essential oil obtained from a tree.

The content of the component (A) in the oral composition of the present invention is appropriately set depending on the formulation form and application of the oral composition, but from the viewpoint of exhibiting an excellent bactericidal action, it is usually 0.005-0.2% by weight, preferably 0.01-0.2% by weight. In general, as the content of hinokitiol in the composition increases, the rate of decrease with time increases, so that it is more difficult to prevent the decomposition of hinokitiol over time in a composition having a high content of hinokitiol as an active ingredient. Become. However, in the oral composition of the present invention, even if the content of hinokitiol is increased (specifically, 0.05% by weight or more, and further 0.1% by weight or more with respect to the total amount of the oral composition. However, a sufficient level of storage stability can be achieved. In view of such effects of the present invention, the preferable range of the content of the component (A) in the oral composition of the present invention is 0.05 to 0.2% by weight, particularly 0.1 to 0.2%. % By weight.

(B) Component The oral composition of the present invention contains ε-aminocaproic acid and/or a salt thereof as an antiplasmin agent.

The salt of ε-aminocaproic acid is not particularly limited as long as it is pharmaceutically acceptable, and specifically, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; Examples thereof include inorganic acid salts such as hydrochlorides and sulfates. These ε-aminocaproic acid salts may be used alone or in combination of two or more.

In the composition for oral cavity of the present invention, as the component (B), either ε-aminocaproic acid or a salt thereof may be used alone or in combination.

Among these (B) components, ε-aminocaproic acid is preferable.

The lower limit of the content of the component (B) in the oral composition of the present invention is not particularly limited and may be appropriately set according to the formulation form of the oral composition, etc., but in the coexistence with aluminum lactate. From the viewpoints of more effectively suppressing the destabilization of the produced ε-aminocaproic acid and/or its salt, and effectively exerting the effect as an antiplasmin agent, 0.01% by weight or more, preferably 0. It may be 05% by weight or more. The upper limit of the content of the component (B) is not particularly limited, and may be appropriately set according to the formulation form of the oral composition, etc., but is not limited to ε-aminocaproic acid and/or ε-aminocaproic acid produced in the presence of aluminum lactate. From the viewpoint of more effectively suppressing destabilization of the salt and more effectively preventing destabilization of hinokitiol, 0.5% by weight or less, and preferably 0.2% by weight or less. ..

In the composition for oral cavity of the present invention, the ratio of the component (B) to the component (A) is not particularly limited, and the mixing ratio of the component (A) and the component (C) described later, and the component (B) and ( The compounding ratio of the component (C) may be appropriately set within a range that can satisfy the condition. For example, 100 to 5000 parts by weight, and preferably 250 to 1000 parts by weight of the component (B) are included per 100 parts by weight of the component (A). ..

(C) Component The oral composition of the present invention contains aluminum lactate. Aluminum lactate may be anhydrous or hydrated.

The lower limit of the content of the component (C) in the oral composition of the present invention is not particularly limited and may be appropriately set depending on the formulation form of the oral composition, etc., but improves the stability of hinokitiol. From this point of view, 0.05% by weight or more is preferable, and 0.1% by weight or more is more preferable. Further, the upper limit of the content of the component (C) is not particularly limited and may be appropriately set according to the formulation form of the oral composition, etc., and ε-aminocaproic acid generated in the coexistence with aluminum lactate and From the viewpoint of more effectively suppressing the destabilization of the salt thereof, 1% by weight or less, and preferably 0.5% by weight or less.

In the oral composition of the present invention, the ratio of the component (C) to the component (A) is set such that the component (C) is 250 to 2500 parts by weight per 100 parts by weight of the component (A). By satisfying such a blending ratio, it becomes possible to improve the stability of hinokitiol. From the viewpoint of further improving the stability of hinokitiol, the compounding ratio of the component (C) per 100 parts by weight of the component (A) is preferably 500 to 2500 parts by weight, more preferably 1000 to 2500 parts by weight. ..

In the composition for oral cavity of the present invention, the ratio of the component (C) to the component (B) is 25 to 250 parts by weight, preferably 50 to 50 parts by weight, relative to 100 parts by weight of the component (B). It is set to be 250 parts by weight. By satisfying such a ratio, it is possible to improve the stability of hinokitiol while effectively suppressing the destabilization of ε-aminocaproic acid and/or a salt thereof which occurs in the presence of aluminum lactate. Become.

Other Ingredients The oral composition of the present invention may contain components usually used in the technical field depending on the formulation form of the oral composition, as long as the effects of the present invention are not impaired. Examples of such components include abrasives, antiseptics, bactericides, antibacterial agents, antiphlogistics, plaque suppressors, hyperesthesia suppressants, anticalculus agents, binders, thickeners, excipients, and lubricants. Examples include a lubricant, a fragrance, a sweetener, a refreshing agent, a pigment, a deodorant, a surfactant, a pH adjuster, a tooth strengthening agent, and an anti-cavity agent.

Examples of the abrasive include dibasic calcium phosphate (dihydrate or anhydrous), dibasic calcium phosphate, tribasic calcium phosphate, calcium pyrophosphate, calcium carbonate, aluminum hydroxide, alumina, magnesium carbonate, tribasic magnesium phosphate, insoluble Various silica-based abrasives such as sodium metaphosphate, insoluble potassium metaphosphate, titanium oxide, zeolite, silicic acid anhydride, hydrous silicic acid, titanium silicate, zirconium silicate, and abrasive silica; synthetic resin-based abrasives and the like. ..

Examples of antiseptics, bactericides and antibacterial agents include benzoic acids, salicylic acids, sorbic acids, parabens, decalinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine chloride, chlorhexidine gluconate, isopropylmethylphenol, cetylpyridinium chloride. , Triclosan, hinokitiol, lysozyme chloride, chlorhexidine hydrochloride, potassium iodide and the like.

Examples of the anti-inflammatory agent include allantoins, tranexamic acid, azulene, glycyrrhizinate, glycyrrhetinic acid, sodium chloride, vitamins and the like.

Examples of plaque inhibitors include zinc citrate, dextranase, mutanase, gluconic acid and the like.

Examples of the hypersensitivity inhibitor include potassium nitrate, strontium chloride and the like.

Examples of the anticalculus agent include polyphosphates, zeolite, ethanehydroxydiphosphonate and the like.

Examples of the binder include polysaccharides such as pullulan, pullulan derivative, starch; hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose salts (carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose potassium, etc.) , Methyl cellulose, ethyl cellulose, polyacrylic acid, polyacrylic acid salt (sodium polyacrylate, acrylic acid/octyl acrylate copolymer, etc.), methacrylic acid copolymer (methacrylic acid and n-butyl acrylate) Polymers, polymers of methacrylic acid and methyl methacrylate and polymers of methacrylic acid and ethyl acrylate, etc.); synthesis of carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, etc. Polymeric substances; lectins, alginic acid, alginates (sodium alginate, potassium alginate, magnesium alginate, propylene glycol alginate, triethanolamine alginate, triisopropanolamine alginate, ammonium alginate, butylamine alginate, diamylamine alginate, etc.), sodium chondroitin sulfate, Natural polymer substances such as agar, chitosan, carrageenan; amino acid polymer substances such as collagen and gelatin; gum polymer substances such as gum arabic, karaya gum, tragacanth gum, xanthan gum, locust bin gum, guar gum, tamarind gum and gellan gum Is mentioned.

Examples of the thickening agent include glycerin, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, xylitol, maltitol, lactol and the like.

Examples of the excipient include lactose, sucrose, mannitol, starch, dextrin, crystalline cellulose, calcium hydrogen phosphate, calcium carbonate, light anhydrous silicic acid and the like.

Examples of the lubricant include magnesium stearate, talc, sodium stearyl fumarate, light anhydrous silicic acid, hydrous silicon dioxide and the like.

Examples of the fragrances include natural fragrances (such as fennel oil), synthetic fragrances, and mixed fragrances thereof.

Examples of the sweetener include saccharin sodium, stevioside, stevia extract, aspartame, xylitol, starch syrup, honey, sorbitol, maltitol, mannitol, erythritol, sugars (lactose, sucrose, fructose, glucose, etc.) and the like.

Examples of the cooling agent include menthol, erythritol, camphor, borneol, geraniol, and essential oils containing these.

Examples of pigments include natural pigments, synthetic pigments, and mixtures thereof.

Examples of the deodorant include zinc chloride, sodium copper chlorophyllin, coffee green bean extract, burdock powder, green tea and the like.

Examples of the surfactant include sodium polyoxyethylene lauryl ether sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristolyl sarcosinate, sodium dodecylbenzene sulfonate, and hydrogenated coconut fatty acid. Anionic surface active agents such as monoglyceride sodium monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutamate, sodium N-methyl-N-acyl taurine, sodium N-lauroyl-L-glutamate Agents: sucrose fatty acid ester, maltose fatty acid ester, maltitol fatty acid ester, lactol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan monostearate, polyoxyethylene higher alcohol ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene poly Nonionic surfactants such as oxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, polyglycerin fatty acid ester; coconut oil fatty acid amide propyl betaine, lauryl dimethylamino acetic acid betaine, lauryl dimethyl amine oxide, 2-alkyl- Amphoteric surfactants such as N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-lauryldiaminoethylglycine, N-myristyldiaminoethylglycine, N-alkyl-1-hydroxyethylimidazoline betaine sodium; lauryltrimethylammonium chloride, chloride Examples thereof include cationic surfactants such as stearyl trimethyl ammonium, benzethonium chloride, benzalkonium chloride, and stearyl dimethyl benzyl ammonium chloride.

Examples of the pH adjuster include acetic acid, hydrochloric acid, sulfuric acid, nitric acid, citric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium acetate, sodium carbonate, sodium citrate, sodium hydrogen citrate, sodium phosphate, phosphorus. Sodium hydrogenate and the like can be mentioned.

Examples of the anti-cavity agent and the tooth strengthening agent include alkali metal monofluorophosphates such as sodium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride.

The composition for oral cavity of the present invention can contain an edible base material or a pharmaceutically acceptable base material (water, alcohol, polyhydric alcohol, etc.) depending on its formulation form. As such a base material, one that can be used is known depending on the formulation form, and in the oral composition of the present invention, the base material is appropriately selected and applied according to the target formulation form. It may be contained in an amount. Further, the oral composition of the present invention, the destabilization of the component (B) that occurs in the presence of the component (C) is particularly likely to occur when it contains water, even in such a case, According to the invention, the destabilization of the component (B) can be suppressed, and the oral composition can be provided with excellent storage stability. In view of such effects of the present invention, a preferable embodiment of the present invention is an oral composition containing water as a base material.

Formulation Form The shape of the oral composition of the present invention is not particularly limited, and may be liquid, solid, semisolid (gel, ointment, paste) or the like.

The oral composition of the present invention may be edible or inedible as long as it is applied to the oral cavity and can stay in the oral cavity for a certain period of time. The oral composition of the present invention is, for example, any of oral hygiene agents, foods (including functional foods, foods for health and health, foods for patients), pharmaceuticals (including quasi-drugs), cosmetics, etc. It may be in the form. As a formulation form of the oral composition of the present invention, specifically, a liquid dentifrice, a toothpaste, a moisturizing dentifrice, a powder dentifrice, a mouthwash (mouthwash), a mouthrinse, a mouthwash, a mouth rinse Oral hygiene agents such as agents (mouse spray, etc.), oral pasta agents, gingival massage creams, oropharyngeal agents (lozenges, etc.); edible film, chewing gum, candy, gummy candy, tablets, granules, fine particles, powder , Edible oral agents such as capsules, and the like. Among these, the oral hygiene agent is a suitable formulation because it easily imparts the effect of suppressing inflammation and bleeding due to the components (B) and (C) to the oral mucosa. Among oral hygiene agents, liquid dentifrices, toothpastes, moisturizers and mouthwashes are preferred, and toothpastes are more preferred.

Manufacturing method The oral composition of the present invention is prepared by blending the components (A) to (C) described above, and other components that are blended as necessary, into a predetermined shape depending on the formulation form. It can be manufactured.

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Test example 1
The oral compositions (toothpaste) having the compositions shown in Tables 1 and 2 were prepared, and the following tests were conducted to evaluate the stability of hinokitiol and ε-aminocaproic acid.

About 35 mL of each oral composition was filled in a 40 mL tube (a tube in which layers made of aluminum are laminated and the inside of which is shielded from light) and stored at 50° C. for 1 month. For each oral composition before and after storage, the amounts of hinokitiol and ε-aminocaproic acid were measured by high performance liquid chromatography under the following conditions.

<Measurement conditions for high-performance liquid chromatography (hinokitiol)>
Equipment used: High Performance Liquid Chromatograph LC-20AD (manufactured by Shimadzu Corporation)
Detector: UV absorptiometer-Measurement wavelength 350 nm
Column: ODS column length 15 cm
Column temperature: 40°C
Mobile phase: EDTA + phosphate buffer/acetonitrile mixture flow rate: 0.9 mL/min

<Measurement conditions for high performance liquid chromatography (ε-aminocaproic acid)>
Equipment used: High Performance Liquid Chromatograph LC-20AD (manufactured by Shimadzu Corporation)
Detector: UV absorptiometer-Measuring wavelength 250 nm
Column: ODS column length 15 cm
Column temperature: 40°C
Mobile phase: Tetrabutylammonium bromide + Acetate buffer/acetonitrile mixture Flow rate: 0.6 mL/min

From the measured values of the amounts of hinokitiol and ε-aminocaproic acid, the reduction rate (%) of hinokitiol and ε-aminocaproic acid was calculated according to the following formula.

Reduction rate (%) of each component =
{(Amount of each component before storage-amount of each component after storage)/(amount of each component before storage)}×100

Based on the obtained reduction rate (%), the stability of hinokitiol and ε-aminocaproic acid was evaluated based on the following criteria.
<Evaluation criteria>
-: Reduction rate is 10% or more +: Reduction rate is 7% or more and less than 10% ++: Reduction rate is 5% or more and less than 7% ++ +: Reduction rate is 4% or more and less than 5% ++++: Reduction rate is 3% or more 4 Less than %+++++: Reduction rate is less than 3%

The obtained results are shown in Tables 1-2. From these results, by adding 250 to 2500 parts by weight of aluminum lactate to 100 parts by weight of hinokitiol and adding 25 to 250 parts by weight of aluminum lactate to 100 parts by weight of ε-aminocaproic acid, hinokitiol and ε- were obtained. It was confirmed that the storage stability of aminocaproic acid was improved (Examples 1 to 12). Further, comparing Example 1 and Comparative Example 3, the contents of hinokitiol and aluminum lactate are the same, but when the ratio of aluminum lactate to 100 parts by weight of ε-aminocaproic acid is less than 25 parts by weight, hinokitiol is not contained. It was confirmed to be stable. In particular, the ratio of aluminum lactate to 100 parts by weight of hinokitiol is 500 to 2500 parts by weight, the ratio of aluminum lactate to 100 parts by weight of ε-aminocaproic acid is 50 to 250 parts by weight, and the content of aluminum lactate is 0. It was confirmed that the stability of both hinokitiol and ε-aminocaproic acid was excellent when the amount was 1 to 0.5% by weight (Examples 2 to 5, 7 to 9 and 11). Further, ε-aminocaproic acid tends to be destabilized by aluminum lactate, and in Examples 2 to 4 and 7 to 9, ε-aminocaproic acid equivalent to Comparative Example 1 containing no aluminum lactate was used. Was shown, and the stability of hinokitiol was also excellent.

The unit of the content of each component in the table is% by weight.

The unit of the content of each component in the table is% by weight.

Production Examples 1-10 (toothpaste)
A toothpaste having the composition shown in Table 3 was produced. In each toothpaste, destabilization of hinokitiol and ε-aminocaproic acid could be suppressed.

The unit of the content of each component in the table is% by weight.

Production Example 11 (liquid dentifrice)
A liquid dentifrice having the composition shown in Table 4 was produced. Also in this liquid dentifrice, destabilization of hinokitiol and ε-aminocaproic acid could be suppressed.

The unit of the content of each component in the table is% by weight.

Claims (2)

(A) Hinokitiol, (B) ε-aminocaproic acid and/or a salt thereof, and (C) containing aluminum lactate,
250 to 2500 parts by weight of the component (C) is contained with respect to 100 parts by weight of the component (A) ,
The component (C) is contained in an amount of 25 to 250 parts by weight, the component (A) is contained in an amount of 0.01 to 0.2% by weight, and the component (B) is contained in an amount of 0 to 100 parts by weight of the component (B). A composition for oral cavity containing 0.05 to 0.5% by weight and 0.05 to 1% by weight of the component (C) . The oral composition according to claim 1, which is a liquid dentifrice, a toothpaste, a moisturizing dentifrice, or a mouthwash.