JP2003528902A - Composition - Google Patents

Abstract

  (57) [Summary] An oral hygiene composition comprising chlorhexidine for the treatment of halitosis is described.

Description

Detailed Description of the Invention

The present invention relates to an oral hygiene composition for removing bad breath, which contains chlorhexidine, which is a cationic antibacterial agent.

Cationic antibacterial agents, such as chlorhexidine, have their natural in vitro
It has long been recognized as an effective therapeutic agent for treating various oral health conditions such as plaque, tooth decay, periodontal disease and halitosis because of its antibacterial activity and stainability to oral tissues. Cationic antimicrobial agents are therefore absorbed on the oral surface and slowly released over a period of time, producing a long-lasting antimicrobial effect.

EP-A-920857 contains 0.025-0.20% by weight of chlorhexidine salt and 0.025-0.10.
Wt% quaternary ammonium salt (eg cetylpyridinium chloride), 100-100
An oral composition for the treatment of halitosis is described which comprises a combination with a zinc or copper salt which provides 0 ppm of zinc or copper ion.

WO-00 / 51559 (published on September 8, 2000 after the priority date of the present application) contains 0.005-0.05% w / v selected from bisguanides and quaternary ammonium compounds.
Mouthwash compositions for the treatment of halitosis comprising an antibacterial agent according to claim 1 and 0.05-0.5% w / v zinc acetate.

It has now been found that particularly low concentrations of chlorhexidine are surprisingly effective in removing halitosis.

Accordingly, a first aspect of the invention is an oral cavity comprising chlorhexidine or an orally acceptable addition salt thereof at a concentration of less than 0.025% by weight of the total composition, and an orally acceptable carrier or excipient. Hygiene compositions are provided. However, when the oral hygiene composition is a mouthwash composition, 0.05 to 0.5% w / v zinc acetate is not included.

In a second aspect, the present invention provides the use of chlorhexidine or an orally acceptable addition salt thereof in the manufacture of an oral hygiene composition for the removal of halitosis as described above.

[0008] In a third aspect, the present invention provides a method for removing halitosis by administering an oral hygiene composition as described above to a patient in need of eliminating halitosis.

Suitably the chlorhexidine or orally acceptable addition salt thereof is 0.001 to 0.024% by weight of the oral hygiene composition, preferably 0.002 to 0.020% by weight, more preferably 0.
It is present in an amount of 005 to 0.015% by weight.

Suitably, the oral hygiene composition is free of zinc or copper salts. Preferably, chlorhexidine or an orally acceptable addition salt thereof is present as the only antibacterial agent.

Such suitable chlorhexidine salts have a solubility of at least 0.005% w / v at 20 ° C., for example digluconate, diformate, diacetate, dipropionate, diiodide. Includes hydrohydrates, dihydrochlorides, dilactates, dinitrates, sulphates and tartrates. Of these, digluconate, diacetate and dihydrochloride are preferred.

The oral hygiene composition of the present invention can also effectively contain an ionic fluorine-containing compound. Preferred ionic fluorine-containing compounds include, for example, fluoride salts such as amine fluorides and alkali metal fluoride salts (eg sodium fluoride),
And monofluorophosphates such as alkali metal monofluorophosphates (eg sodium monofluorophosphate). Suitably, the ionic fluorine-containing compound is incorporated into the above composition to provide 100-3000 ppm, preferably 500-2000 ppm, of fluoride ion.

The oral hygiene composition of the present invention comprises a presentation form commonly used in such products, such as dentifrices including toothpaste and toothpaste, abrasive and non-abrasive gels, mouthwashes, mouthwashes, It can be provided in any of the user's licking or chewing presentation forms such as mouthwash, mouth spray, and gums, troches, lozenges and wafers that can be quickly melted in the mouth. The components of the orally acceptable carrier or excipient are selected according to the particular type of presentation form involved.

In order to ensure that the antibacterial activity of the cationic antibacterial agent is not substantially reduced, compatible components are selected for inclusion in an orally acceptable carrier or excipient. As will be appreciated by those skilled in the art. Thus, one of ordinary skill in the art will readily understand that anionic species should preferably be avoided when necessary. This is because such species may cause inactivation of the cationic antimicrobial agent by forming an insoluble precipitate with the cationic antimicrobial agent. For this reason, preferably anionic surfactants and anionic thickeners should be excluded and non-anionic, cationic or amphoteric surfactants and non-ionic thickeners such as non-anionic thickeners should be excluded. Use ionic counterparts. Similarly, abrasives that can act as a source of anions are either slightly soluble or are substantially insoluble but are themselves contaminated, for example, by soluble impurities resulting from their manufacture. For reasons it is preferable to avoid and use compatible abrasives.

Preferred nonionic surfactants include, by way of example, polyethoxylated sorbitol esters, especially polyethoxylated sorbitol monoesters, for example
PEG (40) sorbitan diisostearate and a product marketed by ICI under the trade name "Tween"; a polycondensate of ethylene oxide and propylene oxide (poloxamer), eg BASF-Wyandotte under the trade name "Pluronic". Commercially available products from the company; propylene glycol condensates; polyethoxylated hydrogenated castor oils such as cremophors; and sorbitan fatty esters.

Suitable amphoteric surfactants include, by way of example, long-chain imidazoline derivatives, such as the product marketed by the company Miranol under the trademark "Miranol C2M"; long-chain alkylbetaines, such as "Empigen BB". Products available from Albright + Wilson, Inc., and long chain alkylamidoalkyl betaines such as cocamidopropyl betaine, and mixtures thereof.

Suitable cationic surfactants include ethyl-N-cocoyl-L-alginate D, L-2-pyrrolidone-5-carboxylic acid commercially available from Ajinomoto under the trade name "CAE". Contains salt.

Advantageously, the surfactant is present in the range of 0.005 to 20% by weight of the dentifrice, preferably 0.1 to 10% by weight, more preferably 0.1 to 5% by weight.

Suitable nonionic thickeners include, for example, (C1-6) -alkyl cellulose ethers (eg methylcellulose), hydroxy (C1-6) -alkyl cellulose ethers (
Examples include hydroxypropyl cellulose), (C2-6) -alkylene oxide modified (C1-6) -alkyl cellulose ethers (eg, hydroxypropyl methylcellulose), and mixtures thereof. Advantageously, the nonionic thickener is present in the range 0.01 to 30% by weight of the composition, preferably 0.1 to 15% by weight, more preferably 1 to 5% by weight.

Suitable abrasives include sparingly soluble salts or substantially insoluble compounds in combination with substances that suppress the formation of anions.

Suitable sparingly soluble salts that can be used as abrasives are, for example, calcium carbonate, calcium phosphate, magnesium carbonate, insoluble sodium metaphosphate, and suitable mixtures thereof. The substance that suppresses the formation of anions is typically a cation that may form a substantially insoluble or sparingly soluble salt with the anion of the polishing agent (which may be the same as the cation of the polishing agent). Water-soluble salts including are included. Preferably,
The sparingly soluble salt used as an abrasive is calcium carbonate, which is advantageously used in combination with dicalcium phosphate, which also effectively buffers the pH of the formulation. Suitable types of calcium carbonate include both natural and synthetic chalk. The substance that suppresses anion formation may be an alkaline earth metal salt such as calcium chloride. This material is preferably present in 0.0001 to 1% by weight of the dentifrice, more preferably 0.005 to 0.1% by weight.

As used herein, "substantially insoluble compound" means a compound that is originally insoluble in aqueous solution, "Handbook of Chemistry and Physics", 48th Edition, Chemical Rubber Compamy, B. Chapter, “Physical Constants of Inorganic Compounds”
nts of Inorganic Compounds) ”include compounds listed as“ insoluble ”in cold water. Furthermore, such compounds, when used as abrasives,
It will contain very little, if any, contaminating anionic impurities. Suitably, the anionic impurities contained in the insoluble abrasive compound should be less than 1%, preferably less than 0.5%, more preferably less than 0.25%, based on the weight of the abrasive. Substantially insoluble compounds suitable for use as abrasives include, for example, silica, zinc orthophosphate, plastic particles, alumina, aluminum oxide trihydrate and calcium pyrophosphate, or mixtures thereof.

Suitably, the abrasive is silica. Suitable silicas include natural amorphous silica,
For example, diatomaceous earth; and synthetic amorphous silica, such as precipitated silica, or silica gel (eg silica xerogel); or mixtures thereof. Preferred synthetic amorphous silicas have low levels of water-soluble anionic impurities (hereinafter "low anionic silica"). These can be obtained from a carefully controlled manufacturing process to keep the levels of anionic impurities (sulfate and silicate, respectively from sodium sulfate and sodium silicate, respectively) to a minimum. Alternatively or additionally, the level of anionic impurities can be reduced to the required level by carefully washing the initially produced silica with, for example, deionized or distilled water. Suitable low anion silica is less than 0.5% by weight, preferably 0.25% by weight
Less than 0.1% by weight, more preferably less than 0.1% by weight of water-soluble impurities such as sodium sulphate and / or sodium silicate.

The abrasive is advantageously present in the range of 1 to 80% by weight of the dentifrice, preferably 5 to 70% and more preferably 5 to 60%.

Each of the thickeners, surfactants and abrasives should be compatible with the cationic antimicrobial agent at the level used in dentifrice. That is, each should not substantially reduce the efficacy of the cationic antimicrobial agent, eg, by more than 30%, preferably by more than 20%. This is achieved, for example, by the conventional microbial assay using M. luteus as the assay organism in the standard agar diffusion method in the presence and absence of each of the aforementioned thickeners, surfactants and abrasives. It can be confirmed by measuring the biological activity of.

The mouthwash according to the present invention preferably comprises, as components of the carrier, a surfactant and a wetting agent in an aqueous solution or a water / ethanol solution. The gel according to the invention preferably comprises, as a component of the carrier, a surface-active agent, a wetting agent, a thickener and optionally water. The dentifrice according to the present invention comprises, as components of the carrier, surfactants, wetting agents, thickeners,
It is preferable to contain an abrasive and optionally water.

Suitable wetting agents for use in the compositions of the present invention include, for example, glycerin, sorbitol, propylene glycol or polyethylene glycol, or mixtures thereof. The humectant is 5 to 70% by weight of the dentifrice, preferably 5 to 30%.
It may be present in the range of wt%, more preferably 10 to 30 wt%.

If desired, other substances such as sweeteners, flavoring agents, coloring agents and whitening agents, preservatives and emulsifiers may be added to the composition.

The pH of the composition according to the invention is within the orally acceptable range, typically the pH
It is in the range of 4-9.

The oral hygiene composition according to the invention is prepared by mixing the components thereof in the required proportions and in any convenient order, and then adjusting the pH, if necessary, to the required value. You can

[0031]   The invention will be illustrated by the following examples.

Example 1 Measurement of Halitosis Suppressing Efficacy The ability of low doses of chlorhexidine to eliminate halitosis (oral malodor) was evaluated using the cysteine challenge method. This method
It is a method of measuring the ability of oral bacteria to produce volatile sulfur compounds (VSC), which is the main odor component of the malodor in the oral cavity, from cysteine and correlating it with the sensory evaluation by odor examiners.

The test consists of rinsing the mouth for 30 seconds with 5 ml of 6 mM cysteine and the resulting VS
It consists of measuring the C reaction (mainly hydrogen sulfide) with a chemical sensor device such as a Halimeter. The cysteine challenge test consists of determining an initial baseline VSC, followed by introduction of a cysteine challenge substrate, measurement of the VSC response over 20 minutes, introduction of a test rinse, and then at a set time. It consists of repeating cysteine challenges through time.

The inhibition of halitosis was quantitatively evaluated by the degree of inhibition of VSC production from cysteine by chlorhexidine digluconate, which is a test agent, compared with the reference VSC production from cysteine. The duration of inhibition was VS vs. consecutive cysteine challenges.
It was evaluated as the time required for C generation to return to the reference VSC generation.

A mouthwash containing chlorhexidine digluconate at a concentration of 0.025% (v / v)
It was found that VSC production was significantly suppressed. Maximum inhibition was seen 2 hours after rinsing, and inhibition was maintained for 7 hours after the first rinse, with progressively decreasing levels. Lower concentrations (eg 0.020, 0.015, 0.0125 and 0.010% by weight of the composition)
The same advantageous results are obtained with chlorhexidine digluconate.

Example 2: Low dose chlorhexidine mouthwash % W / W Chlorhexidine digluconate 0.0125 Sorbitol 3.0 Ethanol 96% 6.0 Cremophor RH60 0.20 Perfume oil 0.12 Dye solution 0.10 Saccharin sodium 0.01 Water Total 100

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, C A, CH, CN, CO, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (12)

[Claims] 1. An oral hygiene composition comprising chlorhexidine or an orally acceptable addition salt thereof at a concentration lower than 0.025% by weight of the total composition, and an orally acceptable carrier or excipient. When the hygiene composition is a mouthwash composition,
The above oral hygiene composition, provided that it does not contain 0.05-0.5% w / v zinc acetate. 2. The composition of claim 1, wherein chlorhexidine or orally acceptable addition salt thereof is present in an amount of 0.001 to 0.024% by weight of the oral hygiene composition. 3. A composition according to claim 2 wherein chlorhexidine or orally acceptable addition salt thereof is present in an amount of 0.002-0.020% by weight of the oral hygiene composition. 4. The composition according to claim 3, wherein chlorhexidine or orally acceptable addition salt thereof is present in an amount of 0.005 to 0.015% by weight of the oral hygiene composition. 5. The composition according to claim 1, which is free of zinc salt or copper salt. 6. The composition according to claim 1, wherein chlorhexidine or an orally acceptable addition salt thereof is present as the only antibacterial agent. 7. The composition according to claim 1, wherein chlorhexidine is present as a digluconate salt. 8. A composition according to claim 1, which is in the form of a mouthwash, mouthwash, mouthwash solution or mouth spray. 9. The composition according to claim 1, which is in the form of a dentifrice. 10. A composition according to any one of claims 1 to 7 for licking or chewing by a user. 11. Use of chlorhexidine or an orally acceptable addition salt thereof in the manufacture of the oral hygiene composition according to any one of claims 1 to 10 for removing halitosis. 12. A method for removing halitosis by administering the oral hygiene composition according to any one of claims 1 to 10 to a patient in need of removing halitosis.