EP1536759A1 - Oral care composition comprising tropolone compounds and essential oils - Google Patents
Oral care composition comprising tropolone compounds and essential oilsInfo
- Publication number
- EP1536759A1 EP1536759A1 EP03766579A EP03766579A EP1536759A1 EP 1536759 A1 EP1536759 A1 EP 1536759A1 EP 03766579 A EP03766579 A EP 03766579A EP 03766579 A EP03766579 A EP 03766579A EP 1536759 A1 EP1536759 A1 EP 1536759A1
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- European Patent Office
- Prior art keywords
- oil
- group
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- composition
- oral care
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/298—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with manganese derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/707—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a three- to five-membered ring
Definitions
- the present invention is related generally to oral care compositions, more particularly to oral care compositions comprising substituted tropolone compounds and essential oils, and methods of using the same for oral care.
- Oral malodor, plaque, gingivitis, periodontal disease, and discoloration of the teeth are all undesirable conditions that affect many people.
- First malodor of the oral cavity also known as halitosis or bad breath, has been broadly estimated to afflict 20 to 90 million individuals in the US. It is generally believed that the presence of anaerobic bacteria, especially gram-negative anaerobic bacteria, in the mouth contributes to this condition.
- Other oral conditions caused by microorganisms include periodontal disease, tooth decay, inflammation and the like.
- Periodontal disease is a major cause of tooth loss in adults, and can manifest itself in people as young as age 12. Periodontal disease affects the periodontum, which is the investing and supporting tissues surrounding a tooth (i.e., the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontatitis are disorders of the gingiva and the deeper periodontal tissues, respectively. Periodontal disease is generally associated with the accumulation of plaque on the teeth. The teeth are coated with a salivary proteinaceous material (pellicle) and thereafter streptococci adhere to this coating. Gingivitis is generally caused by dental plaque, and periodontatitis is caused by the infection spreading to the periodontal pocket or space between the gingival and the tooth root.
- compositions including toothpastes, mouthwashes, rinses and tooth gels are formulated to clean the oral cavity and kill pathogenic microbes.
- Such oral care compositions are typically formulated with one or more antimicrobial agents to suppress the microorganisms that contribute both to the initiation and progression of oral malodor, periodontal disease and other undesirable oral conditions.
- Current oral care compositions comprise antimicrobial agents and are formulated to maximize the kinetics of the antimicrobial agent. The antimicrobial agents are dissolved to provide effective prevention of bad breath, eradication of oral microbes, and penetration, reduction, and elimination of plaque and gingivitis.
- thymol also known as an essential oil, which is utilized for its antimicrobial activity in a range of oral care preparations.
- thymol has been utilized in oral hygiene compositions such as mouthwashes in sufficient quantities to provide desired beneficial therapeutic effects.
- LISTERINE® Brand mouth rinse is a well-known antiseptic mouthwash that has been used by millions of people for over one hundred years and has been proven effective in killing microbes in the oral cavity that are responsible for plaque, gingivitis, and bad breath.
- Thymol and other essential oils such as methyl salicylate, menthol, and eucalyptol, are active ingredients (e.g., antimicrobial agents) in antiseptic mouth rinses such as LISTERINE®.
- the present invention relates to oral care compositions and methods of using the same for preventing or treating diseases or conditions of the oral cavity in warm-blooded animals including humans.
- the oral care composition comprises substituted tropolone compounds in combination with one or more essential oils in amounts effective for suppressing or eliminating the presence of harmful pathogenic oral microorganisms in the oral cavity.
- the oral care compositions provide a high level of antimicrobial kinetics and efficacy useful for preventing, among others, plaque, gum disease, and oral malodor.
- the oral care composition can be formulated into a range of oral care products including, but not limited to, toothpastes, tooth gels, tooth powders, mouthwashes, lozenges, chewing gums, tooth strips, dental floss, orally consumable film and mouth spray.
- an oral care composition comprising:
- Ri, R2, R3, R 4 , and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkylene group, an alkenylene group, an alkaryl group, an alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an aliphatic group optionally substituted with 1 to 3 halogens, an aromatic group optionally substituted with 1 to 3 halogens and a carbonyl group, and isomers and pharmaceutically acceptable salts thereof;
- the oral care composition comprises an oral care effective amount of at least one compound of Formula (I) wherein R 2 , R3, and R 5 are each independently selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbons, a hydroxyalkyl group having 1 to 6 carbons, and an alkoxyalkyl group wherein the "alkoxy" portion and the "alkyl” portion each have from 1 to 6 carbons, and Ri and R 4 are each hydrogen.
- R 2 , R3, and R 5 are each independently selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbons, a hydroxyalkyl group having 1 to 6 carbons, and an alkoxyalkyl group wherein the "alkoxy" portion and the "alkyl” portion each have from 1 to 6 carbons, and Ri and R 4 are each hydrogen.
- the essential oil is selected from the group consisting of thymol, eucalyptol, menthol, methyl salicylate, and combinations thereof.
- a method for preventing or treating diseases or conditions of the oral cavity comprising administering an oral care effective amount of the oral care composition of the present invention to a warm-blooded animal including humans.
- the present invention is directed to oral care compositions with antimicrobial efficacy against microorganisms, particularly oral microorganisms responsible for producing undesirable diseases or conditions in the oral cavity, including oral malodor, plaque build-up, and the like, and the resulting tooth and gum diseases that may follow.
- the oral care compositions may be in a form selected from, for example, mouthwashes, toothpastes, tooth powders, dental creams, dental flosses, liquids, gels, chewing gums, liquid center filled gums, mints, lozenges, orally consumable films and the like.
- One preferred aspect of the present invention is directed to an oral care composition containing an effective amount of at least one substituted tropolone compound having antimicrobial activity in combination with one or more essential oils.
- an oral care composition preferably a mouthwash, containing an effective amount of at least one substituted tropolone compound in combination with at least one essential oil.
- Essential oils are volatile aromatic oils which may be synthetic or may be derived from plants by distillation, expression or extraction, and which usually carry the odor or flavor of the plant from which they are obtained. In the oral care composition of the present invention, the essential oils provide antiseptic activity. Some of these essential oils also act as flavoring agents.
- the essential oils of this invention include but are not limited to thymol, menthol, methyl salicylate (wintergreen oil), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl alcohol, citronel, a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalaol, safrola vanillin, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil, cedar leaf oil, gerianol, verbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter almond, chlorothymol, cinnamic aldehyde
- Preferred essential oils are selected from thymol, methyl salicylate, eucalyptol, menthol and combinations thereof.
- the present invention is effective for cleaning the oral cavity and/or treating diseases and conditions of the oral cavity including, but not limited to, gingivitis, periodontitis, oral malodor, tooth decay, and the like.
- the oral care compositions of the present invention provide a high degree of antimicrobial efficacy against microorganisms, particularly pathogenic oral microorganisms, including, but not limited to, Fusobacterium nucleatum, Prevotella intermedia, Actinomyces viscosus, Campylobacter rectus, Porphyromonas gingivalis, Streptococcus sanguis, Streptococcus mutans, Actinobacillus, Bacteroides, Capnocytophaga, Eikenella, Propionibacterium, and Candida albicans responsible for oral malodor and build-up of plaque and calculus and the resulting tooth and gum diseases that may follow.
- Fusobacterium nucleatum Prevotella intermedia
- Actinomyces viscosus Campylobacter rectus
- Porphyromonas gingivalis Streptococcus sanguis
- Streptococcus mutans Streptococcus mutans
- the present invention is also directed to methods of cleaning the oral cavity, and/or treating or preventing diseases or conditions of the oral cavity in warmblooded animals including humans, by applying to the oral cavity an oral care effective amount of the oral care composition of the present invention.
- diseases or conditions of the oral cavity is meant to include diseases of the oral cavity including, but not limited to, periodontal disease, gingivitis, periodontatitis, periodontosis, adult and juvenile periodontatitis, and other inflammatory conditions of the tissues within the oral cavity in warmblooded animals including humans, plus caries, necrotizing ulcerative gingivitis, and other conditions such as oral malodor or disagreeable mouthfeel.
- the compositions and methods of treatment and oral care provided by the present invention are particularly effective for preventing or treating periodontal disease (gingivitis and/or periodontatitis) and oral malodor in warm-blooded animals including humans.
- an oral care composition comprising:
- R-i, R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkylene group, an alkenylene group, an alkaryl group, an alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an aliphatic group optionally substituted with 1 to 3 halogens, an aromatic group optionally substituted with 1 to 3 halogens, and a carbonyl group, and isomers and pharmaceutically acceptable salts thereof;
- the oral care ;omposition comprises an oral care effective amount of at least one compound of Formula (I) wherein R 2 , R3, and R 5 are each independently selected from the group onsisting of hydrogen, an alkyl group having 1 to 6 carbons, a hydroxyalkyl group having 1 to 6 carbons, and an alkoxyalkyl group wherein the "alkoxy" portion and the "alkyl” portion each have from 1 to 6 carbons, and Ri and R are each hydrogen.
- R 2 , R3, and R 5 are each independently selected from the group onsisting of hydrogen, an alkyl group having 1 to 6 carbons, a hydroxyalkyl group having 1 to 6 carbons, and an alkoxyalkyl group wherein the "alkoxy" portion and the "alkyl” portion each have from 1 to 6 carbons, and Ri and R are each hydrogen.
- compounds of Formula (I) or pharmaceutically acceptable salts thereof may be present in the form of addition products with water or various solvents, and these addition products are also included in the scope of the present invention.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. They can be derived from a variety of organic and inorganic cations well known in the art and include, by way of example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and anions, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
- Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trome
- alkyl refers to monovalent straight and branched alkyl groups preferably having from about 1 to 18 carbon atoms, more preferably from about 1 to 14 carbon atoms, and still more preferably from about 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl, and the like.
- alkylene refers to divalent alkylene groups preferably having from about 1 to 18 carbon atoms and more preferably from about 1 to 14 carbon atoms which can be straight or branched.
- the term is exemplified by groups such as methylene (--CH 2 --), ethylene ( ⁇ CH 2 CH 2 ⁇ ), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
- alkaryl refers to -alkylene-aryl groups preferably having from about 1 to 18 carbon atoms in the alkylene moiety and from about 6 to 14 in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl, and the like.
- alkcycloalkyl refers to -alkylene-cycloalkyl- groups preferably having from about 1 to 18 carbons atoms in the alkylene moiety and from about 3 to 14 in the cycloalkyl moiety.
- alkcycloalkyl groups are exemplified by -CH 2 - cyclopropyl, -CH 2 -cyclopentyl, -CH 2 CH 2 -cyclohexyl, and the like.
- alkoxy refers to the group "alkyl-O-".
- the alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, and the like, preferably having from about 1 to 6 carbon atoms.
- alkoxyalkyl refers to the groups “alkyl-O-alkyl-", preferably the alkyl portion of the group has 1 to 6 carbon atoms and the alkoxy portion of the group has 1 to 6 carbon atoms.
- alkenyl refers to alkenyl groups preferably having from about 2 to 18 and more preferably having from about 2 to 14 carbon atoms and having at least 1 and preferably from 1 to 2 sites of alkenyl unsaturation.
- alkynyl refers to alkynyl groups preferably having from about 2 to 18 carbon atoms and more preferably from about 2 to 14 carbon atoms and having at least 1 and preferably 1 to 2 sites of alkynyl unsaturation. Such alkynyl groups
- aryl refers to an unsaturated aromatic carbocyclic groups from about 6 to 18 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Examples of aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the individual substituent, such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, acyloxy, hydroxy, and the like.
- cycloalkyl refers to cyclic alkyl groups of from about 3 to 18 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups.
- Such cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1- methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
- cycloalkenyl refers to cyclic alkenyl groups of from about 4 to 18 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups.
- suitable cycloalkenyl groups include, for instance, cyclopent-3-enyl, cyclohex-2-enyl, cyclooct-3-enyl, and the like.
- Preferred tropolone compounds of Formula (I) for use in the oral care compositions of the present invention include those selected from the group consisting of 2-hydroxy-7-methyl-2,4,6-cycloheptatrien-1 -one; 2-hydroxy-7-heptyl- 2,4,6-cycloheptatrien-1 -one; 2-hydroxy-7-(methoxymethyl)-2,4,6-cycloheptatrien- 1 - one; 2-hydroxy-4-methyl-2,4,6-cycloheptatrien-1 -one; 2-hydroxy-4-dimethylethyl- 2,4,6-cycloheptatrien-1 -one; and 2-hydroxy-7-(hexloxymethyl)-2,4, 6- cycloheptatrien-1 -one, and combinations thereof.
- a cation is a monovalent material such as sodium, potassium or ammonium, but it can also be a multivalent cation in combination with a pharmaceutically acceptable monovalent anion, for example calcium with a chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, acetate, tartate, oxalate, succinate, palmoate, or the like anion; magnesium with such anions; zinc with such anions or the like.
- oral care composition is meant to include products, which are retained in the oral cavity for a sufficient time to contact the dental surfaces and/or oral mucosal tissues and exhibit the desired oral activity.
- oral care effective amount as used herein is meant to be an amount of at least one tropolone compound, sufficient to prevent or treat diseases or conditions of the oral cavity, or to significantly eliminate or at least suppress the presence of undesirable microorganisms in the oral cavity, without causing side effects within the scope of sound medical and dental judgment.
- the oral care effective amount of the tropolone compounds of the present invention may vary with the particular condition (e.g., to treat disease of the oral cavity or malodor) being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific form (i.e., salt) of the tropolone compound employed, and the particular carrier from which the tropolone compound is applied.
- the particular condition e.g., to treat disease of the oral cavity or malodor
- the age and physical condition of the patient being treated e.g., the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific form (i.e., salt) of the tropolone compound employed, and the particular carrier from which the tropolone compound is applied.
- the concentration of the tropolone compounds in the oral care composition of the present invention depends on the type of composition (e.g., toothpaste, mouthwash and rinse, lozenge, gum, etc.) used to apply the tropolone compounds to the gingival/mucosal tissue and/or teeth, due to differences in efficiency of the compositions contacting the tissue and teeth and due also to the amount of the composition generally used.
- the concentration may also depend on the diseases or conditions being treated.
- the oral care compositions of the present invention can include from about 0.001% to 10.0% by weight based on the total weight of the oral care composition, preferably from about 0.01% to 5.0% by weight, and more preferably from about 0.1% to 2.0% by weight of the tropolone compounds of the present invention with the remainder of the formulation being the essential oils, the carrier and other materials known in the art as oral care composition components.
- additional components may include buffers, surfactants, solubilizers, preservatives, emulsifying agents, isotonizers, stabilizers, pH adjusting agents, sweeteners, coloring agents, and the like.
- the oral care composition of the present invention contains an antimicrobial effective amount of an antimicrobial compound having a structure of Formula (I) in combination with one or more antimicrobially-effective essential oils as the active components.
- antimicrobially-effective essential oils may include thymol, menthol, methyl salicylate (wintergreen oil), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl alcohol, citronel, a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalaol, safrola vanillin, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil, cedar leaf oil, ger
- the admixture of the antimicrobial compounds of Formula (I) and antimicrobial essential oils preferably those selected from the group consisting of thymol, menthol, eucalyptol, methyl salicylate, and combinations thereof, provides a synergistic antimicrobial effect.
- the essential oils are used in amounts effective to provide oral care including the elimination or suppression of oral microorganisms in the oral cavity.
- the essential oils may be in the oral care composition of the present invention in an amount of from about 0.001% to 8.0% by weight based on the total weight of the composition; preferably in an amount of from about 0.004% to 3.0% by weight; and more preferably in an amount of from about 0.007% to 2.0% by weight.
- compositions of the present invention generally contain thymol and/or one or more other essential oils.
- the additional essential oils are eucalyptol, menthol, or methyl salicylate, or mixtures thereof.
- the composition contains all four of these essential oils.
- Thymol ((CH 3 ) 2 CHC 6 H3(CH 3 )OH; isopropyl-m-cresol), also known by the chemical formula 5-methyl 2-(1-methylethyl) phenol, is an effective antimicrobial agent, and is typically obtained from the essential oil of Thymus vulgaris Labiatae and Monarda punctata Labiatae. Thymol is a white crystalline powder with an aromatic odor and taste and is soluble in organic solvents but only slightly soluble in deionized water.
- Thymol may be in the oral care composition of this invention in an amount of from about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of from about 0.01% to 0.6% by weight; and more preferably in an amount of from about 0.02% to 0.5% by weight.
- Menthol CH 3 C 6 H9(C3H7)OH; hexylhydroxythymol
- Menthol also possesses antiseptic properties and provides a cooling, tingling sensation.
- Menthol is isolated principally from the oil of Mentha arvensis. In its commercial form, menthol is available as L- menthol crystals obtained from a process involving cooling of the oil.
- Menthol may be in the oral care composition of the present invention in an amount of from about 0.001 % to 2.0% by weight based on the total weight of the composition; preferably in an amount of from about 0.01 % to 0.7% by weight; and more preferably in an amount of from about 0.01% to 0.6% by weight.
- Eucalyptol (C ⁇ oH ⁇ 8 0; cineol), another essential oil with antiseptic properties, is derived from the eucalyptus tree.
- Eucalyptol is a terpene ether that provides a cooling, spicy taste and antiseptic activity. Having a camphoraceous odor and cooling taste, this essential oil is often combined with other essential oils such as menthol in confection formulations to impart medicinal effect.
- Combinations of menthol and eucalyptol are widely used.
- Particularly preferred uses of the menthol- eucaiyptol combination include, according to the present invention, dentifrices such as toothpastes or dental gels.
- Eucalyptol may be in the oral care composition of the present invention in an amount of from about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of from 0.005% to 0.5% by weight; and more preferably in an amount of from about 0.007% to 0.4% by weight.
- Methyl salicylate C 6 H 4 OHCOOCH 3
- wintergreen oil is the main ingredient in many essential oils, constituting about 99% of oil of wintergreen (Gaultheria procumbens) and sweet birch (Betula lenta).
- Methyl salicylate which has a distinctive refreshing aroma, is used widely in mouthwashes, chewing gums and other oral and pharmaceutical preparations.
- Methyl salycylate is capable of providing flavoring and organoleptic flavor tones to the oral care composition together in addition to its antimicrobial function.
- Methyl salicylate may be in the oral care composition of the present invention in an amount of from about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of from about O.004% to 0.6% by weight; and more preferably in an amount of from about 0.01% to 0.6% by weight.
- the oral care composition of the present invention may contain the following essential oils in percentages by weight based on the total weight of the oral care composition: (a) thymol from about 0.001% to 2.0% by weight; (b) menthol from about 0.001 % to 2.0*% by weight; (c) eucalyptol from about 0.001% to 2.0% by weight; and (d) methyl salicylate from about 0.001% to 2.0% by weight.
- the oral care composition may contain the following essential oils in percentages by weight based on the total weight of the oral care composition: (a) thymol from about 0.01 % to 0.6% by weight; (b) menthol from about 0.01% to 0.7% by weight; (c) eucalyptol from about 0.005% to 0.5% by weight; and (d) methyl salicylate from about 0.004% to 0.6% by weight.
- the oral care composition may contain the following essential oils in percentages by weight based on the total weight of the oral care composition: (a) thymol from about 0.02% to 0.5% by weight; (b) menthol from about 0.01% to 0.6% by weight; (c) eucalyptol from about 0.007% to 0.4% by weight; and (d) methyl salicylate from about 0.01 % to 0.6% by weight.
- the oral care compositions of the present invention containing tropolone compounds of Formula (I), and thymol and/or at least one other essential oil provides effective antimicrobial activity.
- the oral care compositions may further comprise other antimicrobial agents if desired.
- Such exemplary antimicrobial agents include chlorhexidine, chitosan, triclosan, cetylpyridiumchlor.de, domiphen bromide, and the like.
- the amount of such antimicrobial agents employed in the composition of this invention can be readily determined by those skilled in the art.
- the carrier for the oral care compositions of the present invention, and particularly for the essential oils containing compositions may be aqueous medium.
- the aqueous medium may be a water-alcohol mixture, generally a water-ethanol or water-1 -propanol mixture.
- the ethanol content level can be from about 0.01 % to 70% by weight based on the total weight of the composition to solubilize and deliver the antimicrobial agents and to provide a clear, aesthetically attractive liquid medium.
- a favorable amount of ethanol for enhancement of the organoleptic cues of the oral care compositions, specifically mouthwash compositions may range from about 0.1% to 30% by weight, more preferably from about 20% to 30% weight, although lesser amounts may be used if desired.
- the aqueous medium is water.
- the oral care compositions may be selected, for example, from the group consisting of mouthwashes or rinses, toothpastes, tooth powders, dental creams, dental flosses, liquids, gels, chewing gums, liquid center filled gums, mints, lozenges, oral film forming dentifrices, orally consumable films and the like.
- compositions of the present invention comprise a pharmaceutically acceptable oral carrier, in an amount appropriate to accommodate the other components of the formulation.
- pharmaceutically acceptable oral carrier refers to a vehicle capable of being mixed with the active components for delivery to the intended target in an oral cavity, and which will not cause harm to warm-blooded animals including humans.
- the oral carriers further include those components of the composition that are capable of being commingled without interaction in a manner which would substantially reduce the composition's stability and/or efficacy for oral care including preventing or treating diseases or conditions of the oral cavity in warm-blooded animals including humans, in accordance with the compositions and methods of the present invention.
- the pharmaceutically acceptable oral carriers of the oral care compositions can include one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for oral administration.
- the carriers or excipients of the present invention may be in any form appropriate to the mode of delivery, for example, solutions, colloidal dispersions, emulsions, suspensions, rinses, gels, foams, powders, solids, and the like, and can include the usual and conventional components of toothpastes (including gels and gels for subgingivial application), mouthwashes and rinses, mouth sprays, chewing gums, orally consumable films and lozenges (including breath mints).
- Carriers suitable for the preparation of compositions of the present invention are well known in the art. Their selection will depend on secondary considerations like taste cost, and shelf stability, etc.
- Types of carriers which may be included in the oral compositions of the present invention are abrasives, fluoride ions, thickening agents, humectants, flavoring and sweetening agents, anticalculus agents, alkali metal bicarbonate salts, surfactants including nonionic and amphoteric surfactants, and anionic surfactants, and miscellaneous carriers such as water, titanium dioxide, anti-inflammatory agents, and the like.
- compositions of the present invention are mouthwashes, rinses, and mouth sprays.
- Components of such mouthwashes, rinses and mouth sprays typically include water being present in an amount of from about 45% to 95% by weight, and one or more of ethanol up to 70%, a humectant up to 50%, a surfactant from about O.01 % to 7%, a flavoring agent from about 0.04% to 2%, a sweetening agent from about 0.1 % to 3%, and a coloring agent from about 0.001% to 0.5%.
- Such mouthwashes, rinses and mouth sprays may also include one or more of an anticaries agent from about 0.05% to 0.3% (e.g., fluoride ion), and an anticalculus agent from about 0.1 % to 3%.
- compositions of the present invention are dental solutions.
- Components of such dental solutions generally include water from about 90% to 99% by weight based on the total weight of the oral care composition, and one or more of a preservative from about 0.01% to 0.5%, a thickening agent up to 5%, a flavoring agent from about 0.1 % to 3%, and a surfactant up to 5%.
- compositions of the present invention are orally consumable films or thin strips.
- Orally consumable films typically comprise a rapidly dissolvable non-self-adhering polymer-based thin film vehicle. Such compositions are typically administered to the oral cavity where they rapidly dissolve upon contact with saliva and provide rapid delivery of the active ingredients.
- LISTERINE ® POCKETPAKSTM brand oral care strip products made by PFIZER, Inc. of Morris Plains, New Jersey are perhaps the most successful examples of an edible film compositions effective in delivering therapeutic agents particularly antimicrobial agents in the form of LISTERINE ® essential oils to the oral cavity.
- Components of such compositions generally include water in an amount up to 75% by weight, a water soluble film forming polymer including, but not limited to, pullulan, in an amount of up to 25%, a flavoring agent in an amount of from about 0.01% to 10%, a surfactant in an amount up to 5%, and optionally, copper salts in an amount of from about 0.01% to 5%.
- a water soluble film forming polymer including, but not limited to, pullulan, in an amount of up to 25%
- a flavoring agent in an amount of from about 0.01% to 10%
- a surfactant in an amount up to 5%
- copper salts in an amount of from about 0.01% to 5%.
- Other preferred compositions of the present invention are in the form of dentifrices such as toothpastes, tooth gels, and tooth powders.
- Components of such toothpaste, and tooth gels generally include one or more of a dental abrasive, generally from about 10% to 50% by weight, a surfactant such as anionic, nonionic, or zwitterionic detergent from about 0.5% to 10%, a thickening agent from about 0.1% to 5%, a humectant from about 10% to 55%, a flavoring agent from about 0.04% to 2%, a sweetening agent from about 0.1% to 3%, a coloring agent from 0.01% to 0.5%, and water from about 2% to 45%.
- a dental abrasive generally from about 10% to 50% by weight
- a surfactant such as anionic, nonionic, or zwitterionic detergent from about 0.5% to 10%
- a thickening agent from about 0.1% to 5%
- a humectant from about 10% to 55%
- a flavoring agent from about 0.04% to 2%
- a sweetening agent from about 0.1% to 3%
- a coloring agent
- Such toothpastes or tooth gels may also include one or more of an anticaries agent from about 0.05% to 0.3% (e.g., fluoride ion), and an anticalculus agent from about 0.1% to 13%.
- an anticaries agent from about 0.05% to 0.3% (e.g., fluoride ion)
- an anticalculus agent from about 0.1% to 13%.
- the liquids and solids are proportioned to form a creamy or gelled mass, which is extrudable from a pressurized container or from a collapsible tube. Tooth powders, of course, contain substantially all non-liquid components.
- compositions of the present invention are in the form of microcaps or more commonly known as gel beads, which generally comprise a flavorant in an amount of from about 0.1% to 10% by weight, a lipophilic filler in an amount of from about 1% to 60%, an emulsifier in an amount of from about 0.1% to 5% and a sweetening agent in an amount of from about 0.01 % to 3%.
- Chewing gum compositions typically include one or more of gum base from about 50% to 99% by weight, a flavoring agent from about 0.4% to 2% and a sweetening agent from about 0.01 % to 5%.
- the term "lozenge” as used herein includes: breath mints, troches, pastilles, microcapsules, and fast-dissolving solid forms including freeze dried forms (cakes, wafers, thin films, and tablets) and fast dissolving solid forms including compressed tablets.
- fast dissolving solid form as used herein means that the solid dosage form dissolves in less than about 60 seconds, preferably less than about 15 seconds, more preferably less than about 5 seconds, after placing the solid dosage form in the oral cavity.
- Lozenges include discoid shaped solids comprising a therapeutic agent in a flavored base.
- the base may be a hard sugar candy, glycerinated gelatin, or combination of sugar with sufficient mucilage to give it form.
- Lozenge compositions compressed tablet type typically include one or more fillers (compressible sugar), flavoring agents and lubricants.
- surfactants can be employed in the composition of the present invention. They are organic materials which aid in the complete dispersion of the components including the active agents and flavoring oils throughout the solution as well as dispersing the preparation throughout the oral cavity and enable the compositions to provide a clear, uniform appearance that is aesthetically more appealing.
- the surfactant used in the compositions of the present invention is a non-ionic surfactant or anionic surfactant employed in an amount sufficient to help solubilize the active components.
- sufficient amount it is meant that the surfactant is present in an amount that effectively assists in the solubilization and delivery system kinetics of the tropolone compounds and the essential oils. Additional components may be added as known by those skilled in the art.
- acidic preservatives such as sorbic or benzoic acid may be added to reduce pH levels.
- Buffer systems may be necessary to control the pH of the composition at optimal levels. This is generally accomplished through the addition of a weak acid and its salt or a weak base and its salt.
- Useful systems have been found to be sodium benzoate and benzoic acid in amounts of from about 0.01% to 4.0% by weight, and sodium citrate and citric acid in amounts of from about 0.001% to 0.2% by weight.
- the buffers are incorporated in amounts that maintain the pH at levels of from about 3.5 to 9.0, and more preferably from about 4.0 to 7.0.
- a method of treating or preventing diseases or conditions of the oral cavity in warm-blooded animals including humans by applying an oral care effective amount of the oral care composition of the present invention to the oral cavity.
- the oral care effective amount of the oral care compositions of the present invention is preferably applied to the mucosal tissue of the oral cavity, to the gingival tissue of the oral cavity, and/or surface of the teeth, for the treatment or prevention of the above-mentioned diseases or conditions of the oral cavity, in one or more conventional ways.
- the gingival or mucosal tissue may be rinsed with a solution (e.g., mouthwash, rinse) containing the composition of the present invention; if a dentifrice (e.g., toothpaste, tooth gel, or tooth powder) is employed, the gingival/mucosal tissue or teeth may be bathed in the liquid and/or lather generated by brushing the teeth; etc., for a sufficient time, preferably from about 10 seconds to 10 minutes, more preferably from about 30 seconds to 60 seconds.
- a solution e.g., mouthwash, rinse
- a dentifrice e.g., toothpaste, tooth gel, or tooth powder
- the method of the present invention generally further involves expectoration of most of the composition following such contact.
- the frequency of such contact is preferably from about once a week to about four times per day, more preferably from about 3 times per week to three times per day, even more preferably once per day to twice per day.
- the period of such treatment typically ranges from about one day to a lifetime.
- the duration of treatment depends on the severity of the oral disease or condition being treated, the particular delivery form utilized and the patient's response to treatment. If the delivery to the periodontal pockets is desirable, such as with the treatment of periodontal disease, a mouthwash or rinse can be delivered to the periodontal pocket using a syringe or a water injection device, for example.
- the subject can swish the wash in the mouth to also cover the dorsal portion of the tongue and other gingival/mucosal surfaces.
- toothpaste non- abrasive gel, tooth gel, etc.
- Non-limiting examples include chewing gum that contains the composition of the present invention, chewing or sucking on a breath tablet or lozenge.
- Preferred methods of applying the oral care compositions of the present invention to the gingival/mucosal tissue and/or teeth include rinsing with a mouthwash or rinse solution and brushing with a dentifrice.
- Other methods of applying the present composition to the gingival/mucosal tissue and surfaces of the teeth are apparent to those skilled in the art.
- the present substituted tropolone compounds of Formula (I) employed in the present invention may be prepared from readily available starting materials using the following general methods and procedures. It will be understood that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, however such reaction conditions may be determined by one of ordinary skill in the art through routine optimization procedures.
- Compounds of Formula (I) can be prepared as shown in Scheme 1 by reacting dichloroacetyl chloride with an R 2 -substituted cyclopentadiene compound in the presence of a base such as triethylamine to yield a cycloadduct of Formula (III).
- the cycloadduct of Formula (III) is then treated with an acid such as acetic acid and a base such as triethylamine to yield the final desired product, a 4- alkyltropolone compound.
- R 2 is isopropyl the resulting compound is hinokitiol which is used as a starting material in Scheme 2.
- a base such as potassium hydroxide
- an acid such as hydrochloric acid
- the 4-isopropyl-7-hydroxyalkyltropolone compound is then treated with a chlorinating agent such as SOCI 2 in the presence of a base such as pyridine to yield a 4-isopropyl-7-chloroalkyltropolone compound.
- a chlorinating agent such as SOCI 2
- a base such as pyridine
- the 4-isopropyl-7- chloroalkyltropolone compound is reacted with an alcohol (R 7 OH; wherein R 7 is an alkyl group) such as methanol, ethanol, propanol, and the like, in the presence of heat to yield the corresponding a 4-isopropyl-7-alkoxyalkyltropolone compound.
- Compounds of Formula (I) can further be prepared as shown in Scheme 3 by reacting 4-isopropyl-7-hydroxymethyltropolone with an oxidizing agent such as Mn0 2 to yield 4-isopropyl-7-formyltropolone.
- the starting compound, 4-isopropyl-7- hydroxymethyltropolone may be prepared by reacting hinokitiol with formaldehyde in the presence of a base such as potassium hydroxide, and thereafter treating the reaction with an acid such as hydrochloric acid.
- 4-isopropyl-7-formyltropolone is reacted with an alkylmagnesium bromide compound (R 8 MgBr; wherein R 8 is an alkyl group) and the reaction is quenched with an acid such as hydrochloric acid to yield a 4-isopropyl-7-hydroxyalkyltropolone compound.
- the 4-isopropyl-7- hydroxyalkyl-tropolone compound is treated with a reducing agent such as phosphorus, preferably red phosphorus, in the presence of an acid such as acetic acid, whereupon as oxidizing agent such as iodine is added to the reaction to yield a final product of a 4-isopropyl-7-alkyltropolone compound.
- a mouthwash composition was prepared having the following components shown below in Table 1.
- the composition was prepared by adding the essential oils (thymol, menthol, methyl salicylate and eucalyptol) and the compound of Formula (I), flavoring oils, poloxamer 407 and benzoic acid to alcohol followed by addition of 250 ml of water. Sorbitol, saccharin, and the dye were added to the resulting mixture followed by the addition of water to provide a 1000 ml sample of the mouthwash composition.
- a solution comprising 25 mL of triethylamine and 100 mL of a mixture of hexanes was added dropwise to a solution containing 48.5 g of methylcyclopentadiene (prepared from cracking methylcyclopentadiene dimer) and 22.5 g of dichloroacetyl chloride in 200 mL of a mixture of hexanes at 0 9 C.
- the mixture was stirred for about one hour and thereafter poured into 150 mL of water at about 0 9 C.
- the layers were separated and the aqueous phase was extracted with two 75 mL portions of hexanes.
- the combined organic layers were washed twice with water, then dried over Na 2 S0 and concentrated to yield an oil.
- the layers were separated and the organic layer was dried over Na 2 S0 .
- the solvent was removed and the resulting oil was triturated with petroleum ether to yield 4-isopropyl-7- hydroxyhexyltropolone in the form of a yellow oil.
- the oil product was mixed in 2 mL of water, 1g of red phosphorus and 15 mL of acetic acid. The mixture was stirred well and 1 g of l 2 was added. The reaction mixture was refluxed for about an hour, and thereafter filtered. 150 mL of water was added the filtrate. K 2 C0 3 was added to the mixture to generate a basic pH. The mixture was extracted with petroleum ether. The organic layer was washed with Na 2 S 2 0 and then with water, and was dried over Na 2 S0 4 to yield 4-isopropyl-7-hexyltropolone in the form of an oil.
Abstract
Description
Claims
Applications Claiming Priority (5)
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US207726 | 1998-12-08 | ||
US207618 | 2002-07-29 | ||
US10/207,726 US6689342B1 (en) | 2002-07-29 | 2002-07-29 | Oral care compositions comprising tropolone compounds and essential oils and methods of using the same |
US10/207,618 US6787675B2 (en) | 2002-07-29 | 2002-07-29 | Substituted tropolone compounds, oral care compositions containing the same and methods of using the same |
PCT/IB2003/003449 WO2004012692A1 (en) | 2002-07-29 | 2003-07-17 | Oral care composition comprising tropolone compounds and essential oils |
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EP1536759A1 true EP1536759A1 (en) | 2005-06-08 |
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EP03766579A Withdrawn EP1536759A1 (en) | 2002-07-29 | 2003-07-17 | Oral care composition comprising tropolone compounds and essential oils |
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JP (2) | JP2005537294A (en) |
AU (1) | AU2003249466B2 (en) |
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MX (1) | MXPA05001182A (en) |
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JP5209864B2 (en) * | 2006-10-20 | 2013-06-12 | 花王株式会社 | Biofilm formation inhibitor composition |
EP1993355B1 (en) | 2006-03-23 | 2017-10-11 | Kao Corporation | Biofilm formation inhibitor composition |
JP5545729B2 (en) * | 2009-05-19 | 2014-07-09 | クラシエフーズ株式会社 | Antibacterial agent and oral composition and food / beverage product using the same |
MY166027A (en) * | 2011-06-17 | 2018-05-21 | The Government Of The State Of Sarawak Malaysia | Oral care product for oral hygiene and growth inhition of microorganisms |
EP2864311A4 (en) | 2012-06-22 | 2015-12-02 | Univ Connecticut | Substituted tropolone derivatives and methods of use |
JP6347947B2 (en) * | 2013-12-27 | 2018-06-27 | 花王株式会社 | Mycelium formation inhibitor |
JP2018058795A (en) * | 2016-10-06 | 2018-04-12 | ライオン株式会社 | Composition for oral cavity and method for suppressing color change of preparation and liquid separation |
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US4656192A (en) * | 1983-09-28 | 1987-04-07 | Mect Corporation | Tropolone derivatives, processes for the preparation thereof and the use thereof as anti-tumor agents |
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JPS59175410A (en) * | 1983-03-26 | 1984-10-04 | Kanebo Shokuhin Kk | Cariostatic agent |
JPS62142109A (en) * | 1985-12-14 | 1987-06-25 | Lotte Co Ltd | Composition for removing foul breath and method therefor |
JP2778987B2 (en) * | 1989-05-29 | 1998-07-23 | マリーンバイオ株式会社 | Abrasive composition |
JPH03128313A (en) * | 1989-07-13 | 1991-05-31 | Nippon Koutai Kenkyusho:Kk | Dentifrice composition |
JPH03279321A (en) * | 1990-03-28 | 1991-12-10 | Shiseido Co Ltd | Oral cavity cleaning agent |
US5281411A (en) * | 1992-07-31 | 1994-01-25 | The Procter & Gamble Company | Oral compositions |
JP3558138B2 (en) * | 1993-12-24 | 2004-08-25 | ライオン株式会社 | Liquid oral composition |
JPH07187977A (en) * | 1993-12-24 | 1995-07-25 | Lion Corp | Composition for oral cavity |
US5683678A (en) * | 1995-03-09 | 1997-11-04 | The Procter & Gamble Company | Oral compositions |
EE9800110A (en) * | 1995-10-11 | 1998-10-15 | Warner-Lambert Company | An ethanol-reduced and ethanol-free antimicrobial composition |
JP3884808B2 (en) * | 1997-01-08 | 2007-02-21 | 日本ゼトック株式会社 | Oral composition |
US5939050A (en) * | 1997-04-04 | 1999-08-17 | Optiva Corp. | Antimicrobial compositions |
JP3646765B2 (en) * | 1997-06-17 | 2005-05-11 | ライオン株式会社 | Oral composition |
JPH1135436A (en) * | 1997-07-24 | 1999-02-09 | Lion Corp | Composition for oral cavity |
EP0900560A1 (en) * | 1997-09-09 | 1999-03-10 | Hironori Oka | Tooth coating composite and its preparation |
JPH11130648A (en) * | 1997-10-29 | 1999-05-18 | Lion Corp | Composition for oral cavity |
JP4087938B2 (en) * | 1998-02-04 | 2008-05-21 | 高砂香料工業株式会社 | Antibacterial agent comprising branched cyclodextrin inclusion compound of hinokitiols and composition containing the same |
JP2000095656A (en) * | 1998-07-23 | 2000-04-04 | Lion Corp | Liquid composition for oral cavity |
JP2000143468A (en) * | 1998-09-04 | 2000-05-23 | Lion Corp | Liquid composition for oral cavity |
JP4347973B2 (en) * | 1999-12-20 | 2009-10-21 | 希能 澤口 | Oral or external medicine composition |
JP2003212743A (en) * | 2002-01-18 | 2003-07-30 | Lion Corp | Composition for oral cavity for hyperesthesia |
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2003
- 2003-07-17 BR BR0313012-6A patent/BR0313012A/en not_active Application Discontinuation
- 2003-07-17 EP EP03766579A patent/EP1536759A1/en not_active Withdrawn
- 2003-07-17 AU AU2003249466A patent/AU2003249466B2/en not_active Ceased
- 2003-07-17 CA CA2492827A patent/CA2492827C/en not_active Expired - Fee Related
- 2003-07-17 JP JP2004525702A patent/JP2005537294A/en active Pending
- 2003-07-17 MX MXPA05001182A patent/MXPA05001182A/en active IP Right Grant
- 2003-07-17 WO PCT/IB2003/003449 patent/WO2004012692A1/en active Application Filing
- 2003-07-17 NZ NZ537681A patent/NZ537681A/en not_active IP Right Cessation
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2009
- 2009-06-16 JP JP2009142879A patent/JP2009263375A/en not_active Abandoned
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US4656192A (en) * | 1983-09-28 | 1987-04-07 | Mect Corporation | Tropolone derivatives, processes for the preparation thereof and the use thereof as anti-tumor agents |
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BR0313012A (en) | 2005-06-07 |
JP2009263375A (en) | 2009-11-12 |
CA2492827A1 (en) | 2004-02-12 |
JP2005537294A (en) | 2005-12-08 |
WO2004012692A1 (en) | 2004-02-12 |
CA2492827C (en) | 2010-07-13 |
NZ537681A (en) | 2007-06-29 |
AU2003249466A1 (en) | 2004-02-23 |
AU2003249466B2 (en) | 2009-10-01 |
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