• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Summary "oral care compositions" are described herein as oral aqueous compositions comprising cationic steroid compound and a quaternary ammonium compound; and methods for producing and using them.
    公开号:BR112014015144B1
    申请号:R112014015144-0
    申请日:2011-12-21
    公开日:2018-03-27
    发明作者:Vazquez Joe；Chen Dandan；M. Trivedi Harsh；Mehreteab Ammanuel；Du-Thumm Laurence；Szewczyk Gregory；Hao Zhigang
    申请人:Brigham Young University；
    IPC主号:
    专利说明:

    (54) Title: WATER COMPOSITION FOR ORAL CARE, USE OF A CATIONIC STEROID COMPOUND AND NON-THERAPEUTIC METHOD OF REDUCING SULFUR VOLATILE COMPOUNDS (51) Int.CI .: A61K 8/63; A61K 8/21; A61Q 11/00 (52) CPC: A61K 8/63, A61K 8/21, A61Q 11/00 (73) Holder (s): BRIGHAM YOUNG UNIVERSITY (72) Inventor (s): JOE VAZQUEZ; DANDAN CHEN; HARSH M. TRIVEDI; AMMANUEL MEHRETEAB; LAURENCE DU-THUMM; GREGORY SZEWCZYK; ZHIGANG HAO
    1/18 “WATER COMPOSITION FOR ORAL CARE, USE OF A CATIONIC STEROID COMPOUND AND NON-THERAPEUTIC METHOD OF REDUCING SULFUR VOLATILE COMPOUNDS”
    BACKGROUND [001] Ceragenins are cationic steroidal antimicrobials that are produced synthetically from a sterol base.
    [002] Quaternary ammonium compounds are known to have antibacterial activity, as well as, for their use in oral care. However, oral care products that contain a combination of a quaternary ammonium compound and a cationic steroid compound are still unknown.
    SUMMARY [003] Some embodiments of the present invention provide an aqueous composition for oral care comprising: a cationic steroid compound; and a quaternary ammonium compound.
    [004] Other embodiments provide methods for treating a disease or condition of the oral cavity, which comprises administering a composition, according to any of the preceding claims, into the oral cavity of a patient in need thereof.
    [005] Other areas of application of the present invention will be evident from the detailed description provided hereinafter. It should be understood that the detailed description and the specific examples, while indicating the preferred embodiment of the invention, are for illustrative purposes only and are not intended to limit the scope of the invention.
    DETAILED DESCRIPTION [006] Some embodiments of the present invention provide an aqueous composition for oral care comprising: a steroid compound
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    2/18 cationic; and a quaternary ammonium compound.
    [007] As used herein, the term aqueous refers to a free water content of at least about 40% by weight.
    [008] In some embodiments, the compositions comprise from about 40 to about 97%, by weight, of free water. In some embodiments, the compositions comprise more than about 50%, by weight, of free water. In some embodiments, the compositions comprise from about 50 to about 90%, by weight, of free water. In some embodiments, the compositions comprise from about 60 to about 85%, by weight, of free water. In some embodiments, the compositions comprise from about 73% to about 83%, by weight, of free water. Some embodiments comprise about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81% or about 82%, by weight of free water.
    [009] In some embodiments, the cationic steroid compound is a compound of Formula (I):
    where Ri is selected from -OH and NH-R2, where R2 is C2-C14 alkyl, C2-C14 alkenyl or C2-C14 alkynyl, and n is 3 or 4.
    [010] Some embodiments provide a composition in which the compound of Formula (I) is selected from a compound of Formula (II):
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    3/18
    a compound of general Formula (III):
    [011] In some embodiments, the cationic steroid compound is a compound of Formula (II):
    [012] In some embodiments, the cationic steroid compound has a molecular weight of about 500 to about 1000. In some embodiments, the cationic steroid compound has a molecular weight of about 650 to about 850.
    [013] In some embodiments, the cationic steroid compound is present at a concentration of about 0.01% to about 0.1%, by weight, of the composition. In some embodiments, the cationic steroid compound is present at a concentration of about 0.05%, by weight, of the composition.
    [014] In some embodiments, the quaternary ammonium compound is selected from: benzalkonium chloride, benzethonium chloride, chloride
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    4/18 methylbenzethonium, ketalkonium chloride, cetylpyridinium chloride, cetrimonium, cetrimide, dofanium chloride, tetraethylammonium bromide, didecyl dimethyl ammonium chloride and domiphene bromide. In some embodiments, the quaternary ammonium compound comprises cetylpyridinium chloride.
    [015] Quaternary ammonium compounds are a group of ammonium salts, in which organic radicals have replaced all four hydrogens in the original ammonium cation. They have a central nitrogen atom, which is attached to four organic radicals and an acidic radical. Examples of quaternary ammonium compounds suitable for use in the present invention include, in addition, others, such as benzalkonium or benzethonium halides / halides, including, but not limited to, benzalkonium or benzethonium bromide or fluoride, propylalkonium cetyl chloride (cetylp alkylamidopropalkonium chloride), berrenalkonium chloride (behenalkonium chloride), berrenthrimony methosulfate (behentrimonium methosulfate), berrenamidopropylethyldonium ethosulfate, stearyl chloride, ethylene chloride, stearalcium chloride, stearalcium chloride -miristyl-Nmethyl-morpholine, poly [N- [3- (dimethylammonium) propyl] dichloride -N '- [3- (ethylene oxyethylene dimethylammonium) propyl] urea], alpha-4- [chloride-2-butenyl chloride 1-tris (2-hydroxyethyl) ammonium] -Omega-tris (2-hydroxyethyl) -ammonium chloride, poly [oxyethylene (dimethylimino) ethylene (dimethyliminio) -ethylene dichloride].
    [016] In some embodiments, the quaternary ammonium compound is present at a concentration of about 0.01% to about 0.1%, by weight, of the composition. In some embodiments, the quaternary ammonium compound is present at a concentration of about 0.05%, by weight, of the composition.
    [017] In some embodiments, the cationic steroid compound and the quaternary ammonium compound are present at a 1: 1 ratio, based on their respective concentrations, by weight, in the composition.
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    5/18 [018] Some embodiments of the present invention further comprise a source of fluoride ions, in which the source of fluoride ions is selected from tin fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and a combination of two or more of these. In some embodiments, the fluoride ion source comprises sodium fluoride.
    [019] Other embodiments provide a method for treating a disease or condition of the oral cavity which comprises administering a composition, according to any of the preceding claims, into the oral cavity of a patient in need thereof. In some embodiments, the disease or condition of the oral cavity is an inflammatory disease or condition. In some embodiments, the disease or condition is selected from gingivitis, periodontitis and caries.
    [020] In some embodiments, the present invention provides methods for treating an inflammatory condition of the oral cavity, which comprises administering a composition comprising a cationic steroid compound into the oral cavity of a patient in need thereof.
    [021] Some embodiments provide a method for treating bad breath which comprises administering a composition containing a cationic steroid compound into the oral cavity of a patient in need of it. In some embodiments, the compositions of the present invention reduce volatile sulfur compounds (VSC) generated from odor-producing salivary bacteria.
    [022] The present inventors have found that a combination of a cationic steroidal compound (eg, a ceragenin) and a quaternary ammonium compound (eg, cetylpyridinium chloride) provides an unexpected improvement in antimicrobial activity.
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    6/18 [023] As used herein, the term a ceragenin includes combinations of ceraginins and a quaternary ammonium compound includes combinations of quaternary ammonium compounds.
    [024] Ceraginins are cationic steroid antibiotics (CSAs). They can be produced synthetically and are small chemical compounds of molecules that consist of a sterol base with amino acids and other chemical groups attached to it. These compounds have a net positive charge, which is electrostatically attracted to the negatively charged cell membranes of certain viruses, fungi and bacteria. CSA has a high binding affinity with such membranes and is able to rapidly disrupt target membranes, leading to rapid cell death.
    [025] The cationic properties of ceraginins mimic the cationic load of peptides. Ceraginins considered useful in the present invention are disclosed by US Patent No. 6,767,904 In one embodiment, ceragenin is a
    [026] The biological activity of the ceragenin and quaternary ammonium compounds can be determined by conventional methods known to those skilled in the art, such as the minimum inhibitory concentration (MIC) assay, that is, the assay by which the lowest concentration is determined. low where no change in optical density (OD) is observed over a period of time. When the compound alone is tested against a control, which lacks the compound, the antimicrobial effect of the compound alone is determined.
    [027] In addition, fractional inhibitory concentration (FIC) is also useful for
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    7/18 determining the synergy between the compounds. The terms synergistic and synergy, used in the present invention, mean an antibacterial effect created from the application of two or more compounds that produce an antibacterial effect that is greater than the sum of the antibacterial effects produced by the application of the individual compounds. The FIC procedure allows the determination of the synergistic effects of a combination of the compounds. FICs can be performed through the checkerboard titration of a compound in one dimension of the microtiter plate, and of another compound in the other dimension, for example. The FIC is calculated by observing the impact of one compound on the MIC of the other and vice versa. The FIC of one indicates that the influence of the compounds is an additive and the FIC of less than one indicates synergy. In some embodiments, an FIC of less than 0.7 indicates synergy between the compounds to be evaluated.
    [028] As used herein, the FIC can be determined as follows:
    FIC = A + B, where A = (MIC of combination X + Y / (MIC of X alone)
    B = (MIC of combination X + Y / (MIC of Y alone) [029] The combination of the antimicrobial compounds of the present invention is effective against a wide variety of microorganisms, such as oral bacteria. Examples of such bacteria include, but are not limited to, are necessarily limited to, Actinomyces viscosus, Streptococcus mutans, Porfyromonas gingivalis, Fusobacterium nucleatum, and the like.
    [030] In some embodiments, the compositions of the present invention are able to provide the antimicrobial effect after about 30 seconds. This ability is particularly advantageous for the embodiments of the present invention that are in the form of a mouthwash / mouthwash, since 30 seconds correspond to the normal duration of use of a mouthwash.
    [031] In some embodiments, the compositions comprise a
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    8/18 buffering agent such as sodium phosphate buffer (for example, monobasic sodium phosphate and disodium phosphate).
    [032] In some embodiments, the compositions comprise a humectant. Humectants useful for this invention include polyhydric alcohols, such as glycerin, sorbitol, xylitol or low molecular weight PEG, alkylene glycol, such as polyethylene glycol or propylene glycol. In various embodiments, humectants are used to prevent curing of paste or gel compositions when exposed to air. In various embodiments, humectants also function as sweeteners.
    [033] In some embodiments, the humectant is present in an amount of about 1 to about 40%, by weight, each. In some embodiments, the humectant is sorbitol. In some embodiments, sorbitol is present at a concentration of about 5 to about 25%, by weight. In some embodiments, sorbitol is present at a concentration of about 5 to about 15%, by weight. In some embodiments, sorbitol is present at a concentration of about 10%, by weight. The allusion here to sorbitol refers to the material normally available commercially in 70% aqueous solutions. In some embodiments, the total concentration of humectant ranges from about 1 to about 60%, by weight. In some embodiments, the humectant is glycerin. In some embodiments, glycerin is present at a concentration of about 5 to about 15%, by weight. In some embodiments, glycerin is present at a concentration of about 7.5%, by weight. In some embodiments, the humectant is propylene glycol. In some embodiments, propylene glycol is present at a concentration of about 5 to about 15%, by weight. In some embodiments, propylene glycol is present at a concentration of about 7%, by weight.
    [034] In some embodiments, the compositions comprise a
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    9/18 cellulosic polymer, such as methyl hydroxy-alkyl-cellulose (such as hydroxylpropyl-methyl-cellulose, hydroxyl-butyl-methyl-cellulose, hydroxyl-ethyl-methyl-cellulose, hydroxyl-methyl-cellulose and hydroxyl-cellulose ethyl-propyl-methyl-cellulose); carboxy-alkyl-methylcellulose (such as carboxy-propyl-methyl-cellulose, carboxy-butyl-methyl-cellulose, carboxy-ethyl-methylcellulose, carboxymethyl-methyl-cellulose and carboxy-ethyl-propyl methyl-cellulose); hydroxylalkyl-celluloses (such as hydroxyl-propyl-cellulose, hydroxyl-butyl-cellulose, hydroxyl-ethylcellulose, hydroxyl-methyl-cellulose and hydroxyl-ethyl-propyl-cellulose); alkyl celluloses (such as propyl cellulose, butyl cellulose, ethyl cellulose, methyl cellulose); carboxy-alkylcelluloses (such as carboxy-propyl-cellulose, carboxy-butyl-cellulose, carboxy-ethylcellulose, carboxymethylcellulose and carboxy-ethyl-propyl cellulose), and combinations thereof. In some embodiments, the cellulosic polymer comprises carboxymethylcellulose.
    [035] In some embodiments, the compositions comprise a gum polymer, such as carrageenan gum, xanthan gum, and combinations thereof. In some embodiments, the gum polymer comprises xanthan gum.
    [036] Some embodiments comprise a polyacrylate polymer or copolymer, such as a carbomer. In some embodiments, the polyacrylate polymer or copolymer is selected from homo-and copolymers of acrylic acid cross-linked with a polyalkenyl polyether. High molecular weight synthetic acrylic acid polymers, known as carbomers, can be crosslinked acrylic acid homopolymers with a pentaerythritol allyl, sucrose allyl or propylene allyl. The carbomer has a USP classification of Type A carbomer homopolymer. Carbomers have the ability to adsorb, retain water and increase their original volume many times. The carbomer codes (910, 934, 940, 941,971,974 and 934P) are an indication of molecular weight and the specific components of the polymer. The
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    10/18 carbomers are commercially available under the trade name Carbopol ® from Lubrizol and other companies.
    [037] Some embodiments provide a composition obtained or attainable by combining the ingredients, as set out in any of the embodiments described herein.
    [038] In some embodiments, the composition is in the form selected from a mouthwash, mouthwash, mousse, foam, mouth spray, lozenge, tablet, dental instrument (dentalimplement), and a pet care product . In some embodiments, the composition is a mouthwash or mouthwash.
    [039] Some embodiments of the present invention provide aqueous compositions comprising the following ingredients, by weight:
    Ingredient Concentration Range% w / w Water 50 - 90 Humectants 1 - 25 Surfactant 0.01 - 10 Preservative 0.01 - 1 Flavor 0.01 - 1 Cellulosic Polymer 0.01 - 0.5 Gum polymer 0.01-0.5 Polyacrylate Polymer or Co-Polymer 0.01 - 0.5 Sodium Fluoride 0 - 0.05 Ethyl alcohol 0 - 8 Sweetener 0.01 - 0.5 Cetylpyridinium chloride 0.01 - 1 Compound of Formula (II) 0.01 - 1
    [040] Some embodiments provide a method for the treatment of halitosis, which comprises administering any embodiment of the present invention in the oral cavity of a patient in need thereof.
    [041] Some embodiments contain dyes. Dyes, such as substances with pigments, can be food additives dyes, currently certified by the Food Drug & Cosmetic Act for use in foods and medicines
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    11/18 ingested, including dyes such as FD & C Red No. 3 (tetraiodofluorescein sodium salt), Food Red 17, disodium salt of 6-hydroxy-5 - {(2-methoxy-5-methyl-4sulfophenyl) azo} -2-naphthalenesulfonic acid, Food Yellow 13, sodium salt of a mixture of quinophthalone mono- and disulfonic acids or 2- (2-quinolyl) indanedione, FD & C Yellow No. 5 (sodium salt of 4- psulfophenylazo-1-p-sul-fofenil-5-hydroxypyrazole3 carboxylic), FD & C Yellow No. 6 (sodium salt of p-sulfophenylazo-B-naphthol-6 monosulfonate), FD & C Green No. 3 (disodium salt of 4 - {[4- (N-ethyl-psulfobenzylamino) -phenyl] - (4-hydroxy-2-sulfonylphenyl) -methylene} - [1- (N-ethyl-N-psulfobenzyl) -DELTA-3,5-cyclohexadienimine ], FD & C Blue No. 1 (disodium dibenzyldiethyl-diamino-triphenylcarbinol trisulfonic acid anhydride salt), FD & C Blue No. 2 (indigotine disulfonic acid sodium salt) and mixtures of these compounds in various proportions. , dyes, if included, are present in quantities very small.
    [042] Flavoring agents can also be included in some embodiments of the present invention. These flavorings can be chosen from synthetic and aromatic flavoring oils and / or oils, oil resins and extracts derived from plants, leaves, flowers, fruits and so on, and their combinations. Representative flavor oils include: peppermint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and bitter almonds. These flavoring agents can be used individually or in a mixture. Commonly used flavors include mint, such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, used individually or in a mixture. Generally, any flavoring or food additive, such as those described in Chemicals Used in Food Processing, publication 1274 by the National Academy of Sciences, pages 63-258, can be used. Normally, flavorings, if included, are present at 0.01
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    - 1% by weight. In some embodiments, the flavoring may be present at about 0.2%, by weight.
    [043] Sweeteners include both natural and artificial sweeteners. Suitable sweeteners include water-soluble sweetening agents, such as monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, soluble artificial sweeteners water, such as soluble saccharin salts, for example, sodium or calcium saccharin salts, dipeptide based on cyclamate salts, such as L-aspartic acid based sweeteners, such as L methyl ester -aspart-L-phenylalanine (aspartame). In general, the effective amount of sweetener used to provide the desired level of sweetness for a particular composition will vary with the chosen sweetener. This amount will normally be from about 0.001% to about 5%, by weight, of the composition. In some embodiments, the sweetener is sodium saccharin and is present at about 0.01%, by weight, of the composition.
    [044] Optional breath-freshening agents can be provided. Any breath freshener that is orally acceptable can be used, including, without limitation, zinc salts, such as zinc gluconate, zinc citrate and zinc chloride, alpha-ionone and mixtures thereof. One or more breath freshening agents are optionally present in a total and effective amount of the breath cooling agent.
    [045] Optionally, the composition may include an agent for the control of tartar (anticalculations). Tartar control agents that are useful in this context include phosphates and polyphosphates (eg, pyrophosphates), polyamino-propane-sulfonic acid (AMPS), polyolefin sulfonates, polyolefin phosphates, diphosphonates, such as azacycloalkane -2,2-diphosphonates (for example, azacycloheptane-2,2-diphosphonic acid), N-methyl-azacyclopentane-2,3-diphosphonic acid,
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    13/18 ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) and ethane-1-amino-1,1-diphosphonate, phosphonoalkane carboxylic acids and the salts of all these agents, for example, their alkali metal salts and ammonium. Useful inorganic phosphate and polyphosphate salts include monobasic, dibasic and tribasic sodium phosphate, sodium tripolyphosphate, tetrapolyphosphate, mono-, di-, tri- and tetrasodium pyrophosphate, sodium trimetaphosphate, sodium hexametaphosphate and mixtures thereof, and mixtures thereof. sodium can optionally be replaced by potassium or ammonium. Other useful anti-calculating agents include polycarboxylate polymers and polyvinyl methyl ether / maleic anhydride (PVME / MA) copolymers, which are available under the ISP Gantrez ® brand, Waine, NJ.
    [046] In some embodiments, the tartar control agent is present at a concentration of about 0.01 to 10%, by weight. In some embodiments, the tartar control agent is present at a concentration of about 1%, by weight. In some embodiments, the tartar control agent also acts as a buffer. For example, in a phosphate buffer system, monobasic sodium phosphate is present at a concentration of about 0.01 to about 5% by weight, and disodium phosphate is present at a concentration of about 0.01 at about 5% by weight, where the precise proportion depends on the other excipients in the formulation and the desired pH.
    [047] Antioxidants are another class of optional additives. Any orally acceptable antioxidant can be used, including butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin A, carotenoids, vitamin E, flavonoids, polyphenols, ascorbic acid, herbal antioxidants, chlorophyll, melatonin, and mixtures thereof .
    [048] The saliva stimulating agent can also be included as an option, as it is useful, for example, in improving dry mouth. Any orally acceptable saliva stimulating agent can be used, including, without limitation, dietary acids, such as citric, lactic, malic, succinic, ascorbic,
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    14/18 adipic, fumaric, and tartaric, and mixtures thereof. One or more saliva stimulating agents are optionally present in a total and effective amount of saliva stimulator.
    [049] Optionally, an anti-plaque agent (for example, plaque rupture agent) can be included. Any orally acceptable anti-plaque agent can be used, including, without limitation, tin, copper, magnesium and strontium salts, dimethicone copolyols, such as cetyl dimethicone copolyol, papain, glycoamylase, glucose oxidase, urea, lactate calcium, calcium glycerophosphate, strontium polyacrylates and mixtures thereof.
    [050] Optional desensitizing agents include potassium citrate, potassium chloride, potassium tartrate, potassium bicarbonate, potassium oxalate, potassium nitrate, strontium salts and mixtures thereof.
    [051] In some embodiments, the methods comprise the washing / rinsing step of the oral cavity with a composition as described herein. In some embodiments, 5 ml or more of the composition is gargled. In some embodiments, 10 ml or more is used. In some embodiments, 10 - 50 ml are used. In some embodiments, 15 - 25 ml or more are used. In some embodiments, 15 ml or more is used. In some embodiments, the individual garages with the composition several times a day. In some embodiments, the individual garages with the composition in several days. In some embodiments, the individual gargles with the composition every 4 to 6 hours, up to 6 times a day.
    [052] Throughout the document, ranges are used as abbreviations to describe each and every value that is within the range. Any value within the range can be selected as the end of the range. In addition, all references cited herein are incorporated herein in their entirety as a reference. In the event of a conflict between a definition in this
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    15/18 disclosure and a definition in the cited reference, the present disclosure predominates. [053] Unless otherwise stated, all percentages and quantities expressed here, and elsewhere in the specification, should be understood as percentages by weight. The quantities indicated are based on the active weight of the material.
    EXAMPLES
    Example 1 [054] Table 1 (below) describes the formulation of two examples of compositions of the present invention (Composition I and Composition II).
    TABLE 1
    Composition I Composition II Ingredient Weight % Sucralose 0.02 0.02 Sodium Fluoride 0.05 0.05 Sodium benzoate 0.11 0.11 Glycerin 7.5 7.5 Sorbitol 5.5 5.5 Propylene glycol 5 5 Pluronic F127 0.15 0.15 Ethyl alcohol - - 6 Water 81.57 75.57 Cetylpyridinium chloride 0.05 0.05 Compound of Formula (II) 0.05 0.05 Total 100 100
    Example 2: Preparation Method Example [055] Some embodiments of the present invention can be prepared according to the following procedure. A premix is prepared by adding propylene glycol in a container and adding menthol to it. The combination is mixed until the menthol is dispersed. The flavoring is added and mixed for about 3 minutes. The water is then added to the main mixer and the mixer is then switched on. Pluronic is then added until it is sufficiently dispersed. Saccharin, potassium sorbate and a compound of Formula (II) are then added to the main mixer, where they have been
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    16/18 mixed for about 3 minutes. Citric acid is added to the main mixer, where it was mixed for about 5 minutes. Glycerin is added to the main mixer. Sorbitol is added to the main mixer, where it was mixed for about 5 minutes. The premix is then added to the main mixer, where it was mixed for about 15 minutes.
    Example 3 [056] To evaluate the minimum inhibitory concentrations (MIC), the concentration of the culture of twenty four hours, in log phase, is adjusted by dilution in soybean triptych broth (TSB), so that the optical density of 0, 2 to 610 nm is obtained. The bacterial culture is therefore ready for use in the assay.
    [057] Three solutions are prepared: (1) 1% CPC solution in ethanol; (2) 1% solution of the compound of Formula (II) in water; and (3) 0.5% of a compound of Formula (II) + 0.5% CPC. The solutions are diluted 1: 9 in TSB. They are added to a 96-well plate and a serial dilution (dilution factor 1: 2) is performed across the plate. The bacterial inoculum with OD 0.2, 100 pL, is added to each well. The plate is incubated overnight and read in a plate reader the next day.
    TABLE 2
    Active MIC (ppm) Negative Control > 250 Compound of Formula (II) 0.49 CPC 0.98 Compound of Formula (II) + CPC <0.12
    0.5% CSA-13 + 0.5% CPC is <0.4 = synergistic EXAMPLE 4 [058] Water is used as a negative control. 0.04 mL of each sample is added to a GC headspace vial for each sample to be tested in duplicate. A saliva inoculum is prepared using 65% of all saliva collected after lunch, 30% deionized water, and 5% FTG media. Three milliliters of
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    17/18 saliva mixture are added to the tubes containing the samples. The vials containing the saliva mixture and the samples are sealed.
    [059] The sealed flasks are incubated overnight at 37 ° C in a shaking water bath. Gas chromatography (GC) is used to determine the amount of reduction in volatile sulfur compounds (VSC) compared to the negative control.
    [060] The data described in Table 3 (below) demonstrates that the compositions of the present invention are effective in reducing volatile sulfur compounds, and would therefore be likely to be effective in the treatment of bad breath.
    TABLE 3
    Formulation VSC reduction Negative Control 13.1 0.05% of the Compound of Formula (II) 97
    EXAMPLE 5 [061] In this assay, the two fluorescent dyes are used to give a quick measure of bacterial viability.
    [062] A sample of a chemostatic culture of mixed bacterial species, OD ~ 0.6, is transferred to 1.5 ml sterile microcentrifuge tubes and centrifuged for 10 minutes at 12,000 x g to sediment the bacteria. The bacteria are then resuspended in 100 µl of sterile phosphate buffered saline (PBS). The samples are treated with 100 pL (high dose) or 20 pL (low dose) of the mouthwash or control solution. Suppression / death is stopped after 30 seconds, as indicated by the addition of 1.35 mL of Neutralization Buffer D / E (Invitrogen). The samples are centrifuged for 10 min at 12,000 x g to sediment the bacteria, and the pellets are resuspended in 500 pL of sterile PBS to wash and then centrifuged again. Finally, the samples are suspended in 150 pL of sterile PBS and 50 pL aliquots are transferred to each of the three wells of the sterile 96-well plates, where they are subjected to bacterial staining using the BacLight Live / Dead viability kit, from Invitrogen. Are
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    18/18 50 μΙ_ of 2 x solution containing two dyes (SYTO9 dyes [green] and propidium iodide [red]) added to the samples contained in the 96-well plates. The plates are incubated for 15 minutes at room temperature, protected from light and subjected to fluorescence reading at the excitation wavelength of 485 nm and at the emission wavelength of 535 and 635 nm. The results are presented as a percentage of cells that are viable compared to a control sample treated with PBS.
    [063] Table 4 (below) presents data that demonstrate that the compositions of the present invention provide a synergistic antimicrobial effect after 30 seconds of use.
    TABE A 4
    Formulation Log reduction in 30 seconds 0.05% CPC 3.93 0.05% of the Compound of Formula (II) 0.38 0.05% of the Compound of Formula (II) + 0.05% of CPC 7.52
    EXAMPLE 6 [064] The anti-inflammatory activity of a compound of Formula (II) is studied in relation to six human inflammatory cytokines, PGE2, IL-1 β, IL-6, IL-8, TNF-α and GM-CSF in separate sets of experiments; first for PGE2, then for the other five cytokines. The cells of the human monocyte line U937 are differentiated into macrophages and the production of cytokines is induced by the stimulation of the cells through the use of P. gingivalis killed by the action of heat (HKPG, 1 x 10 8 cells). Different types of inflammatory cytokines are produced by U973 cells and released into the supernatant.
    [065] A compound of Formula (II) has a greater anti-inflammatory efficacy against three cytokines, IL-1e, IL-6 and TNF-α. Specifically, at a concentration of 0.1 ppm, a compound of Formula (II) reduces 21% IL-10, 60% IL-6 and 80% TNF-α.
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    1/3
    权利要求:
    Claims (15)
    [1]
    1. Aqueous composition for oral care, CHARACTERIZED by the fact that it comprises:
    a cationic steroid compound, where the cationic steroid compound is a compound of Formula (I):
    - (I) where Ri is selected from -OH and NH-R2, where R2 is C2-C14 alkyl, C2-C14 alkenyl or C2-C14 alkynyl, and n is 3 or 4; and a quaternary ammonium compound, in which the quartenary ammonium compound is selected from: benzalkonium chloride, benzethonium chloride, methylbenzetonium chloride, ketalconium chloride, cetylpyridinium chloride, cetrimonium, cetrimide, dofanium chloride, dofanium chloride tetraethylammonium, didecyl dimethyl ammonium chloride and domiphene bromide.
    [2]
    2. Composition, according to claim 1, CHARACTERIZED by the fact that the composition is a mouthwash.
    [3]
    3. Composition according to claim 1, CHARACTERIZED by the fact that the compound of Formula (I) is selected from a compound of and a compound of Formula (III):
    Petition 870170096590, of 12/11/2017, p. 31/34
    2/3 (III).
    [4]
    Composition according to any one of claims 1 to 3,
    [5]
    Composition according to any one of claims 1 to 4, CHARACTERIZED by the fact that the quaternary ammonium compound comprises cetylpyridinium chloride.
    [6]
    6. Composition according to any one of claims 1 to 5, CHARACTERIZED by the fact that the cationic steroid compound is present at a concentration of about 0.01% to about 0.1%, by weight, of the composition.
    [7]
    7. Composition according to any one of claims 1 to 6, CHARACTERIZED by the fact that the quaternary ammonium compound is present at a concentration of about 0.01% to about 0.1%, by weight, of the composition .
    [8]
    8. Composition according to any one of claims 1 to 7, CHARACTERIZED by the fact that the cationic steroid compound and the quaternary ammonium compound are present in a 1: 1 ratio, based on their respective concentrations, by weight, in the composition.
    [9]
    9. Composition according to any one of claims 1 to 8, CHARACTERIZED by the fact that the cationic steroid compound is present at
    Petition 870170096590, of 12/11/2017, p. 32/34
    3/3 a concentration of about 0.05%, by weight, of the composition.
    [10]
    10. Composition according to any one of claims 1 to 9, CHARACTERIZED by the fact that the quaternary ammonium compound is present at a concentration of about 0.05%, by weight, of the composition.
    [11]
    11. Composition according to any one of claims 1 to 10, CHARACTERIZED by the fact that it further comprises a source of fluoride ions, wherein the source of fluoride ions is selected from stannous fluoride, sodium fluoride, potassium fluoride, monofluorophosphate sodium, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride and a combination of two or more of them.
    [12]
    12. Composition according to claim 11, CHARACTERIZED by the fact that the source of fluoride ions comprises sodium fluoride.
    [13]
    13. Use of a cationic steroid compound and a quaternary ammonium compound CHARACTERIZED by the fact that it is in the manufacture of an aqueous oral care composition as defined in any of claims 1 to 12 for the treatment of a disease or condition of the cavity oral.
    [14]
    14. Use of a cationic steroid compound CHARACTERIZED by the fact that it is in the manufacture of an aqueous oral care composition for the treatment of an inflammatory condition of the oral cavity, in which the cationic steroid compound is a compound of Formula (I) as defined in claim 1.
    [15]
    15. Non-therapeutic method of reducing volatile sulfur compounds, CHARACTERIZED by the fact that it comprises administering a composition comprising a cationic steroid compound to the oral cavity of a patient in need of it, in which the cationic steroid compound is a compound of Formula (I) as defined in claim 1.
    Petition 870170096590, of 12/11/2017, p. 33/34
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    同族专利:
    公开号 | 公开日
    IL233216D0|2014-08-31|
    EP2793832B1|2018-05-23|
    RU2625838C2|2017-07-19|
    AR089372A1|2014-08-20|
    US20160045421A1|2016-02-18|
    AU2011385377A1|2014-07-03|
    RU2014129813A|2016-02-10|
    TW201332581A|2013-08-16|
    NZ626144A|2016-05-27|
    CA2859325A1|2013-07-25|
    MX2014007496A|2015-02-17|
    UA113298C2|2017-01-10|
    KR20140116111A|2014-10-01|
    EP3449900A1|2019-03-06|
    CN104379120A|2015-02-25|
    JP2015502978A|2015-01-29|
    TWI559936B|2016-12-01|
    WO2013109236A2|2013-07-25|
    JP6051230B2|2016-12-27|
    WO2013109236A3|2013-10-10|
    BR112014015144A2|2017-06-13|
    AU2011385377B2|2017-06-01|
    EP2793832A2|2014-10-29|
    US20140369941A1|2014-12-18|
    US9345655B2|2016-05-24|
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    法律状态:
    2017-09-12| B15K| Others concerning applications: alteration of classification|Ipc: A61K 8/63 (2006.01), A61K 8/21 (2006.01), A61Q 11/ |
    2017-09-12| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2018-01-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2018-03-27| B16A| Patent or certificate of addition of invention granted|
    2021-01-12| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: REFERENTE A 9A ANUIDADE. |
    2021-05-04| B24J| Lapse because of non-payment of annual fees (definitively: art 78 iv lpi, resolution 113/2013 art. 12)|Free format text: EM VIRTUDE DA EXTINCAO PUBLICADA NA RPI 2610 DE 12-01-2021 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDA A EXTINCAO DA PATENTE E SEUS CERTIFICADOS, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2011/066482|WO2013109236A2|2011-12-21|2011-12-21|Oral care compositions|
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