Classifications

• • 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
• • 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
  • A61K8/34—Alcohols
• • 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
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • 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
  • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
  • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
• • 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
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/005—Antimicrobial preparations

Definitions

• the present invention relates to antimicrobial agents for use in oral hygiene products and methods for using such agents.
• Periodontal disease and dental caries are of major public health and economic interest worldwide. It is now widely recognized that both of these oral diseases are caused by bacteria which grow in masses on the teeth and in the gingival area. A commonly used descriptive term for these bacterial masses is "dental plaque”.
• Schluger et al. Scholuger, Yuodelis, Page & Johnson, Periodontal Diseases, second edition, pp. 153-262, Lea & Febiger, 1990
• dental plaque bacteria growing in the area where the teeth and gingival tissues meet, cause an inflammation of the gingiva called "gingivitis". This is characterized by swollen, edematous gingiva ("gums”) which are reddened and bleed easily.
• Periodontitis generally is a characterized by a chronic inflammation of the tissues around the teeth, which leads to a resorption of supporting bone. Periodontal disease is the leading cause of tooth loss among adults.
• Dental caries (cavities) are also caused by bacteria, with Streptococcus mutans being the principal etiologic agent (McGhee, Michalek & Cassell, Dental Microbiology, p. 279, Harper & Row, 1982).
• cocamidopropyl betaine, hinokitiol, and berberine and the essential oils, citral, geraniol, and juniper berries oil individually exhibit antimicrobial properties against certain bacteria.
• U.S. Patent No. 3,940,476 describes a method for inhibiting the formation of dental plaque, which comprises topically applying to the teeth as an active ingredient an amount of either one or a combination of (a) allyl isothiocyanate, (b) uranine, (c) obtusastyrene, (d) citral, (e) citronellol, (f) nerol, or (g) geraniol.
• U.S. Patent No. 4,913,895 describes an oral composition including a linear polyphosphate or a cyclic polyphosphate and menthol, anethol, or mixtures thereof in an aqueous medium. The composition is reported to have antibacterial effects and prevent the development of calculus and periodontal diseases.
• U.S. Patent No. 4,966,754 describes that certain essential oils and combinations thereof possess antimicrobial properties against Aspergillus niger, Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa, and therefore are suitable as preservatives in cosmetic compositions.
• a blend of 14 essential oils is described as providing desirable antimicrobial properties against the noted microorganisms.
• U.S. Patent No. 4,999,184 describes oil compositions containing certain pyrophosphate salts which are reported to provide an anticalculus benefit.
• U.S. Patent No. 5,316,760 describes a mouth care product that contains a combination of Urtica dioica extract and an extract of Juniperus communis. The combination of these extracts is described as leading to a synergistic reduction of both dental plaque and bleeding or inflammation of the gingiva. Achillaea millefolium extract is also described as being a suitable additive to the combination of the Urtica dioica and Juniperus communis extracts.
• U.S. Patent No. 5,472,684 describes a composition including thymol and eugenol, and optionally a sesquiterpene alcohol, such as farnesol, that reportedly has antiplaque and antigingivitis effects.
• Australian tea tree oil, sage oil, and eucalyptol are described as enhancing the antiplaque and antigingivitis activity of mouth rinses formulated from the disclosed compositions.
• MIC minimum inhibitory concentration
• antimicrobial agents are introduced into the oral cavity at an initial concentration. Almost immediately, the initial concentration begins to decrease because of the dynamics of the oral cavity. Eventually, the concentration of the antimicrobial agent within the oral cavity will fall below the MIC. Thus, it has been a goal of those working to develop antiplaque and anticalculus formulations to use antimicrobial agents that have low MICs.
• Chlorhexidine has a MIC of about one ⁇ g/ml and is the standard against which other antimicrobial agents are measured. While chlorhexidine has a desirable MIC, it also exhibits undesirable taste and has the undesirable side effect of staining teeth. Summary of the Invention
• the present invention is an oral hygiene composition that includes an antimicrobial agent selected from cedarwood oil, chloramphenicol, citronella oil, Glycyrrhiza glabra extract, juicy fruit basil oil, lemon basil oil, and Rosmarinus officinalis oil.
• oral hygiene compositions including these antimicrobial agents are effective at inhibiting and preventing the growth of bacteria present in oral cavities such as Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis.
• Oral hygiene compositions formed in accordance with the present invention are characterized in that the antimicrobial agent is present in an amount sufficient to retard the growth of bacteria or kill bacteria.
• the antimicrobial agents can be combined with components typically found in oral hygiene products such as dentifrices. These components include abrasives, humectants, binders, and surfactants. Other dentifrice components include flavoring agents and thickening agents.
• the oral hygiene compositions and products of the present invention can be used in the method of practicing oral hygiene that includes the step of contacting an oral cavity with an antimicrobial agent selected from cedarwood oil, chloramphenicol, citronella oil, Glycyrrhiza glabra extract, juicy fruit basil oil, lemon basil oil, lemon oil, or Rosmarinus officinalis oil.
• cedarwood oil refers to volatile whole oil extracts from the heartwood of Juniperus virginiana or Juniperis ashei.
• Constituents of the whole oil extract include thujopsene, cedrol, alpha-copaene, alpha-cedrene, beta-cedrene and widdrol.
• the CAS number for cedarwood oil is 8000-27-9.
• Chloramphenicol refers to 2,2-dichloro-N-[2-hydroxyl-l-(hydroxymethyl)- 2-(4-nitrophenyl) ethyl] acetamide. Chloramphenicol is derived from Streptomyces venezuelae or by organic synthesis. The CAS number for chloramphenicol is 56-75-7.
• Citronella oil refers to a commercially available oil produced by steam distillation of either Cymbopogon nardus or Cymbopogon winterianus. The CAS number for citronella oil is 8000-29-1.
• Glycyrrhiza glabra extract also known as licorice root extract, refers to the crude powder extract from Glycyrrhiza glabra L. Several varieties including G. typica and G. glandulifera exist. Glycyrrhiza glabra extract contains glycyrrhizic acid and glycyrrhetinic acid. The whole extract is available from commercial sources or may be collected by solvent extraction, such as ethanol extraction described below.
• Juicy fruit basil oil refers to the whole extract of a selected variety of basil with a juicy fruit component. Juicy fruit basil is a cultivar of Ocimum bascilicum L.
• Lemon basil oil refers to the volatile whole oil extract from a selected variety of basil with a citral component.
• Lemon basil is a cultivar of Ocimum bascilicum L. with a high content of citral.
• Lemon oil refers to the volatile whole oil extract from the fresh peel of Citrus limon. Lemon oil is also known as oil of lemon or citrus limon oil. The CAS number for lemon oil is 8008-56-8.
• Rosmarinus officinalis oil refers to the whole oil extract from the flowering tops of Rosmarinus officinalis. Rosmarinus officinalis oil is also known as the extract of Rosemary, or the extract of Rosmarinus officinalis oil. The CAS number for Rosmarinus officinalis oil is 84604-14-8.
• Minimal inhibitory concentration or MIC refers to the minimum concentration in micrograms per milliliter of an antimicrobial agent at which no bacterial growth are observed. At concentrations below the MIC, the antimicrobial agent is ineffective at killing or inhibiting the growth and reproduction of bacteria. At concentrations above the MIC, the antimicrobial agent is effective at killing or inhibiting the growth and reproduction of bacteria.
• An oral hygiene composition formed in accordance with the present invention includes an antimicrobial agent selected from cedarwood oil, chloramphenicol, citronella oil, Glycyrrhiza glabra extract, juicy fruit basil oil, lemon basil oil, and Rosmarinus officinalis oil.
• an antimicrobial agent selected from cedarwood oil, chloramphenicol, citronella oil, Glycyrrhiza glabra extract, juicy fruit basil oil, lemon basil oil, and Rosmarinus officinalis oil.
• Preferred oral hygiene compositions include an antimicrobial agent selected from cedarwood oil, chloramphenicol, and Glycyrrhiza glabra extract. Particularly preferred for incorporation into an oral hygiene composition formulated in accordance with the present invention are antimicrobial agents selected from cedarwood oil and Glycyrrhiza glabra extract. The preferred antimicrobial agents are selected because these agents are surprisingly effective at retarding the growth of and/or preventing the growth of representative gram-positive and gram-negative oral pathogenic bacteria such as Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis.
• the antimicrobial agent is effective against more than one of the bacteria noted above, and preferably all of the bacteria noted above.
• the particular amount of antimicrobial agent present in compositions formed in accordance with the present invention is not limited to any particular value, provided that the amount present is effective at retarding the growth of bacteria and/or preventing the growth of bacteria, i.e., an amount that is greater than the MIC of the antimicrobial agent with respect to the particular bacteria.
• the antimicrobial agents of the present invention exhibit MICs that range from about 3.1 to about 156 against the representative oral pathogens Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis.
• Dentifrices or toothpastes, are generally a thickened slurry of an abrasive polishing material in an aqueous humectant system.
• dentifrices include an abrasive to remove stained pellicle, humectant(s) to provide a vehicle for the flavor, abrasive, thickening agent(s) to structure and stabilize the dentifrice, surfactant mainly to supply foam during use, fluoride to prevent dental caries, and flavor to make the product taste pleasant.
• abrasives are available for use in dentifrices, examples include silica xerogel, silica precipitates, dicalcium phosphate, dicalcium phosphate dihydrate, alumina trihydrate, calcium pyrophosphate, calcium carbonate, and insoluble sodium metaphosphate.
• humectants examples include sorbitols, glycerin, and polyethylene glycols.
• Silica aerogels, pyrogenic silica, silica precipitates, carboxymethylcellulose, carboxyvinyl polymers, xanthan gum, and carrageenan are examples of materials that are suitable as thickeners.
• Exemplary surfactants include sodium lauryl sulfate and dodecylbenzene sulfonate. Numerous flavoring agents are commercially available with those providing mint or other refreshing flavors such as cinnamon being commonly used.
• Oral rinses or mouth washes are generally, aqueous, pourable emulsions of flavors into which, in most instances, an antimicrobial has been incorporated.
• Typical components of an oral rinse include flavoring agent to make the product pleasant to use and to emphasize therapeutic or freshness qualities, surfactant(s) to maintain flavor in stable dispersion, humectant(s) to improve mouth feel, thickening agent, and an active agent. Often times, a surfactant is used to impart light foaming properties to the oral rinse.
• Dentifrices and oral rinses incorporating the antimicrobial agents for inhibiting the growth of bacteria in the oral cavity in accordance with the present invention are formulated in a conventional manner with the antimicrobial agents being present in an amount ranging from about 0.001 wt. % to about 5.0 wt. % based on total weight of dentifrice.
• the antimicrobial agents are present in an amount ranging from about 0.01 wt. % to about 2.5 wt. %.
• the specific components used in the dentifrices and oral rinses incorporating the antimicrobial agents of the present invention are not limited to those set forth above; however, the components selected preferably do not have an antagonistic effect on the antimicrobial properties of the selected antimicrobial agent.
• the following examples illustrate the effectiveness of oral hygiene compositions of the present invention against bacteria present in the oral cavity, the
• Example 1 Determination of Minimum Inhibitory Concentration of Antimicrobial Agents
• the following example illustrates how antimicrobial agents useful in accordance with the present invention retard or prevent the growth of dental plaque bacteria present in the oral cavity.
• the example illustrates the lowest concentration of various antimicrobial agents that will inhibit visible in vitro growth of a particular bacteria.
• the assay used a microtiter plate to dilute the antimicrobial agent to varying concentrations in order to determine the MIC.
• Table 1 below provides a listing of antimicrobial agents used in this example and abbreviations therefor.
• Rosmarinus officinalis oil A bacteria culture was incubated overnight at 37°C. Prior to dilution of the antimicrobial agents as described below, the bacterial culture was spun down at 2000 rpm into a pellet and resuspended in a solution of buffered phosphate. The irmoculum was normalized with a spectraphotometer to an optical density at 550 nanometers of between 0.18-0.22, equivalent to 5.0 x 10 7 colony-forming units (CFU per milliliter). The irmoculum was set aside until the completion of the antimicrobial agent dilution.
• a sterile polystyrene 96-well plate was used to dilute the antimicrobial agents. Using aseptic technique, 100 microliters of distilled water was placed in each test well. In the first well in each column, 100 microliters of antimicrobial agent was added. Stock solutions of antimicrobial agents were prepared with methanol as a solvent to bring the agents into solution. This resulted in a one-half dilution of the stock solution. 100 microliters from these wells was then transferred to the next well in the column, and so on, down each column. Each transfer accomplished a one -half dilution of the concentration in the preceding well.
• the 96-well plate was incubated under conditions that varied depending on the particular microorganism.
• the incubation conditions are set forth in Table 2.
• the aerobic bacteria were incubated under normal room conditions and the anaerobic bacteria were incubated under an atmosphere of 10% hydrogen gas, 5% carbon dioxide gas and the balance nitrogen gas.
• the incubated plate was read for microbial growth with a spectraphotometer by optical density (OD).
• OD optical density
• the well containing the lowest dilution achievable with a spectraphotometer reading below 0.05 OD (i.e., no detectable microbial growth) was considered representative for the antimicrobial agent.
• the MIC for the agent was determined by accounting for the starting stock solution concentration and the resulting dilutions in the 96-well plate.
• the specific bacteria inoculated into the 96-well plate are set forth in Table 2 below, along with the growth media and incubation conditions for that microorganism.
• yeast extract 0.01%, sodium formate 0.2%, sodium fumerate 0.03%, hemin 0.005% and 990 millileters distilled water.
• This example illustrates the minimum inhibitory concentration of the noted antimicrobial agents and the ability of the antimicrobial agents to inhibit growth of the specific bacteria.
• Example 2 Dentifrice Formulations This example describes dentifrice formulations comprising antimicrobial agents of the present invention. Formulation 18-88 does not include antimicrobial agents in accordance with the present invention.
• Poloxamer 407 (PLURONIC® F127) 9.50
• Carbomer 940 (CARBOPOL® 940) 0.30
• Carbomer 940 (CARBOPOL® 940) 0.30
• Titanium dioxide 1.00
• Carbomer 940 (CARBOPOL ® 940) 0.30
• Titanium dioxide 1.00
• Formulation 18-90 1% Cedarwood Oil (W/W)
• Carbomer 940 (CARBOPOL® 940) 0.30
• Titanium dioxide 1.00
• Carbomer 940 (CARBOPOL® 940) 1.00
• Poloxamer 407 (PLURONIC ® F127) 9.50
• Carbomer 940 (CARBOPOL® 940) 0.30
• Carbomer refers to a polymer composed of acrylic acid crosslinked with allyl sucrose available as CARBOPOL® 940.
• CARBOPOL® 940 is commercially available from B.F. Goodrich.
• SYLODENT ® 750 and 700 are silica gels (silicon dioxide), and SYLODENT® 15 is a silica gel (silicon dioxide).
• SYLODENT® is available commercially from W.R. Grace & Co. Conn. Davison Chemical Division.
• the fo ⁇ nulations described above are formed in a vacuum mixer by adding deionized water and dispersing the Carbomer while pulling a vacuum. When the Carbomer was well dispersed, the sodium hydroxide was added.
• the 70% sorbitol and Poloxamer were heated and mixed in another vessel.
• the Poloxamer mixture was then added to the vacuum mixer and blended with the Carbomer mixture.
• Xanthan gum was mixed with glycerin and then added to the solution in the vacuum mixer and incorporated therein.
• the salts were then added to the vacuum mixer followed by the silicas. These components were slowly mixed in.
• the active agents, flavoring agents, sodium lauryl sulfate and coloring agents were added followed by mixing until well incorporated.
• This example illustrates several dentifrice formulations incorporating antimicrobial agents of the present invention.
• Example 3 Customer Acceptance This example illustrates customer acceptance of dentifrice formulations incorporating an antimicrobial agent in accordance with the present invention.
• the formulations set forth above in Tables 4-9 were evaluated for customer acceptance.
• several commercially available dentifrices were also evaluated. These included Viadent Gel (Formulation 5-35), available from Viadent, Inc.; Crest Regular Blue Paste (Formulation 5-97), available from Proctor & Gamble Company; and Listerine Teal Gel (Formulation 5-99), available from Warner Wellcome.
• This example illustrates how the overall consumer satisfaction for the formulations with active agents in accordance with the present invention is greater than the overall consumer satisfaction for certain commercially available products.
• This example illustrates how dentifrice formulations including compositions of the present invention reduce bacteria levels in the gingival margin.
• the subject's brushing habits remained constant. On the day of sampling, subjects had not brushed their teeth for 16-18 hours (overnight) prior to testing. The level of bacteria was enumerated by recovering in vivo samples and counting the number of bacterial colonies formed on agar after 48 hours.
• Subjects were 18-65 years old, had a minimum of 20 teeth, and had normal salivary flow. Subjects were rejected if they had systemic diseases that affect the oral tissues, such as diabetes, blood cell abnormalities, Down's syndrome, or known HIV-infection; had glossitis, moderate to severe gingivitis, periodontitis or other oral infections, or were taking a systemic antibiotic or had done so in the two weeks preceding the initiation of the test.
• systemic diseases that affect the oral tissues such as diabetes, blood cell abnormalities, Down's syndrome, or known HIV-infection
• had glossitis, moderate to severe gingivitis, periodontitis or other oral infections or were taking a systemic antibiotic or had done so in the two weeks preceding the initiation of the test.
• Each of the formulations was assayed for antimicrobial efficacy on approximately 20 subjects.
• the subjects were requested to have overnight plaque the morning they were sampled for a "single brushing effect" of a formulation.
• a gingival margin plaque sample was taken with a sterile cotton swab and placed in 1 milliliter of sterile phosphate buffered saline (PBS). Swabs were gently rubbed along the gingival margin of the mandibular buccal surface between the incisors. Subjects then brushed immediately after the baseline sample with a dentifrice formulation using an electric toothbrush for two minutes. At intervals of one and two hours after completion of the brushing, gingival plaque samples were recovered with swabs as described above.
• PBS sterile phosphate buffered saline
• the clinical design was a multi-period crossover study.
• multi-period crossover study is meant an experiment in which subjects are administered first one treatment, then “crossed over” to receive a second, then third and finally a fourth treatment.
• the experimental design enables each subject to serve as his or her own control.
• a "wash-out" period of 2 days was used between testing different antibacterial formulations.
• the gingival samples were placed in test tubes and remained at room temperature until processed within one hour.
• the test tube samples were serially diluted in sterile PBS with a Spiral Plater (Spiral Systems, Cincinnati, Ohio) and plated on blood agar supplemented with 5% sheep blood (BBL, Becton Dickinson, Cockeysville, Maryland). The plated samples were then incubated aerobically at 37°C for 48 hours. Bacteria were counted for total aerobic colony forming units. The bacterial counts were transformed into log 10 units. Mean and standard deviations for each test condition were generated. Data was paired by subject for relevant comparisons and analyzed by the nonparametric Wilcoxon sign-rank test for significance level. Hypothesis testing relied on statistics utilizing the multiperiod crossover design of the clinical study. The data are presented below in Table 12. Formulations 18-25, 18-87, and
• Formulation 18-90 included components set forth in Tables 9, 7 and 8, respectively.
• Formulation 18-88 included the components set forth in Table 10 (no antibacterial agent) and was used as a control for comparison purposes against formulations 18-25, 18-87 and 18-90.
• NA Not Applicable This example illustrates how the dentifrice formulations including antimicrobial agents of the present invention reduce gingival in vivo bacterial levels.
• Example 5 Ethanol Extraction of Glycyrrhiza slabra 25 grams of powdered plant material from Glycyrrhiza glabra was combined with 250 grams of a 95:5 ethanol/water mixture. The mixture was stirred overnight at room temperature. Solids were removed from the stirred mixture with a No. 4

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• 1998
  • 1998-04-01 CA CA002257596A patent/CA2257596A1/en not_active Abandoned
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  • 1998-04-01 AU AU68773/98A patent/AU6877398A/en not_active Abandoned
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