JP7605720B2 - Composition containing a copper compound, a zinc compound, and L-menthol - Google Patents

Description

The present invention relates to a composition that is effective against bacteria that cause bad breath and periodontal disease, and can prevent or improve bad breath and/or periodontal disease.

Unpleasant odors emanating from the oral cavity make people around you feel uncomfortable and are an obstacle to social communication. Because reducing bad breath leads to overall health as well as maintaining good social communication, research and development has been carried out from various perspectives on substances that reduce bad breath.

Periodontal disease is an inflammatory disease caused by bacterial infection. Periodontal disease not only leads to tooth loss, but also has been shown to have toxic effects on the digestive tract when periodontal disease bacteria are swallowed, changes to the intestinal flora, and even to invade the blood circulatory system directly from periodontal tissues, causing damage to blood vessels and various organs.

It is well known that in most cases, bad breath is caused by volatile sulfur compounds (VSCs) such as methyl mercaptan, hydrogen sulfide, and dimethyl sulfide. These volatile sulfur compounds are produced by the metabolism of anaerobic bacteria living in the oral cavity. In particular, bacteria such as Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythensis, Campylobacter rectus, Treponema denticola, and Fusobacterium nucleatum, which are also pathogenic bacteria of periodontal disease, are said to have a high VSC production ability, and therefore the oral cavity of patients with periodontal disease produces a particularly strong malodor.
VSCs, the substances that cause bad breath, are produced when oral bacteria metabolize substrates such as cysteine and methionine present in proteins and sloughed epithelial cells in saliva, or in food residues. To fundamentally prevent bad breath, it is essential to kill or inhibit the proliferation of oral bacteria, just as with periodontal disease.

Copper compounds and zinc compounds are known to have antibacterial properties (Patent Document 1), and a toothpaste that contains copper gluconate and zinc chloride, as well as xanthan gum or hydroxyethyl cellulose, and has improved astringent properties and spinnability is known (Patent Document 2).

Regarding menthol, a technology has been disclosed in which food flavoring ingredients, such as peppermint oil, which contains menthol as a main component, are used as antibacterial agents (Patent Document 3).

However, it has not been known that the combined use of copper compounds, zinc compounds, and L-menthol can dramatically kill or inhibit the proliferation of bacteria that cause bad breath and periodontal disease.

JP 2013-001701 A JP 2011-105682 A JP 2004-018470 A

The objective of the present invention is to provide a composition that can prevent or improve bad breath and/or periodontal disease by killing or inhibiting the growth of bacteria that cause bad breath and periodontal disease.

In the course of intensive research to solve these problems, the inventors discovered that a combination of a copper compound, a zinc compound, and L-menthol exhibits excellent antibacterial and saliva secretion effects, leading to the completion of the present invention. In other words, the present invention is a composition for preventing or improving bad breath and/or periodontal disease, which contains a copper compound, a zinc compound, and L-menthol.

That is, the present invention relates to the following (1) to (5).
(1) An oral composition comprising a copper compound, a zinc compound, and L-menthol.
(2) The composition according to (1), wherein the copper compound is one or more selected from the group consisting of copper sulfate, copper gluconate, copper chlorophyllin sodium, and copper chlorophyll.
(3) The composition according to (1) or (2), wherein the zinc compound is one or more selected from the group consisting of zinc oxide, zinc carbonate, zinc chloride, zinc sulfate, zinc gluconate, zinc undecylenate, low-temperature calcined zinc oxide, zinc paraphenolsulfonate, zinc palmitate, zinc pyrithione, zinc myristate, and zinc laurate.
(4) The composition according to (1), wherein the copper compound is copper gluconate and the zinc compound is zinc chloride.
(5) A composition according to any one of (1) to (4) for use in the prevention or amelioration of bad breath and/or periodontal disease.

According to the present invention, it is possible to provide a composition for preventing or improving bad breath and/or periodontal disease, which has an excellent antibacterial effect. The composition of the present invention kills or inhibits the growth of bacteria that cause bad breath and periodontal disease in the oral cavity, and the saliva produced by the saliva secretion-promoting effect of the composition of the present invention kills or inhibits the growth of the above-mentioned causative bacteria.

The concentrations of bacteria when cultured for 24 hours are shown for the following culture solutions: culture solution containing only bacteria (control); culture solution containing 0.001% copper gluconate, 0.01% zinc chloride, or 0.001% L-menthol added to the bacteria solution; culture solution containing 0.001% copper gluconate and 0.01% zinc chloride added; and culture solution containing 0.001% copper gluconate, 0.01% zinc chloride, and 0.001% L-menthol plus the test substance added. The results of the total saliva secretion volume for 30 minutes after administration of the vehicle alone (control), a solution containing copper gluconate and zinc chloride, and a solution containing copper gluconate, zinc chloride, and L-menthol are shown.

In the present invention, "prevention" means preventing the onset of bad breath and/or periodontal disease by killing the bacteria that cause bad breath and periodontal disease or inhibiting the growth of the bacteria.

In the present invention, "improvement" means alleviating the symptoms of bad breath and/or periodontal disease by reducing the bacteria that cause bad breath and periodontal disease.

The "copper compound" used in the present invention refers to an inorganic or organic salt of copper, and may be any salt that is used as a raw material for pharmaceuticals, foods, and cosmetics, such as copper oxide, copper borate, copper carbonate, copper fluoride, copper iodate, copper chloride, copper sulfate, copper nitrate, copper acetate, copper lactate, copper butyrate, copper formate, copper citrate, copper phosphate, copper gluconate, copper aspartate, copper glutamate, copper propionate, copper oxalate, copper phytate, copper tartrate, copper malate, copper succinate, copper malonate, copper maleate, copper benzoate, copper salicylate, and copper fumarate. , copper glycerate, copper glycerophosphate, copper glycolate, copper picolinate, copper ascorbate, copper bisglycinate, copper lysinate, copper methionine, copper pyrophosphate, copper oleate, copper stearate, copper lauroyl sarcosine, copper fluorosilicate, copper fluoroborate, zinc undecylenate, copper chlorophyllin sodium, or copper chlorophyll, and the like are preferred, copper sulfate, copper gluconate, copper chlorophyllin sodium, or copper chlorophyll is more preferred.

The "zinc compound" used in the present invention refers to an inorganic or organic salt of zinc, and may be any salt that is used as a raw material for pharmaceuticals, foods, and cosmetics, such as zinc oxide, zinc borate, zinc carbonate, zinc fluoride, zinc iodate, zinc chloride, zinc sulfate, zinc nitrate, zinc acetate, zinc lactate, zinc butyrate, zinc formate, zinc citrate, zinc phosphate, zinc gluconate, zinc aspartate, zinc glutamate, zinc propionate, zinc oxalate, zinc phytate, zinc tartrate, zinc malate, zinc succinate, zinc malonate, zinc maleate, zinc benzoate, zinc salicylate, zinc fumarate, zinc glycerate ... Examples include zinc lyserophosphate, zinc glycolate, zinc picolinate, zinc ascorbate, zinc bisglycinate, zinc lysinate, zinc methionine, zinc pyrophosphate, zinc oleate, zinc stearate, zinc lauroyl sarcosine, zinc fluorosilicate, zinc fluoroborate, and zinc undecylenate. Preferred examples include zinc oxide, zinc carbonate, zinc chloride, zinc sulfate, zinc gluconate, zinc undecylenate, low-temperature calcined zinc oxide, zinc paraphenolsulfonate, zinc palmitate, zinc pyrithione, zinc myristate, and zinc laurate. More preferred examples include zinc chloride.

The "L-menthol" used in the present invention may be L-menthol alone, or a cooling agent or fragrance containing L-menthol may be used.
The above-mentioned "copper compound", "zinc compound" and "L-menthol" used in the present invention are commercially available as quasi-drugs, foods or cosmetic raw materials and can be easily obtained, or can be produced by known methods.

The present invention is used as medicines, quasi-drugs, cosmetics, etc.

The form of the present invention and the method of application to the oral cavity are not particularly limited. Examples include mouthwash (mouth rinse), toothpaste, liquid toothpaste, tooth powder, gum, lozenge, buccal tablet, gingival adhesive tape preparation, oral gel preparation, oral ointment, oral spray, oral paste, oral paste, oral pill, oral tablet, oral powder, oral powder, oral liquid, oral suspension, oral emulsion, oral granule, and oral capsule. Mouthwash (mouth rinse), toothpaste, liquid toothpaste, or tooth powder are preferred.

In the present invention, the amount of the copper compound in the composition is preferably 0.001 to 10% by weight, and more preferably 0.01 to 1% by weight.

In the present invention, the concentration of the zinc compound in the composition is preferably 0.001 to 1% by weight, and more preferably 0.01 to 0.1% by weight.

In the present invention, the amount of L-menthol in the composition is preferably 0.001 to 5% by weight, and more preferably 0.01 to 1% by weight.

In the present invention, the copper compound, zinc compound, and L-menthol can be mixed in any ratio.

In the present invention, moistening agents, pH adjusters, flavoring agents, preservatives, fragrances, solubilizers, etc. can be added as appropriate.

The humectant may be any one that is commercially available as a pharmaceutical, food, or cosmetic ingredient, such as polyhydric alcohol, or more specifically, sorbitol, glycerin, concentrated glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, propanediol (1,3-propanediol), polyethylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, trehalose, sodium hyaluronate, hydrolyzed collagen, etc., and one or a combination of two or more of these may be appropriately selected and blended as required.

The pH of the composition for periodontal disease or bad breath of the present invention is preferably in the range of 4.5 to 8.0. Examples of pH adjusters that can be used in the present invention include phosphoric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, citric acid, malic acid, pyrophosphoric acid, tartaric acid, acetic acid or salts thereof, sodium hydroxide, etc. One or a combination of two or more of these can be appropriately selected and blended as necessary.

Examples of flavoring agents include saccharin, saccharin sodium, disodium glycyrrhizinate, trisodium glycyrrhizinate, sucrose, glucose, fructose, lactose, honey, aspartame, stevia, sucralose, xylitol, inositol, D-sorbitol, D-mannitol, raffinose, lactulose, lactitol, erythritol, reduced palatinose, palatinose, palatinit, acesulfame K, maltose, maltosyl trehalose, and maltitol. One or more of these may be appropriately selected and blended.

Examples of preservatives include parabens (paraoxybenzoic acid esters) such as methylparaben, ethylparaben, isopropylparaben, propylparaben, butylparaben, isobutylparaben, and benzylparaben; alcohols such as phenoxyethanol and ethanol; and sorbic acid, benzoic acid, dehydroacetic acid, propionic acid, and salts thereof. One or a combination of two or more of these may be appropriately selected and blended.

Examples of flavorings include L-menthol, peppermint, spearmint, or fruit flavorings, peppermint oil, etc. Flavorings also have the advantage of stimulating saliva secretion. One or a combination of two or more of these can be appropriately selected and blended.

A solubilizer may be added to promote dissolution of the additives and medicinal ingredients in water, which is the main base of the present invention. Examples of such solubilizers include polyhydric alcohols such as propylene glycol, dipropylene glycol, butylene glycol, and polyethylene glycol. One or a combination of two or more of these may be appropriately selected and blended.

In addition, abrasives, foaming agents, and thickening agents are used appropriately in toothpastes and ointments.

The present invention can further contain medicinal ingredients such as antibacterial agents, anti-inflammatory agents, fluoride, vitamins, herbal extracts, and plaque decomposing enzymes. There are no particular limitations on these medicinal ingredients as long as they can be used in pharmaceuticals, etc.

The present invention will be described in more detail below with reference to examples and formulation examples, but the scope of the present invention is not limited to these.

(Example 1) Growth inhibition test of bacteria causing bad breath (1) Test substances Copper gluconate (hereinafter, GCu) and zinc chloride (hereinafter, ZnCl ₂ ) manufactured by Wako Pure Chemical Industries, Ltd., and L-menthol (hereinafter, Men) manufactured by Suzuki Mint Co., Ltd. were used.
(2) Test Bacterial Strain In this test, Prevotella intermedia ATCC 25611, which is well known as a causative bacterium of halitosis and periodontal disease, was used.
(3) Test method: Preparation of bacterial solution
Prevotella intermedia was cultured anaerobically on an Anaerobia rabbit blood agar medium (Becton Dickinson Japan) at 35°C for 48-72 hours, then suspended in sterile saline to prepare a bacterial suspension of approximately 3.0 x 10 ⁸ CFU/mL. A bacterial suspension was then prepared in GAM broth to give a bacterial concentration of approximately 10 ⁷ CFU/mL.
(4) Test method: Preparation of test solution The test substances copper gluconate, zinc chloride, and L-menthol were prepared in a medium to give the respective final concentrations, and 0.1 volume of Prevotella intermedia bacterial solution was added to 9.9 volumes of the medium to prepare a test solution. After culturing the solution for 24 hours under anaerobic conditions at 35°C, the viable cell count per 1 mL (CFU/mL) was measured.
(5) Test Results The results of measuring the viable cell count for each test substance and the control (bacterial solution only) are shown in Table 1 and Figure 1, respectively. Table 1 and Figure 1 show the unexpected result that the combined use of copper gluconate (GCu), zinc chloride (ZnCl ₂ ) and L-menthol (Men) dramatically exerts an excellent antibacterial effect against the bacteria that cause bad breath and periodontal disease.

(Example 2) Saliva secretion promoting activity test (1) Test substance Copper gluconate and zinc chloride manufactured by Wako Pure Chemical Industries, Ltd., and L-menthol manufactured by Suzuki Mint were used.
(2) Animals Used Slc:Wistar male rats (6-week-old, Japan SLC Co., Ltd.) were purchased, quarantined, and acclimatized.
(3) Test method After the quarantine and acclimation period (7 days), rats were anesthetized by intraperitoneal administration of urethane (1 g/kg) and α-chloralose (25 mg/kg). A tracheal cannula was inserted to secure the airway, and the esophagus was ligated with suture to prevent the administered solution from entering the stomach.
Next, a test substance administration solution prepared by using a mixture of 4 mg/mL copper gluconate and 10 mg/mL zinc chloride in a vehicle (4% aqueous solution of sodium carboxymethylcellulose: referred to as CMC aqueous solution) was administered in an amount of 100 μL into the oral cavity using a micropipette.
Similarly, a test substance administration solution prepared using a mixture of 4 mg/mL copper gluconate, 10 mg/mL zinc chloride, and 10 mg/mL L-menthol as a vehicle (4% aqueous carboxymethylcellulose sodium solution: referred to as CMC aqueous solution) was administered in an amount of 100 μL into the oral cavity using a micropipette.
As a control, a vehicle (aqueous 4% CMC solution) was administered into the oral cavity in the same amount (100 μL) as that of the test substance.
Ten minutes after administration of the vehicle or test substance, the vehicle or test solution in the oral cavity was wiped off with a cotton ball whose tare weight had been measured. The amount of saliva secreted during administration was estimated by subtracting the weight of the cotton ball and the vehicle or test substance administration solution from the weight after wiping.
Immediately after wiping the vehicle or administration solution from the oral cavity, a cotton ball with a measured tare weight was placed in the oral cavity. For each group, the cotton ball was replaced every 10 minutes, and the amount of saliva secreted was measured by subtracting the weight of the replaced cotton ball from the weight of the new cotton ball. Measurements were continued for up to 30 minutes.
(4) Test Results The results of measuring the total saliva secretion volume for 30 minutes after administration of each test substance and control (vehicle) (n=6 for each) are shown in Table 2 and FIG. 2, respectively.
As shown in Table 2 and FIG. 2, the unexpected result was that the combined use of copper gluconate, zinc chloride and L-menthol exhibited an excellent saliva secretion promoting effect of about 400 times as much as the control.

(Formulation Examples 1, 2, 3, 4, 5) Dentifrice Using the ingredients and amounts shown in Table 3, a paste-like dentifrice is prepared according to a conventional method.

(Formulation Examples 6, 7, 8, 9, 10) Mouthwash Mouthwashes are prepared according to conventional methods using the ingredients and amounts shown in Table 4.

(Formulation Example 11) Oral ointment The ingredients and amounts shown in Table 5 are taken and an oral ointment is prepared according to a conventional method.

(Formulation Example 12) Troches Using the ingredients and amounts in Table 6, troches are prepared in accordance with the section on "Troches" of the Japanese Pharmacopoeia General Provisions for Preparations.

(Formulation Example 13) Tablets for oral administration The ingredients and amounts in Table 7 are taken and tablets for oral administration are produced in accordance with the section on "Tablets for oral administration" of the Japanese Pharmacopoeia General Provisions for Preparations.

Claims (1)

An oral composition containing copper gluconate, zinc chloride, and L-menthol, which is used on a subject carrying Prevotella intermedia, a bacterium that causes bad breath and/or periodontal disease , the oral composition being for killing or inhibiting the growth of Prevotella intermedia, preventing or ameliorating bad breath and/or periodontal disease , and promoting saliva secretion .