(en)A personal care composition and method of using a personal care composition having menthol and/or hydrogen peroxide and a TRPA1 and/or TRPV1 receptor antagonists.

1.ApplicationNumber: US-201313873749-A
1.PublishNumber: US-2013315843-A1
2.Date Publish: 20131128
3.Inventor: HAUGHT JOHN CHRISTIAN
SREEKRISHNA KOTI
DAS SOURAV
HOKE, II STEVE HAMILTON
COFFINDAFFER TIMOTHY WOODROW
BAKES KATHARINE ANNE
GLANDORF WILLIAM MICHAEL

4.Inventor Harmonized: HAUGHT JOHN CHRISTIAN(US)
SREEKRISHNA KOTI(US)
DAS SOURAV(IN)
HOKE II STEVE HAMILTON(US)
COFFINDAFFER TIMOTHY WOODROW(US)
BAKES KATHARINE ANNE(US)
GLANDORF WILLIAM MICHAEL(US)

5.Country: US
6.Claims:
(en)A personal care composition and method of using a personal care composition having menthol and/or hydrogen peroxide and a TRPA1 and/or TRPV1 receptor antagonists.

7.Description:
(en)FIELD OF THE INVENTION
The present invention relates to a composition comprising TRPA1 antagonists, TRPV1 antagonists, or both to reduce the perceived burn sensation associated with menthol or peroxide.
BACKGROUND OF THE INVENTION
In Personal Care Products, such as Oral Care Compositions the use of menthol is extensive and associated with a cleansing feeling and freshness when used at tolerable levels. Hydrogen peroxide is used as an antimicrobial, whitening agent, and in the hair coloring process. When used at high levels (>0.3% menthol or >0.1% hydrogen peroxide), they can be associated with burning and pain, as highlighted by G. Wasner et al, Brain, 127:1159-1171 (2004); K. Hill & M. Schaefer, Cell Calcium 45:155-164 (2009); and Kao in JP 2011136953.
Menthol is a well-established TRPM8 agonist that provides a chemical induced cooling response. Due to menthol's volatility, it also stimulates the olfactory bulb, providing a characteristic scent. At high levels, it can also induce a burning sensation in the nasal cavity (Renner & Schreiber, Exp. Brain Res., 217:1-14 (2012)). Further, at high levels, menthol or hydrogen peroxide are thought to activate the TRPA1 and TRPV1 receptors (P Baraldi et al, J. Med. Chem., 53:5085-5107 (2010)), which have been associated with the sensation of pain and irritation. The sensation of pain due to high levels of menthol or hydrogen peroxide can be characterized as a burning sensation or irritation when below the pain threshold (Craig & Bushnell, Science 265:252-5 (1994)); and (JP 06065044). Ahern and Matta (US Pub. No. 20110104301) attempted to modulate these receptors independent of the pain source by administering, in the presence of anesthetic, high levels of menthol among other compounds. Although menthol and peroxide activate the TRPA1 and TRPV1 receptors, they do so at only high concentrations.
As TRPA1 and TRPV1 are up-regulated by more than one agonist, a broad based blocker to each of these receptors would have the undesirable effects of losing the positive sensations that are generated from them, such as taste, tingle and astringency reduction from TRPA1 agonists and warming and astringency reduction from TRPV1 agonists. In US Pub. No. 20080153845, they illustrate TRPV1 antagonists to capsaicin, which they highlight as eliminating all taste sensations. Maintaining taste and positive sensory responses are necessary for flavor perception from Oral Care products and for scent perception from skin and hair products.
It was found in WO 2009087242 that the capsaicin antagonist trans-tert-butyl cyclohexanol helped to reduce negative skin sensations from cosmetic products. Further, due to the high level of menthol or hydrogen peroxide needed to activate TRPA1 and TRPV1, molecules that can inhibit traditional agonists to these receptors are functionally ineffective and require a molecule or combination of molecules specific to menthol or hydrogen peroxide. As a muscle soothing cream (US20090098213) high levels of menthol are delivered to generate the burning sensation, along with TRPV1 or TRPA1 agonists. Delivering high levels of menthol or hydrogen peroxide whether delivered to the mouth, skin, scalp, or hair, orwithout the burning sensation would be desirable as a positive signal of efficacy. Further, some of these molecules may exhibit the ability to reduce sulfur and amine species present in the body in the form of Michael Acceptors (Yoshida et al., Tetrahedron Letters, 51:5134-5136 (2010)). This effect of sulfur modification was demonstrated on the TRPA1 cysteine residues (C415S, C422S, and C622S) in response to Isothiocyanates in Mustard Oil by Macpherson et al., Nature, 445:541-545 (2007). An additional benefit of high menthol levels would be improved antimicrobial efficacy to dentifrice and rinse formulations, giving rise to formulas able to provide improved plaque and gingivitis reductions.
Therefore, what is needed is a composition and method that can reduce the negative sensations associated with menthol and hydrogen peroxide through activation of the TRPA1 and TRPV1 receptors, but that does not completely inhibit the TRPA1 and TRPV1 receptors.
SUMMARY OF THE INVENTION
A hair coloring composition is provided that comprises at least one of an antagonist to TRPA1 receptor or an antagonist to TRPV1 receptor and hydrogen peroxide.
A personal care composition is provided that comprises at least about 0.2% by weight of the personal care composition is hydrogen peroxide or 0.5% by weight of the personal care composition is menthol; and at least one of an antagonist to TRPA1 receptor or an antagonist to TRPV1 receptor.
A method of reducing the negative sensations produced by the application of personal care compositions is provided that comprises providing an personal care composition having at least about 0.2% by weight of the personal care composition of hydrogen peroxide or about 0.5% by weight of the personal care composition of menthol; at least one of an antagonist to TRPA1 receptor or an antagonist to TRPV1 receptor; and contacting a body surface with the personal care composition.
A method for lowering the odor detection of and irritation caused by volatile sulfur and amines comprising providing a personal care composition comprising a Michael Acceptor, wherein the Michael Acceptor is an antagonist of at least one of TRPA1 receptor or TRPV1 receptor; and contacting a body surface with the personal care composition.
A method of screening for TRPA1 or TRPV1 antagonists is provided that comprises providing a TRPA1 or TRPV1 antagonist and a TRPA1 or TRPV1 agonist; exposing the TRPA1 or TRPV1 antagonist to a cloned TRPA1 or TRPV1 receptor or cultured human neural cell; exposing the TRPA1 or TRPV1 agonist to a cloned TRPA1 or TRPV1 receptor or cultured human neural cell; and measuring the calcium flux to determine antagonistic activity of the TRPA1 or TRPV1 antagonist.
A method for modulating the shade of a personal care surface from a darker shade to a lighter shade comprising applying to the surface a personal care composition comprising a Michael Acceptor, wherein the Michael Acceptor is an antagonist of at least one of TRPA1 receptor or TRPV1 receptor; contacting a body surface with the personal care composition for at least 30 seconds.


DETAILED DESCRIPTION OF THE INVENTION
It has now surprisingly been found antagonists to menthol's TRPA1 and TRPV1 response provide a noticeable reduction in the burning sensation when high levels of menthol are used. It has also been found that hydrogen peroxide acts similarly in activating the TRPA1 and TRPV1 receptors and the antagonists that shut down the menthol negative sensation also help to reduce the perceived burning/warming sensation from hydrogen peroxide. Surprisingly, these antagonists to menthol or hydrogen peroxide act specific to the TPRA1 and TRPV1 evoked sensations from menthol or hydrogen peroxide, as many of these antagonists do not block the standard agonists used on these receptors; allyl isothiocyanate which is specific to TRPA1 (does not activate TRPV1) and capsaicin which is specific to TRPV1 (does not activate TRPA1). Additionally, as menthol and hydrogen peroxide act across both the TRPA1 and TRPV1 receptors, there is a need for antagonists that block activation of both the TRPA1 and TRPV1 receptor. Therefore, there is an unmet need to provide antagonists to this burn sensation generated from the activation of both TRPA1 and TRPV1, which is met by the present invention.
The negative sensorial attributes of menthol's activation of TRPA1 and TRPV1, such as burning/irritation sensation for TRPA1 and warming/burning for TRPV1, can be mitigated by combining the menthol in a personal care composition with an antagonist to menthol's activation of these receptors. Similarly, hydrogen peroxide also activates TRPA1 and TRPV1 receptors and the negative sensorial attributes associated with the activation of these receptors can be mitigated by combining the hydrogen peroxide in a personal care composition with an antagonist to hydrogen peroxide's activation of these receptors. The antagonists may be delivered with the agonist or sequenced by delivering one first and then the other via different products or applications. The present invention relates to personal care compositions and methods of using the personal care compositions containing >0.5% menthol, >0.2% hydrogen peroxide, or both and which also include antagonists to the TRPA1 or TRPV1 receptor.
The present invention also relates to personal care compositions and methods of using the personal care compositions that reduce the amount of volatile sulfur and amines present, by comprising a Michael Acceptor that is an antagonist to the TRPA1 or TRPV1 receptor, thereby lowering the odor detection threshold of these volatile species and potential irritation.
Without being limited by theory, it is now believed that the negative sensations produced by menthol and peroxide activation of TRPA1 and TRPV1 receptors can be reduced by the use of TRPA1 and TRPV1 antagonists specific to menthol and peroxide activation.
All percentages and ratios used hereinafter are by weight of total composition, unless otherwise indicated. All percentages, ratios, and levels of ingredients referred to herein are based on the actual amount of the ingredient, and do not include solvents, fillers, or other materials with which the ingredient may be combined as a commercially available product, unless otherwise indicated.
All measurements referred to herein are made at 25° C. (i.e. room temperature) unless otherwise specified
As used herein, the word “about” means +/−10 percent.
As used herein, the word “include,” and its variants, are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this invention.
As used herein, the word “or” when used as a connector of two or more elements is meant to include the elements individually and in combination; for example X or Y, means X or Y or both.
By “personal care composition” is meant a product which in the ordinary course of usage is applied to or contacted with a body surface to provide a beneficial effect. Body surface includes skin, for example dermal or mucosal; body surface also includes structures associated with the body surface for example hair, teeth, or nails. Examples of personal care compositions include a product applied to a human body for improving appearance, cleansing, odor control or general aesthetics. Non-limiting examples of personal care compositions include hair coloring compositions, oral care compositions, after shave gels and creams, pre-shave preparations, shaving gels, creams, or foams, moisturizers and lotions, cough and cold compositions, leave-on skin lotions and creams, shampoos, conditioners, shower gels, bar soaps, toilet bars, antiperspirants, deodorants, depilatories, lipsticks, foundations, mascara, sunless tanners and sunscreen lotions.
By a “hair coloring composition” it is meant a composition suitable for changing the color of hair. The hair coloring composition can comprise oxidative precursor dyes, direct dyes or even no or substantially no dyes in case of bleaching only compositions where the change of color is mainly caused by the degradation of the natural melanin contained in the hair shaft or bleaching of artificial dyes that have been delivered by a previous coloring event, by hydrogen peroxide.
The hair coloring compositions according to the present invention comprise at least one source of hydrogen peroxide. Hydrogen peroxide is valuable for the initial solubilization and decolorization of the melanin (bleaching) and accelerates the oxidation of the oxidative dye precursors (oxidative dyeing) in the hair shaft. A solution of hydrogen peroxide may be used, as well as water-soluble inorganic oxidizing agents which are capable of yielding hydrogen peroxide in an aqueous solution may also be used. Water-soluble peroxygen oxidizing agents are well known in the art and include hydrogen peroxide, inorganic alkali metal peroxides such as sodium periodate and sodium peroxide and organic peroxides such as urea peroxide, melamine peroxide, and inorganic perhydrate salt bleaching compounds, such as the alkali metal salts of perborates, percarbonates, perphosphates, persilicates, persulphates and the like. The compositions of the invention may typically comprise from about 0.1% to about 10% by weight, or from about 1% to about 7% by weight, or from about 2% to about 5% by weight of an hydrogen peroxide agent.
The hair coloring compositions of the invention may be formulated in any type of known chassis, such as a cream, a water based gel network thickener system, foam, or mousse. An exemplary gel network thickener system of this invention may be provided by a tertiary surfactant system. This system comprises a first anionic component selected from C8 to C30 alkyl phosphates, C8 to C30 alkyl ether phosphates or mixtures thereof, a second component selected from C14 to C30 fatty alcohols and a third non-ionic component selected from polyoxyethylene C14 to C30 alkyl ethers.
Those skilled in the art will recognize that gel network thickener systems usually have a complex structure of networked lamellar bi-layers and/or vesicles and sometimes crystals. These systems usually have creamy appearance and feel and are thus particularly desirable.
The hair coloring compositions of the invention may comprise in addition to the ingredients indicated above further ingredients in order to further enhance the properties of the composition, including but not limited to: solvents (e.g. glycerine); oxidative dyes, direct dyes; oxidizing agents; radical scavengers; thickeners or rheology modifiers; chelants (e.g. EDDS or DTPMP); pH modifiers and buffering agents (e.g. ammonia and ammonia source); carbonate ion sources; peroxymonocarbonate ion sources; anionic, cationic, nonionic, amphoteric or zwitterionic surfactants, or mixtures thereof; anionic, cationic, nonionic, amphoteric or zwitterionic polymers, or mixtures thereof; fragrances; enzymes; dispersing agents; peroxide stabilizing agents; antioxidants; natural ingredients, e.g. proteins and protein compounds, and plant extracts; conditioning agents including silicones and cationic polymers, ceramides, preserving agents; and opacifiers and pearling agents (such as titanium dioxide and mica). Some adjuvants referred to above, but not specifically described below, which are suitable are listed in the International Cosmetics Ingredient Dictionary and Handbook, (8th ed.; The Cosmetics, Toiletry, and Fragrance Association). Particularly, vol. 2, sections 3 (Chemical Classes) and 4 (Functions) are useful in identifying specific adjuvants to achieve a particular purpose or multipurpose. A few of these ingredients are discussed hereinbelow, whose disclosure is of course non-exhaustive. Additional examples of ingredients are listed in WO2011034868 or CA2567189, for example.
The hair coloring compositions of the invention will typically comprise water as a main ingredient, for example at least about 50%, or 60% or 70% by weight of water.
By “oral care composition”, as used herein, is meant a product, which in the ordinary course of usage, is not intentionally swallowed for purposes of systemic administration of particular therapeutic agents, but is rather retained in the oral cavity for a time sufficient to contact dental surfaces or oral tissues. Examples of oral care compositions include dentifrice, tooth gel, subgingival gel, mouth rinse, mousse, foam, mouth spray, lozenge, chewable tablet, chewing gum, tooth whitening strips, floss and floss coatings, breath freshening dissolvable strips, or denture care or adhesive product. The oral care composition may also be incorporated onto strips or films for direct application or attachment to oral surfaces.
The term “dentifrice”, as used herein, includes tooth or subgingival-paste, gel, or liquid formulations unless otherwise specified. The dentifrice composition may be a single phase composition or may be a combination of two or more separate dentifrice compositions. The dentifrice composition may be in any desired form, such as deep striped, surface striped, multilayered, having a gel surrounding a paste, or any combination thereof. Each dentifrice composition in a dentifrice comprising two or more separate dentifrice compositions may be contained in a physically separated compartment of a dispenser and dispensed side-by-side.
The term “dispenser”, as used herein, means any pump, tube, or container suitable for dispensing compositions such as dentifrices.
The term “teeth”, as used herein, refers to natural teeth as well as artificial teeth or dental prosthesis.
The term “TRPV1” or “TRPV1 receptor”, as used herein, refers to the transient receptor potential vanilloid receptor 1. which is a ligand-gated, non-selective cation channel preferentially expressed on small-diameter sensory neurons and detects noxious as well as other substances.
The term “TRPV1 agonist”, as used herein, refers to any compound, which at a concentration of 1 mM gives a calcium flux count of at least 1000 counts or 20% above the background level of calcium present in the cell according to the FLIPR method, as discussed herein. The term “count” is defined as the change in fluorescence of the cell lines due to the influx of calcium across the cell membrane, which reacts with the calcium sensitive dye present within the cells.
The term “TRPV1 antagonist”, as used herein, refers to any component which at a concentration of 1 mM gives a reduction in calcium flux count of at least 1000 counts or 20% below the activation of TRPV1 receptor by 100 mM of hydrogen peroxide or 100 mM L-menthol of calcium present in the cell according to the FLIPR method, as discussed herein. The term “count” is defined as the change in fluorescence of the cell lines due to the influx of calcium across the cell membrane, which reacts with the calcium sensitive dye present within the cells. The antagonistic effect may also be measured by looking at lower concentrations of the receptor agonist, such as hydrogen peroxide or L-menthol at 500 μM or lower. In certain embodiments a TRPV1 receptor antagonist at a concentration of greater than 100 mM does not give a reduction of at least 20% below the maximum calcium flux count from the TRPV1 receptor activated by 350 μM capsaicin.
Wherein the TRPV1 antagonist may include one or more of the following: (−)-Bornyl Acetate; Hydroxycitronellal; Apritone; Methyl N,N-Dimethylanthranilate; 2-Ethoxy-3-ethylpyrazine; L-Piperiton; Isobornyl Isobutyrate; 4-Acetoxy-2,5-dimethyl-3(2H)-furanone; Tripropyl amine; dihydrojasmone; 1-Methyl-2-pyrole carboxaldehyde; 3-Octyl Acetate; 2-Methylbutyl isovalerate; Jasminone B; Piperonyl Isobutyrate; Phenoxyethyl Propionate; Vanillin Propylene Glycol Acetate; Octenyl Cyclopentanone; Butyl Isobutyrate; Guaiacwood Oil; Tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2H pyran.
The term “TRPV1 enhancer”, as used herein, refers to any compound that boosts the calcium flux activity of an agonist that directly activates TRPV1, but does not directly activate TRPV1.
The term “TRPA1” or “TRPA1 receptor”, as used herein, refers to the transient receptor potential cation channel, subfamily A, member 1, having a large cysteine-rich N-terminus that contains 18 predicted ankyrin repeats. TRPA1 is a ligand-gated, non-selective cation channel preferentially expressed on small diameter sensory neurons.
The term “TRPA1 agonist”, as used herein, refers to any compound, which at a concentration of 1 mM gives a calcium flux count of at least 1000 counts or 20% above the background level of calcium present in the cell according to the FLIPR method, as discussed herein. The term “count” is defined as the change in fluorescence of the cell lines due to the influx of calcium across the cell membrane, which reacts with the calcium sensitive dye present within the cells.
The term “TRPA1 antagonist”, as used herein, refers to any component, which at a concentration of 1 mM gives a reduction in calcium flux count of at least 1000 counts or 20% below the activation of TRPA1 receptor by 100 mM of hydrogen peroxide or 100 mM L-menthol of calcium present in the cell according to the FLIPR method, as discussed herein. The term “count” is defined as the change in fluorescence of the cell lines due to the influx of calcium across the cell membrane, which reacts with the calcium sensitive dye present within the cells. The antagonistic effect may also be measured by looking at lower concentrations of the receptor agonist, such as hydrogen peroxide or L-menthol at 100 μM or lower. In certain embodiments a TRPA1 receptor antagonist at a concentration of greater than 100 mM does not give a reduction of at least 20% below the maximum calcium flux count from the TRPA1 receptor activated by 50 mM allyl isothiocyanate.
Wherein the TRPA1 antagonist may include one or more of the following: cinnamon bark oil; γ-Dodecalactone; vanillic acid; γ-Methyl Decalactone; trans, trans-2,4-Nonadienal; 4-Allyl-2,6-dimethoxyphenol; o-Methoxycinnamaldehyde; 4-Methyl-2-phenyl-2 Pentenal (mix of cis and trans); 2-Methoxy-4-propyl-phenol; Methyl 2-methoxy-benzoate; δ-Tetradecalactone; 1-Methyl-2-pyrole carboxaldehyde; 3,3,5-Trimethylcyclohexanol; N-(2-Hydroxyethyl)lactamide; 2-(3-Phenylpropyl)tetrahydrofuran; Anisyl Butyrate; Methyl-4-phenyl butyrate; 3-Heptyldihydro-5-methyl-2(3H)-furanone; 3-acetylsulfanylhexyl acetate; 3-methyl-5-propyl-2-Cyclohexen-1-one; Isobornyl Isobutyrate; Bornyl Valerate; Citronellyl acetate; (2S,5S,6S)-6-)Hydroxy-dihydrotheaspirane; trans-2-Hexenal.
The term “TRPA1 enhancer”, as used herein, refers to any compound that boosts the calcium flux activity of an agonist that directly activates TRPA1, but does not directly activate TRPA1.
The term “Michael Acceptor”, as used herein, refers to alkenes attached to electron-withdrawing groups such as esters, ketones, nitriles, and nitros, where the beta carbon is the electrophile. The addition reaction is the addition of a nucleophile to a carbanion or to another nucleophile of an α,β-unsaturated carbonyl compound.
The Michael Acceptor may have the dual functionality of chelating stain bodies and thus reducing the surface shade from a darker to a lighter color. On teeth, this may have the appearance of whitening and on skin may have the appearance of lightening.
It is desirable that oral care compositions for use in cleaning and care of the oral cavity impart a fresh and clean feeling as this provides users with a signal of continuing freshness and cleanliness. In addition to the feeling of cleanliness, users also want to experience the benefits of oral care actives like anti-tartar agents, for example, through their oral care regimen. The ability to formulate a user acceptable oral care composition, however, raises challenges as many of the components used to impart a flavor, deliver a benefit, or that are part of the base for the oral care composition, add unwanted tastes or sensations along with the targeted benefit for which they are added. Thus, formulating oral care compositions can be a balancing act between acceptable flavor and acceptable benefits.
The first group of components which reduce the burn associated with menthol or hydrogen peroxide in an oral care composition are Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists. In looking at this receptor, it was discovered that combining antagonists of this receptor in the presence of the agonists menthol or hydrogen peroxide, caused a surprising effect. By adding a TRPV1 antagonist to an oral care composition with high levels of menthol or hydrogen peroxide (compositions having >0.5% menthol or >0.2% hydrogen peroxide), the user of an oral care composition experiences an improved perception as compared to an oral care composition without the TRPV1 antagonist. Thus, the TRPV1 antagonist is working to off-set the burning or warming sensation associated with menthol or hydrogen peroxide activation of TRPV1. TRPV1 responds to, for example, both noxious and painful stimuli. A noxious stimulus would include those which give a burning sensation.
The second group of components which help to reduce the burn associated with menthol or hydrogen peroxide in an oral care composition are Transient Receptor Potential Ankryin 1 (TRPA1) antagonists. In looking at this receptor, it was discovered that combining antagonists of this receptor in the presence of the agonists menthol or hydrogen peroxide, caused a surprising effect. By adding a TRPA1 antagonist to an oral care composition with high levels of menthol or hydrogen peroxide, the user of a composition experiences an improved perception as compared to an oral care composition without the TRPA1 antagonist. Thus, the TRPA1 antagonist is working to off-set the burning, irritating, or off-tasting sensation associated with menthol or hydrogen peroxide activation of TRPA1.
Further, where the agonist, such as menthol or hydrogen peroxide, targets both TRPA1 and TRV1, applying antagonists to each receptor in the same composition works synergistically to reduce the burning or negative sensation or to provide a single antagonists that hits both TRPA1 and TRPV1 provided a more desirable effect than having an antagonist to a single receptor.
In addition to the TRPA1 and TRPV1 antagonists the oral care compositions of the present invention may include one or more of the following components, which can include metal salts, sweeteners, carrier materials, antimicrobial agents, bad breath reduction agents, bleaching agents separate from hydrogen peroxide, surfactants, flavors, anti-tartar agents, colorants, sensates, abrasive polishing materials, thickening materials, humectants, and other additives.
Actives and other ingredients may be categorized or described herein by their cosmetic benefit, therapeutic benefit, or their postulated mode of action or function. However, it is to be understood that the active and other ingredients useful herein can, in some instances, provide more than one cosmetic benefit, therapeutic benefit, function, or can operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit an ingredient to the particularly stated function(s) or activities listed.
A metal salt includes zinc salts, stannous salts, potassium salts, copper salts, alkali metal bicarbonate slats, and combinations thereof. Metal salts have a wide range of functions from antimicrobial agents to sensitivity agents or buffers. The oral care compositions of the present invention may contain metal salt in an amount from about 0.05% to about 11%, from about 0.5% to about 7%, or from about 1% to about 5%, by total weight of the oral care composition.
It is common to have a fluoride compound present in dentifrices and other oral care compositions in an amount sufficient to give a fluoride ion concentration in the composition of from about 0.0025% to about 5.0% or from about 0.005% to about 2.0%, by weight of the oral care composition to provide anticaries effectiveness. A wide variety of fluoride ion-yielding materials can be employed as sources of soluble fluoride in the present invention. Representative fluoride ion sources include: stannous fluoride, sodium fluoride, potassium fluoride, amine fluoride, sodium monofluorophosphate, indium fluoride, amine fluorides such as Olaflur, and many others. Examples of suitable fluoride ion-yielding materials are found in U.S. Pat. No. 3,535,421 to Briner et al. and U.S. Pat. No. 3,678,154 to Widder et al.
Stannous salts include stannous fluoride, stannous chloride, stannous iodide, stannous chlorofluoride, stannous actetate, stannous hexafluorozirconate, stannous sulfate, stannous lactate, stannous tartrate, stannous gluconate, stannous citrate, stannous malate, stannous glycinate, stannous pyrophosphate, stannous metaphosphate, stannous oxalate, stannous phosphate, stannous carbonate, and combinations thereof. Dentifrices containing stannous salts, particularly stannous fluoride and stannous chloride, are described in U.S. Pat. No. 5,004,597 to Majeti et al. Other descriptions of stannous salts are found in U.S. Pat. No. 5,578,293 issued to Prencipe et al. and in U.S. Pat. No. 5,281,410 issued to Lukacovic et al. In addition to the stannous ion source, other ingredients used to stabilize the stannous may be included, such as the ingredients described in Majeti et al. and Prencipe et al.
Zinc salts include zinc fluoride, zinc chloride, zinc iodide, zinc chlorofluoride, zinc actetate, zinc hexafluorozirconate, zinc sulfate, zinc lactate, zinc tartrate, zinc gluconate, zinc citrate, zinc malate, zinc glycinate, zinc pyrophosphate, zinc metaphosphate, zinc oxalate, zinc phosphate, zinc carbonate, and combinations thereof.
Potassium salts include potassium nitrate, potassium citrate, potassium oxalate, potassium bicarbonate, potassium acetate, potassium chloride, and combinations thereof.
In one embodiment, the copper salt is selected from copper fluoride, copper chloride, copper iodide, copper chlorofluoride, copper actetate, copper hexafluorozirconate, copper sulfate, copper lactate, copper tartrate, copper gluconate, copper citrate, copper malate, copper glycinate, copper pyrophosphate, copper metaphosphate, copper oxalate, copper phosphate, copper carbonate, and combinations thereof. In a further embodiment, the copper salt is selected from copper gluconate, copper acetate, copper glycinate, and combinations thereof.
Alkali metal bicarbonate salts are soluble in water and unless stabilized, tend to release carbon dioxide in an aqueous system. Sodium bicarbonate, also known as baking soda, is the preferred alkali metal bicarbonate salt. The alkali metal bicarbonate salt also functions as a buffering agent.
Because of the pH at which alkali metal bicarbonate salts buffer, the bicarbonate salt may be in a phase separate from the stannous ion source. In certain embodiments, the oral care composition of the present invention may contain from about 0.5% to about 50%, from about 0.5% to about 30%, from about 2% to about 20%, or from about 5% to about 18% of an alkali metal bicarbonate salt, by weight of the oral care composition.
Some metal salts which may be used in the present invention, such as zinc chloride, zinc citrate, copper gluconate, and zinc gluconate, are also associated with an off taste described as dirty, dry, earthy, metallic, sour, bitter, and astringent. See, for example, an article by Hu, Hongzhen, et al in Nature Chemical Biology (2009), 5 (3), Pages 183-190, entitled: Zinc Activates Damage-Sensing TRPA1 Ion Channels.
Sweeteners include saccharin, chloro-sucrose (sucralose), steviolglycosides, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, dulcoside A, dulcoside B, rubusoside, stevia, stevioside, acesulfame K, xylitol, neohesperidine DC, alitame, aspartame, neotame, alitame, thaumatin, cyclamate, glycyrrhizin, mogroside IV, mogroside V, Luo Han Guo sweetener, siamenoside, monatin and its salts (monatin SS, RR, RS, SR), curculin, monellin, mabinlin, brazzein, hemandulcin, phyllodulcin, glycyphyllin, phloridzin, trilobtain, baiyanoside, osladin, polypodoside A, pterocaryoside A, pterocaryoside B, mukurozioside, phlomisoside I, periandrin I, abrusoside A, cyclocarioside I,N—[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, N—[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, N—[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, salts thereof, and combinations thereof.
Rebiana is a steviolglycoside from Cargill Corp., Minneapolis, Minn., which is an extract from the leaves of the Stevia rebaudiana plant (hereinafter referred to as “Rebiana”). This is a crystalline diterpene glycoside, about 300× sweeter than sucrose. Examples of suitable stevioglycosides which may be combined include rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, dulcoside A, dulcoside B, rubusoside, stevioside, or steviolbioside. According to particularly desirable embodiments of the present invention, the combination of high-potency sweeteners comprises rebaudioside A in combination with rebaudioside B, rebaudioside C, rebaudioside F, rebaudioside F, stevioside, steviolbioside, dulcoside A. Sweeteners are generally included in an oral care composition at a level of about 0.0005% to about 2%, by total weight of the oral care composition.
Carrier materials include water, glycerin, sorbitol, polyethylene glycols having a molecular weight of less than about 50,000, propylene glycol and other edible polyhydric alcohols, ethanol, or combinations thereof. The oral care compositions of the present invention include from about 5% to about 80%, by weight of the composition, of a carrier material. In certain embodiments, the compositions contain carrier materials in an amount of from about 10% to about 40%, by total weight of the oral care composition.
Antimicrobial agents include quaternary ammonium compounds. Those useful in the present invention include, for example, those in which one or two of the substitutes on the quaternary nitrogen has a carbon chain length (typically alkyl group) from about 8 to about 20, typically from about 10 to about 18 carbon atoms while the remaining substitutes (typically alkyl or benzyl group) have a lower number of carbon atoms, such as from about 1 to about 7 carbon atoms, typically methyl or ethyl groups. Dodecyl trimethyl ammonium bromide, tetradecylpyridinium chloride, domiphen bromide, N-tetradecyl-4-ethyl pyridinium chloride, dodecyl dimethyl (2-phenoxyethyl)ammonium bromide, benzyl dimethoylstearyl ammonium chloride, quaternized 5-amino-1,3-bis(2-ethyl-hexyl)-5-methyl hexahydropyrimidine, benzalkonium chloride, benzethonium chloride and methyl benzethonium chloride are exemplary of typical quaternary ammonium antibacterial agents.
Other quaternary ammonium compounds include the pyridinium compounds. Examples of pyridinium quaternary ammonium compounds include bis[4-(R-amino)-1-pyridinium]alkanes as disclosed in U.S. Pat. No. 4,206,215, Jun. 3, 1980, to Bailey and cetylpyridinium and tetradecylpyridinium halide salts (i.e., chloride, bromide, fluoride and iodide).
The oral care compositions of the present invention may also include other antimicrobial agents including non-cationic antimicrobial agents such as halogenated diphenyl ethers, phenolic compounds including phenol and its homologs, mono and poly-alkyl and aromatic halophenols, resorcinol and its derivatives, xylitol, bisphenolic compounds and halogenated salicylanilides, benzoic esters, and halogenated carbanilides. Also useful antimicrobials are enzymes, including endoglycosidase, papain, dextranase, mutanase, and combinations thereof. Such agents are disclosed in U.S. Pat. No. 2,946,725, Jul. 26, 1960, to Norris et al. and in U.S. Pat. No. 4,051,234 to Gieske et al. Examples of other antimicrobial agents include chlorhexidine, and flavor oils such as thymol.
The compositions of the present invention may contain antimicrobial agents in an amount of from about 0.035% or more, from about 0.1% to about 1.5%, from about 0.045% to about 1.0%, or from about 0.05% to about 0.10%, by total weight of the oral care composition.
Examples of bad breath reduction agents include Michael Acceptors, which are antagonists of TRPA1 or TRPV1, such as dihydrojasmone and other cyclopentenones. Other agents include copper salts and carbonyl compounds such as ascorbic acid [3-oxo-L-gulofuranolactone]; cis-jasmone [3-methyl-2-(2-pentenyl-2-cyclopentenone]; 2,5-dimethyl-4-hydroxy-3(2H)-furanone; 5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone; vanillin [4-hydroxy-3-methoxybenzaldehyde]; ethyl vanillin; anisaldehyde [4-methoxybenzaldehyde]; 3,4-methylenedioxybenzaldehyde; 3,4-dimethoxybenzaldehyde; 4-hydroxybenzaldehyde; 2-methoxybenzaldehyde; benzaldehyde; cinnamaldehyde [3-phenyl-2-propenal]; hexyl cinnamaldehyde; α-methyl cinnamaldehyde; ortho-methoxy cinnamaldehyde; citral; linalool; geraniol; eugenol; or combinations thereof. Without being limited by theory, it is believed some bad breath reduction agents work as “traps” by reacting with the thiol or sulfide and forming products with less odor impact. Some of these bad breath reduction agents provide an unwanted taste within an oral care composition, for example, anisaldehyde. The unwanted tastes often associated with these types of bad breath reduction agents include chemical, plastic, bitter, or sour.
The compositions of the present invention may contain bad breath reduction agents in an amount of from about 0.001% to about 4.0%, by total weight of the oral care composition.
Bleaching agents include peroxides, perborates, percarbonates, peroxyacids, persulfates, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, sodium peroxide, zinc peroxide, or combinations thereof. One example of a percarbonate is sodium percarbonate. An example of a persulfate includes oxones. Some bleaching agents provide a burn sensation within an oral care composition, for example peroxides and percarbonates.
The compositions of the present invention may contain bleaching agents in an amount of from about 0.01% to about 30%, from about 0.1% to about 10%, or from about 0.5% to about 5%, by total weight of the oral care composition.
Surfactants may include anionic surfactants such as organophosphate, which include alkyl phosphates. These surface active organophosphate agents have a strong affinity for enamel surface and have sufficient surface binding propensity to desorb pellicle proteins and remain affixed to enamel surfaces. Suitable examples of organophosphate compounds include mono-, di- or triesters represented by the general structure below wherein Z1, Z2, or Z3 may be identical or different, at least one being an organic moiety, in one embodiment selected from linear or branched, alkyl or alkenyl group of from 1 to 22 carbon atoms, optionally substituted by one or more phosphate groups; alkoxylated alkyl or alkenyl, (poly)saccharide, polyol or polyether group.









Some other organophosphate agents include alkyl or alkenyl phosphate esters represented by the following structure:









wherein R1 represents a linear or branched, alkyl or alkenyl group of from 6 to 22 carbon atoms, optionally substituted by one or more phosphate groups; n and m, are individually and separately, 2 to 4, and a and b, individually and separately, are 0 to 20; Z2 and Z3 may be identical or different, each represents hydrogen, alkali metal, ammonium, protonated alkyl amine or protonated functional alkyl amine such as an alkanolamine, or a R1-(OCnH2n)a(OCmH2m)b-group. Examples of suitable agents include alkyl and alkyl (poly)alkoxy phosphates such as lauryl phosphate; PPG5 ceteareth-10 phosphate; Laureth-1 phosphate; Laureth-3 phosphate; Laureth-9 phosphate; Trilaureth-4 phosphate; C12-18 PEG 9 phosphate; Sodium dilaureth-10 phosphate. In one embodiment, the alkyl phosphate is polymeric. Examples of polymeric alkyl phosphates include those containing repeating alkoxy groups as the polymeric portion, in particular 3 or more ethoxy, propoxy isopropoxy or butoxy groups.
Zwitterionic or amphoteric surfactants useful in the present invention include derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water-solubilizing group, such as carboxy, sulfonate, sulfate, phosphate or phosphonate. Suitable amphoteric surfactants include betaine surfactants such as disclosed in U.S. Pat. No. 5,180,577 to Polefka et al. Typical alkyl dimethyl betaines include decyl betaine or 2-(N-decyl-N,N-dimethylammonio) acetate, coco betaine or 2-(N-coco-N,N-dimethyl ammonio) acetate, myristyl betaine, palmityl betaine, lauryl betaine, cetyl betaine, stearyl betaine, etc. Amphoteric surfactants useful herein further include amine oxide surfactants. The amidobetaines are exemplified by cocoamidoethyl betaine, cocamidopropyl betaine (CAPB), and lauramidopropyl betaine. The unwanted tastes often associated with these surfactants are soapy, bitter, chemical, or artificial.
Additional suitable polymeric organophosphate agents include dextran phosphate, polyglucoside phosphate, alkyl polyglucoside phosphate, polyglyceryl phosphate, alkyl polyglyceryl phosphate, polyether phosphates and alkoxylated polyol phosphates. Some specific examples are PEG phosphate, PPG phosphate, alkyl PPG phosphate, PEG/PPG phosphate, alkyl PEG/PPG phosphate, PEG/PPG/PEG phosphate, dipropylene glycol phosphate, PEG glyceryl phosphate, PBG (polybutylene glycol) phosphate, PEG cyclodextrin phosphate, PEG sorbitan phosphate, PEG alkyl sorbitan phosphate, and PEG methyl glucoside phosphate. Suitable non-polymeric phosphates include alkyl mono glyceride phosphate, alkyl sorbitan phosphate, alkyl methyl glucoside phosphate, alkyl sucrose phosphates. The impurities in these phosphates may induce a burning sensation. Impurities may include dodecanol, dodecanal, benzaldehyde, and other TRPA1 or TRPV1 agonists.
Cationic surfactants useful in the present invention include derivatives of quaternary ammonium compounds having one long alkyl chain containing from about 8 to 18 carbon atoms such as lauryl trimethylammonium chloride, cetyl trimethylammonium bromide, coconut alkyltrimethylammonium nitrite, cetyl pyridinium fluoride, etc. Quaternary ammonium halides having detergent properties can be used, such as those described in U.S. Pat. No. 3,535,421 to Briner et al. Certain cationic surfactants can also act as germicides in the oral care compositions disclosed herein.
Examples of some flavors and flavor components that may be used in oral care compositions are mint oils, wintergreen, clove bud oil, cassia, sage, parsley oil, marjoram, lemon, orange, propenyl guaethol, heliotropine, 4-cis-heptenal, diacetyl, methyl-ρ-tert-butyl phenyl acetate, methyl salicylate, ethyl salicylate, 1-menthyl acetate, oxanone, α-irisone, methyl cinnamate, ethyl cinnamate, butyl cinnamate, ethyl butyrate, ethyl acetate, methyl anthranilate, iso-amyl acetate, iso-amyl butyrate, allyl caproate, eugenol, eucalyptol, thymol, cinnamic alcohol, octanol, octanal, decanol, decanal, phenylethyl alcohol, benzyl alcohol, α-terpineol, linalool, limonene, citral, neral, geranial, geraniol nerol, maltol, ethyl maltol, anethole, dihydroanethole, carvone, menthone, β-damascenone, ionone, γ-decalactone, γ-nonalactone, γ-undecalactone, or combinations thereof. Generally suitable flavoring ingredients are chemicals with structural features and functional groups that are less prone to redox reactions. These include derivatives of flavor chemicals that are saturated or contain stable aromatic rings or ester groups.
Flavors are generally present in an amount of from about 0.4% to about 5% or from about 1% to about 3%, by total weight of the oral care composition.
Anti-tartar agents include pyrophosphate salts as a source of pyrophosphate ion. The pyrophosphate salts useful in the present compositions include, for example, the mono-, di- and tetraalkali metal pyrophosphate salts and combinations thereof. Disodium dihydrogen pyrophosphate (Na2H2P2O7), sodium acid pyrophosphate, tetrasodium pyrophosphate (Na4P2O7), and tetrapotassium pyrophosphate (K4P2O7) in their unhydrated as well as hydrated forms are further species. In compositions of the present invention, the pyrophosphate salt may be present in one of three ways: predominately dissolved, predominately undissolved, or a combination of dissolved and undissolved pyrophosphate. The amount of pyrophosphate salt useful in making these compositions is any tartar control effective amount. In varying embodiments, the amount of pyrophosphate salt may be from about 1.5% to about 15%, from about 2% to about 10%, or about 3% to about 8%, by total weight of the oral care composition.
Examples of some colorants that may be used in oral care compositions include D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, D&C Red No. 33 and combinations thereof. In certain embodiments, the composition comprises colorant in an amount of from about 0.0001% to about 0.1% or from about 0.001% to about 0.01%, by weight of the oral care composition. Some colorants provide an unwanted taste, for example, D&C Red No. 33. The unwanted tastes often associated with this colorant are metallic, sharp, or chemical. Colorants are generally present in an amount of from about 0.001% to about 0.5%, by weight of the oral care composition.
Sensates may also be part of an oral care composition. Sensate molecules such as cooling, warming, and tingling agents are useful to deliver signals to the user. Sensates are generally present in an amount of from about 0.001% to about 0.8%, by weight of the oral care composition. The most well-known cooling sensate compound is menthol, particularly L-menthol, which is found naturally in peppermint oil notably of Mentha arvensis L and Mentha viridis L. Other isomers of menthol (neomenthol, isomenthol and neoisomenthol) have somewhat similar, but not identical odor and taste, for instance having disagreeable odor and taste described as earthy, camphor, musty, etc. The biggest difference among the isomers is in their cooling potency. L-menthol provides the most potent cooling, by having the lowest cooling threshold of about 800 ppb, which is the concentration level where the cooling effect can be clearly recognized. At this level, there is no cooling effect for the other isomers. For example, d-neomenthol is reported to have a cooling threshold of about 25,000 ppb and 1-neomenthol about 3,000 ppb. [R. Emberger and R. Hopp, “Synthesis and Sensory Characterization of Menthol Enantiomers and Their Derivatives for the Use in Nature Identical Peppermint Oils,” Specialty Chemicals (1987), 7(3), 193-201].
Of the menthol isomers the 1-isomer occurs most widely in nature and is typically what is referred by the name menthol having coolant properties. L-menthol has the characteristic peppermint odor, has a clean fresh taste and exerts a cooling sensation when applied to the skin and mucosal surfaces.
Among synthetic coolants, many are derivatives of or are structurally related to menthol, for example containing the cyclohexane moiety, and derivatized with functional groups including carboxamide, ketal, ester, ether and alcohol. Examples include the ρ-menthanecarboxamide compounds such as N-ethyl-ρ-menthan-3-carboxamide, known commercially as “WS-3”, and others in the series such as WS-5 (N-ethoxycarbonylmethyl-ρ-menthan-3-carboxamide), WS-12 (1R*,2S*)-N-(4-Methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide] and WS-14 (N-tert-butyl-ρ-menthan-3-carboxamide). Examples of menthane carboxy esters include WS-4 and WS-30. An example of a synthetic carboxamide coolant that is structurally unrelated to menthol is N,2,3-trimethyl-2-isopropylbutanamide, known as “WS-23”. Additional examples of synthetic coolants include alcohol derivatives such as 3-(1-menthoxy)-propane-1,2-diol known as TK-10, isopulegol (under the tradename Coolact P) and ρ-menthane-3,8-diol (under the tradename Coolact 38D) all available from Takasago Corp., Tokyo, Japan; menthone glycerol acetal known as MGA; menthyl esters such as menthyl acetate, menthyl acetoacetate, menthyl lactate known as Frescolat® supplied by Symrise AG, Holzminden, Germany, and monomenthyl succinate under the tradename Physcool from V. Mane FILS, Notre Dame, France. TK-10 is described in U.S. Pat. No. 4,459,425 to Amano et al. Other alcohol and ether derivatives of menthol are described in GB 1,315,626 and in U.S. Pat. Nos. 4,029,759; 5,608,119; and 6,956,139. WS-3 and other carboxamide cooling agents are described in U.S. Pat. Nos. 4,136,163; 4,150,052; 4,153,679; 4,157,384; 4,178,459 and 4,230,688.
Additional N-substituted ρ-menthane carboxamides are described in WO 2005/049553A1 including N-(4-cyanomethylphenyl)-ρ-menthanecarboxamide, N-(4-sulfamoylphenyl)-ρ-menthanecarboxamide, N-(4-cyanophenyl)p-menthanecarboxamide, N-(4-acetylphenyl)-ρ-menthanecarboxamide, N-(4-hydroxymethylphenyl)-ρ-menthanecarboxamide and N-(3-hydroxy-4-methoxyphenyl)-ρ-menthanecarboxamide. Other N-substituted ρ-menthane carboxamides include amino acid derivatives such as those disclosed in WO 2006/103401 and in U.S. Pat. Nos. 4,136,163; 4,178,459 and 7,189,760 such as N-((5-methyl-2-(1-methylethyl)cyclohexyl)carbonyl)glycine ethyl ester and N-((5-methyl-2-(1-methylethyl)cyclohexyl)carbonyl)alanine ethyl ester. Menthyl esters including those of amino acids such as glycine and alanine are disclosed e.g., in EP 310,299 and in U.S. Pat. Nos. 3,111,127; 3,917,613; 3,991,178; 5,5703,123; 5,725,865; 5,843,466; 6,365,215; 6,451,844; and 6,884,903. Ketal derivatives are described, e.g., in U.S. Pat. Nos. 5,266,592; 5,977,166; and 5,451,404. Additional agents that are structurally unrelated to menthol but have been reported to have a similar physiological cooling effect include alpha-keto enamine derivatives described in U.S. Pat. No. 6,592,884 including 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (3-MPC), 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (5-MPC), and 2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone (DMPF); icilin (also known as AG-3-5, chemical name 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one) described in Wei et al., J. Pharm. Pharmacol. (1983), 35:110-112. Reviews on the coolant activity of menthol and synthetic coolants include H. R. Watson, et al. J. Soc. Cosmet. Chem. (1978), 29, 185-200 and R. Eccles, J. Pharm. Pharmacol., (1994), 46, 618-630.
Additional agents that are structurally unrelated to menthol but have been reported to have a similar physiological cooling effect include alpha-keto enamine derivatives described in U.S. Pat. No. 6,592,884 including 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (3-MPC), 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (5-MPC), and 2,5-dimethyl-4-(1-pyrrolidinyl)-3(2H)-furanone (DMPF); icilin (also known as AG-3-5, chemical name 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one) described in Wei et al., J. Pharm. Pharmacol. (1983), 35:110-112 and phosphine oxides as reported in U.S. Pat. No. 4,070,496.
Some examples of warming sensates include ethanol; capsicum; nicotinate esters, such as benzyl nicotinate; polyhydric alcohols; capsicum powder; a capsicum tincture; capsicum extract; capsaicin; homocapsaicin; homodihydrocapsaicin; nonanoyl vanillyl amide; nonanoic acid vanillyl ether; vanillyl alcohol alkyl ether derivatives such as vanillyl ethyl ether, vanillyl butyl ether, vanillyl pentyl ether, and vanillyl hexyl ether; isovanillyl alcohol alkyl ethers; ethylvanillyl alcohol alkyl ethers; veratryl alcohol derivatives; substituted benzyl alcohol derivatives; substituted benzyl alcohol alkyl ethers; vanillin propylene glycol acetal; ethylvanillin propylene glycol acetal; ginger extract; ginger oil; gingerol; zingerone; or combinations thereof. Warming sensates are generally included in an oral care composition at a level of about 0.05% to about 2%, by weight of the oral care composition.
Abrasive polishing material can be any material that does not excessively abrade dentin. The oral care compositions of the present invention may comprise abrasive polishing material in an amount of from about 6% to about 70% or from about 10% to about 50%, by weight of the oral care composition. Typical abrasive polishing materials include silicas including gels and precipitates; aluminas; phosphates including orthophosphates, polymetaphosphates, and pyrophosphates; and mixtures thereof. Specific examples include dicalcium orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble sodium polymetaphosphate, rice hull silica, hydrated alumina, beta calcium pyrophosphate, calcium carbonate, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde, and others such as disclosed by Cooley et al in U.S. Pat. No. 3,070,510. In certain embodiments, if the oral composition or particular phase comprises a polyphosphate having an average chain length of about 4 or more, calcium containing abrasives and alumina are not preferred abrasives.
Silica dental abrasives of various types are often used in oral care compositions due to their exceptional dental cleaning and polishing performance without unduly abrading tooth enamel or dentine. Silica abrasive polishing materials that may be used in the present invention, as well as other abrasives, generally have an average particle size ranging between about 0.1 to about 30 μm or from about 5 to about 15 m. The abrasive can be precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Pat. No. 3,538,230 and DiGiulio, U.S. Pat. No. 3,862,307. Silica xerogels marketed under the trade name “Syloid” by the W.R. Grace & Company, Davison Chemical Division, Augusta, Ga. may be used. Also precipitated silica materials such as those marketed by the J. M. Huber Corporation, Edison, N.J. under the trade name, “Zeodent”, particularly the silica carrying the designation “Zeodent 119”, may be used.
The types of silica dental abrasives useful in the oral care compositions of the present invention are described in more detail in Wason, U.S. Pat. No. 4,340,583; and Rice U.S. Pat. Nos. 5,589,160; 5,603,920; 5,651,958; 5,658,553; and 5,716,601.
Thickening material or binders may be used to provide a desirable consistency to the oral care compositions of the present invention. For example when the oral care compositions are in the form of dentifrices, topical oral gels, mouthrinse, denture product, mouthsprays, lozenges, oral tablets or chewing gums, the amount and type of the thickening material will depend upon the form of the product. Thickening materials include carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, and water soluble salts of cellulose ethers such as sodium carboxymethylcellulose and sodium hydroxyethyl cellulose. Natural gums such as gum karaya, xanthan gum, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening material to further improve texture. Thickening materials can be used in an amount from about 0.1% to about 15%, by weight of the oral care composition.
Humectants keep oral care compositions from hardening upon exposure to air and certain humectants can also impart desirable sweetness of flavor to dentifrice compositions. Suitable humectants for use in the present invention include glycerin, sorbitol, polyethylene glycol, propylene glycol, xylitol, and other edible polyhydric alcohols. The oral care compositions of the present invention may comprise humectants in an amount of from about 0% to about 70% or from about 15% to about 55%, by weight of the oral care composition.
EXAMPLES
For EXAMPLES 1, 2 and 3, the first group of components which will help to reduce the burn associated with menthol or hydrogen peroxide in an oral care composition are Transient Receptor Potential Ankryin 1 (TRPA1) antagonists. In looking at this receptor, it was discovered that combining antagonists of this receptor in the presence of the agonists menthol or hydrogen peroxide, caused a surprising effect. By adding a TRPA1 antagonist to an oral care composition with high menthol levels or hydrogen peroxide, the user of the composition experienced an improved perception and in use experience of the composition, over an oral care composition without the TRPA1 antagonist. Thus, the TRPA1 antagonist is working to off-set the burning, irritating, or off-tasting sensation associated with menthol or hydrogen peroxide activation of TRPA1.
In order to determine whether TRPA1 is activated, the intracellular calcium ion (Ca 2+ ) level from transfected cells with the TRPA1 receptor gene was measured. HEK-2 cells stably transfected with human TRPA1 were grown in 15 ml growth medium [high glucose DMEM (Dulbecco's Modification of Eagle's Medium) supplemented with 10% FBS (fetal bovine serum), 100 μg/ml Penicillin/streptomycin, 100 μg/ml G418] in a 75 Cm 2 flask for 3 days at 37° C. in a mammalian cell culture incubator set at 5% CO 2 . Cells were detached with addition of 10 ml of PBS (phosphate buffered saline) by hand shaking gently and transferred to a 50 ml tube and centrifuged at 850 rpm for 3 minutes to remove PBS. After centrifugation, a pellet of cells was formed in the bottom of the tube separating them from the supernatant solution. The supernatant was discarded and the cell pellet suspended in 1 ml of fresh growth medium to which 5 μl (12.5 μg) of Fluo-4 AM (Molecular Probes, Inc., Eugene, Oreg.) calcium indicator was added and incubated for 30 minutes with gentle shaking. Fluo-4 is a fluorescent dye used for quantifying cellular Ca 2+ concentrations in the 100 nM to 1 μM range. At the end of the 30 minutes, 45 ml of assay buffer [1×HBSS (Hank's Balanced Salt Solution), 20 mM HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)] was added to wash the cells and the resulting combination was then centrifuged at 850 rpm for 3 minutes to remove excess buffer and Fluo-4 AM calcium indicator.
The pelleted cells were re-suspended in 10 ml assay buffer and 90 μl aliquots (˜50,000 cells) per well delivered to a 96-well assay plate containing 10 μl of test compounds (1 mM in assay buffer, final concentration 100 μM) or buffer control and incubated at room temperature for 30 minutes. After 30 minutes, the plate was placed into a fluorometric imaging plate reader (FLIPR384 from Molecular Devices) and basal fluorescence recorded (excitation wave length 488 nm and emission wave length 510 nm). Then 20 μl of the molecule being tested as a TRPA1 antagonist was added and fluorescence recorded. For determining the direct effect of test compounds on TRPA1, fluorescence was measured immediately after addition of each compound.
To determine if a molecule was an antagonist of TRPA1 receptor activation and the level of antagonism, a molecule that had >20% reduction in calcium flux compared to the menthol or hydrogen peroxide activated TRPA1 receptor was viewed as a potential antagonist.
To determine if a compound was an antagonist or a desensitizer the direct effect of a test compound was determined. For determining the direct effect of test compounds on TRPA1 receptor activation, 100 μl aliquots (˜50,000 cells) of cells prepared as described above were delivered to a 96-well assay plate and basal fluorescence recorded as noted above. Then 20 μl of the compound being tested as a TRPA1 activator was added and fluorescence recorded. If any increase in fluorescence over background was noted, then the compound was considered an agonist. The agonist activity was expressed relative to that observed with a benchmark agonist such as 50 μM allyl isothiocyanate for TRPA1 or for the purpose of this invention, L-menthol or hydrogen peroxide. If a compound did not show any agonistic activity when directly added, but inhibited activation by a known TRPA1 agonist in the preincubation study, then it was called an antagonist. If the compound showed agonist activity and caused decrease in activation by a known TRPA1 agonist in the preincubation study, then it was called a desensitizer. Additional discussion of the FLIPR method can be found in Smart et al., Characterization using FLIPR of human vanilloid VR1 receptor pharmacology, European Journal of Pharmacology 417, 51-58 (2001) and Liu et al., Development and validation of a platelet calcium flux assay using a fluorescent imaging plate reader, Analytical Biochemistry 357, 216-224 (2006).
For EXAMPLES 1, 4 and 5, the second group of components tested for their ability to reduce the burn associated with menthol or hydrogen peroxide in an oral care composition are Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists. In looking at this receptor, it was discovered that combining antagonists of this receptor in the presence of the agonists menthol or hydrogen peroxide, caused a surprising effect. By adding a TRPV1 antagonist to an oral care composition with high menthol levels or hydrogen peroxide, the user of the composition experienced an improved perception and in use experience of the composition over an oral care composition without the TRPV1 antagonist. Thus, the TRPV1 antagonist is working to off-set the burning or warming sensation associated with menthol or hydrogen peroxide activation of TRPV1.
To determine whether TRPV1 was activated, the intracellular calcium ion (Ca +2 ) levels from cells transfected with the TRPV1 receptor gene was measured. HEK-239 cells stably transfected with human TRPV1 were grown in 15 ml growth medium [high glucose DMEM (Dulbecco's Modification of Eagle's Medium) supplemented with 10% FBS (fetal bovine serum), 100 g/ml Penicillin/streptomycin, 100 g/ml G418] in a 75 Cm2 flask for 3 days at 33° C. in a mammalian cell culture incubator set at 5% CO 2 . Cells were detached with addition of 10 ml of PBS (phosphate buffered saline) by hand shaking gently. Cells were transferred to a 50 ml tube and centrifuged at 850 rpm for 3 minutes to remove PBS. After centrifugation, a pellet of cells formed in the bottom of the tube separating them from the supernatant solution. The supernatant was discarded and the cell pellet suspended in 1 ml of fresh growth medium to which 5 μl (12.5 g) of Fluo-4 AM (Molecular Probes, Inc., Eugene, Oreg.) calcium indicator was added and incubated for 30 minutes with gentle shaking. Fluo-4 is a fluorescent dye used for quantifying cellular Ca 2+ concentrations in the 100 nM to 1 μM range. At the end of the 30 minutes, 45 ml of assay buffer [1×HBSS (Hank's Balanced Salt Solution), 20 mM HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)]was added to wash the cells and the resulting combination was then centrifuged at 850 rpm for 3 minutes to remove excess buffer and Fluo-4 AM calcium indicator.
The pelleted cells were re-suspended in 10 ml assay buffer and 90 μl aliquots (˜50,000 cells) per well delivered to a 96-well assay plate containing 10 μl of test compounds (1 mM in assay buffer, final concentration 100 μM) or buffer control and incubated at room temperature for 30 minutes. After 30 minutes, the plate was placed into a fluorometric imaging plate reader (FLIPR384 from Molecular Devices) and basal fluorescence recorded (excitation wave length 488 nm and emission wave length 510 nm). Then 20 μl of the compound being tested as a TRPV1 receptor activator was added and fluorescence recorded. The observed value with compound pretreated cells was compared with buffer control, with the difference between the two indicating a measure of effect of the test compound on the activator. It may be no difference (no effect), or negative (means antagonist or desensitizer) or positive (enhancer, also known as positive allosteric modulator). A molecule that had >20% reduction in calcium flux compared to the menthol or hydrogen peroxide activated TRPV1 receptor was viewed as a potential antagonist or a desensitizer. To determine if a compound was an antagonist or a desensitizer, the direct effect of a test compound was determined. For determining the direct effect of test compounds on TRPV1, 100 μl aliquots (˜50,000 cells) of cells prepared as described above were delivered to a 96-well assay plate and basal fluorescence recorded as noted above. Then 20 μl of the compound being tested as a TRPV1 receptor activator was added and fluorescence recorded. If any increase in fluorescence over background was noted, then the compound was considered an agonist. The agonist activity was expressed relative to that observed with a benchmark agonist such as 350 nM Capsaicin for TRPV1. If a compound did not show any agonistic activity when directly added, but inhibited activation by a known TRPV1 agonist in the preincubation study, then it was called an antagonist. If the compound showed agonist activity and caused decrease in activation by a known TRPV1 agonist in the preincubation study, then it was called a desensitizer. Additional discussion of the FLIPR method can be found in Smart et al., Characterization using FLIPR of human vanilloid VR1 receptor pharmacology, European Journal of Pharmacology 417, 51-58 (2001) and Liu et al., Development and validation of a platelet calcium flux assay using a fluorescent imaging plate reader, Analytical Biochemistry 357, 216-224 (2006).
The TRPV1 receptor responds to, for example, both noxious and painful stimuli. A noxious stimulus would include those which give a burning (i.e. hot) sensation.
Example 1
TABLE 1 below shows percent hydrogen peroxide activation (as measured by intracellular Ca 2+ levels) of TRPV1 and TRPA1 receptors, as compared to the level of receptor activation of the control agonists (AITC for TRPA1 and capsaicin for TRPV1) normally used to test for TRPV1 and TRPA1 receptor activation. Table 1 showed the concentrations at which hydrogen peroxide's agonist activity was comparable to the control agonists on the TRPA1 and TRPV1 receptors. AITC was the control agonist for TRPA1 and capsaicin was the control for TRPV1.









TABLE 1





H 2 O 2
TRPA1
TRPV1





100 mM
296.7%
209.29%


10 mM
101.3%
62.81%


1 mM
123.4%
41.13%


500 μM
129.1%
30.21%


200 μM
111.7%
21.18%


100 μM
91.4%
17.45%


10 μM
9.6%
3.10%


1 μM
1.4%
1.51%






Ca 2+
Ca 2+


Controls
Count
Count





50 μM
12219
na


AITC


350 nM
na
16204


Capsaicin

































Example 2
The compounds listed in TABLE 2 below have been found to be antagonists of the TRPA1 receptor, in that they reduce the level of TRPA1 receptor activation when activated by hydrogen peroxide. 100 μM of antagonist was tested against 200 μM hydrogen peroxide to determine the level of reduced TRPA1 receptor activation by hydrogen peroxide. AITC was tested to demonstrate its higher level of activation (higher average Ca 2+ count) as compared to H 2 O 2 .








TABLE 2





Average
% Reduction


Ca ++
of Hydrogen Peroxide


Counts
TRPA1 Activation










Compounds tested at 100 μM



(Set1, TRPA1 assay)

Control-H2O2 (200 μM)
7043.6
0.0

AITC (50 μM)
11209.0
0.0

phloretin
215.0
96.9

copper(i) iodide
678.0
90.4

3-mercapto-2-pentanone
1255.5
82.2

1,2-propanedithiol
2194.5
68.8

ethyl methyl beta-phenylethyl
2253.5
68.0

carbinol

2-methylbutyl 2-methylbutyrate
2685.5
61.9

fenchone
2761.5
60.8

piperazine
2815.5
60.0

isoamyl pyruvate
2824.0
59.9

acetic acid isopropenyl ester
2860.5
59.4

isopropyl hexanoate
2862.0
59.4

manganese chloride
2872.5
59.2

2-acetyl-5-methylfuran
2937.0
58.3

3-acetylpyridine, 98%
2981.0
57.7

n-butyl alcohol
3009.0
57.3

2-undecanol
3049.0
56.7

desoxycholic acid
3058.5
56.6

2-nonanol
3064.5
56.5

2-isobutyl-3-methoxypyrazine
3067.5
56.4

gamma-terpinene
3124.0
55.6

1-stearoyl-rac-glycerol
3131.0
55.5

amyl alcohol
3149.0
55.3

2-methyl-3-ethoxypyrazine
3197.0
54.6

sodium erythorbate
3204.5
54.5

2-methyl-1-butanethiol
3208.0
54.5

1-octen-3-yl acetate
3228.5
54.2

dl-verbenone
3231.0
54.1

4′-methylacetophenone
3244.5
53.9

3-methyl-1,2-cyclopentanedione
3246.5
53.9

3-hydroxybenzoic acid
3284.5
53.4

ferric chloride
3287.0
53.3

phenylethyl isovalerate
3291.5
53.3

ethyl acetoacetate ethylene ketal
3298.5
53.2

6-undecanone
3357.5
52.3

methyl linoleate
3363.5
52.2

alpha,alpha-dimethylhydrocinnamyl
3367.0
52.2

acetate

2-hexyl-4-methyl-1,3-dioxolan
3376.0
52.1

3-hexanone
3381.5
52.0

isobutyl isobutyrate
3383.0
52.0

isobutyric acid isopropyl ester
3392.5
51.8

1-undecanol
3396.0
51.8

4-hydroxybenzaldehyde
3424.5
51.4

2-hydroxy-4-methylbenzaldehyde
3429.0
51.3

quinoline
3440.0
51.2

allyl cyclohexanepropionate
3443.0
51.1

carvacrol
3464.5
50.8

p-cymen-8-ol
3476.5
50.6

Compounds tested at 100 μM (Set2,

TRPA1 assay)

H 2 O 2 (200 μM)
8721.8

AITC (50 μM)
14138.2

2-phenyl-2-butenal
3809.0
56.3

alpha,p-dimethylstyrene
3735.5
57.2

isopentyl alcohol
3778.0
56.7

2-methyl-1,3-dithiolane
2402.0
72.5

methylbenzoate
3817.0
56.2

Compounds tested at 100 μM (Set3,

TRPA1 assay)

H 2 O 2 (200 μM)
10592.2

AITC (50 μM)
15213.0

2-methyl-3-heptanone
4994.0
52.9

3,7-dimethyl-1-octanol, 95%
5168.0
51.2

butyl 4-hydroxybenzoate
411.0
96.1

2,5-dimethyl-1,4-dithiane-2,5-diol
2420.0
77.2

2,4,6-trithiaheptane
4610.5
56.5

phenylacetaldehyde
2578.5
75.7

benzyl cinnamate
4828.5
54.4

2-hydroxy-3-methyl-2-cyclopenten-
4172.0
60.6

1-one hydrate

2,3-butanedithiol
1280.5
87.9

phenyl salicylate
2893.5
72.7

5-methylhexanoic acid
4747.0
55.2

2-pyrazinylethanethiol
1987.5
81.2

2-chloroacetophenone
1199.5
88.7

acetoin
4341.5
59.0

2-propionylthiazole
4875.0
54.0

benzothiazole
5513.0
48.0

butyl lactate
5157.0
51.3

2-ethyl-1-hexanol
4960.5
53.2

but-2-enoic acid
5193.0
51.0

1-hexanol
5664.5
46.5

4-benzo[1,3]dioxol-5-yl-butan-2-
5431.5
48.7

one

phenyl-methanol
5244.5
50.5

furfuryl alcohol
5585.5
47.3

malic acid
5617.5
47.0

2-ethylbenzenethiol
4808.5
54.6

2-undecanone
4581.0
56.8

methyl 4-hydroxybenzoate
4904.5
53.7

butyraldehyde
4725.5
55.4

2-methyl-2-pentenoic acid
5040.0
52.4

2,5-dimethylphenol
5208.0
50.8

7-hydroxycitronellal
6313.0
40.4

urea
5045.5
52.4

Compounds tested at 100 μM (Set4,

TRPA1 assay)

H 2 O 2 (200 μM
5881.5

AITC (50 μM)
8322.5

benzyl tiglate
2385.0
59.4

diphenyl disulfide
1112.0
81.1

ethyl acetoacetate
3314.5
43.6

4-methylthio-2-butanone
3322.5
43.5


































































































































Example 3
The compounds listed in TABLE 3 below have been found to be antagonists of the TRPA1 receptor, in that they reduce the level of TRPA1 receptor activation when activated by hydrogen peroxide. Two different levels of antagonist were tested, 100 μM or 400 μM, against 200 μM hydrogen peroxide to determine the level of reduced TRPA1 receptor activation by hydrogen peroxide. Two different level of antagonist were used to demonstrate that certain antagonists require higher levels to provide a significant inhibitory effect.








TABLE 3






% Reduction of




Hydrogen

Dose of


Peroxide TRPA1

Antagonist
*Cas #
Compound
Activation










100 μM
8015-91-6
Cinnamon Bark Oil
62

100 μM
2305-05-7
γ-Dodecalactone
51

100 μM
121-34-6
Vanillic Acid
19

100 μM
7011-83-8
γ-Methyl Decalactone
48

400 μM
8015-91-6
Cinnamon Bark Oil
74

400 μM
5910-87-2
trans, trans-2,4-Nonadienal
67

400 μM
6627-88-9
4-Allyl-2,6-dimethoxyphenol
54

400 μM
1504-74-1
o-Methoxycinnamaldehyde
51

400 μM
26643-91-4
4-Methyl-2-phenyl-2 Pentenal (mix of cis and
54



trans)

400 μM
2785-87-7
2-Methoxy-4-propyl-phenol
43

400 μM
606-45-1
Methyl 2-methoxy-benzoate
48

400 μM
2721-22-4
δ-Tetradecalactone

400 μM
1192-58-1
1-Methyl-2-pyrole carboxaldehyde
42

400 μM
710-04-3
Undecanoic-δ-Lactone
−42

400 μM
89-88-3
(6-Azulenol, 1,2,3,3a,4,5,6,8a-octahydro-4,8-
−34



dimethyl-2-(1-methylethylidene)-)



Vetiverol

400 μM
4166-20-5
Strawberry Furanone Acetate
63

400 μM
116-02-9
3,3,5-Trimethylcyclohexanol
72

400 μM
5422-34-4
N-(2-Hydroxyethyl) lactamide
65

400 μM
3208-40-0
2-(3-Phenylpropyl) tetrahydrofuran
74

400 μM
6963-56-0
Anisyl Butyrate
54

400 μM
2046-17-5
Methyl-4-phenyl butyrate
60

400 μM
40923-64-6
3-Heptyldihydro-5-methyl-2(3H)-furanone
59

400 μM
136954-25-1
3-acetylsulfanylhexyl acetate
58

400 μM
3720-16-9
(2-Cyclohexen-1-one, 3-methyl-5-propyl-)
56



Celery Ketone

400 μM
85586-67-0
Isobornyl Isobutyrate
80

400 μM
7549-41-9
Bornyl Valerate
52

400 μM
4433-36-7
Citronellyl acetate
70

400 μM
65620-50-0
(1-Oxaspiro[4.5]decan-6-ol, 2,6,10,10-
57



tetramethyl-, (2S,5S,6S)-6-)



Hydroxydihydrotheaspirane

400 μM
6728-26-3
trans-2-Hexenal
52



*CAS# refers to the Chemical Abstracts Service system of classification of chemical entities.

























































Example 4
The compounds listed in TABLE 4 below have been found to be antagonists of the TRPV1 receptor, in that they reduce the level of TRPV1 receptor activation when activated by hydrogen peroxide. Different amounts of antagonist (100 μM or 400 μM-depending on the antagonist's ability to reduce hydrogen peroxide's activation of the TRPV1 receptor) were tested against 500 μM hydrogen peroxide to determine the level of reduced TRPV1 receptor activation by hydrogen peroxide.








TABLE 4






% Reduction




of Hydrogen




Peroxide

Dose of


TRPV1

Antagonist
Cas #
Compound
Activation



100 μM
5655-61-8
(−)-Bornyl Acetate
53

100 μM
107-75-5
Hydroxycitronellal
62

100 μM
68133-79-9
Apritone
96

100 μM
10072-05-6
Methyl N,N-Dimethylanthranilate
60

100 μM
35243-43-7
2-Ethoxy-3-ethylpyrazine
58

100 μM
4573-50-6
L-Piperitone
58

100 μM
85586-67-0
Isobornyl Isobutyrate
52

100 μM
4166-20-5
4-Acetoxy-2,5-dimethyl-3(2H)-furanone
60

400 μM
102-69-2
Tripropylamine
63

400 μM
1128-08-1
Dihydrojasmone
98

400 μM
1192-58-1
1-Methyl-2-pyrole carboxaldehyde
79

400 μM
4864-61-3
3-Octyl Acetate
90

400 μM
2445-77-4
2-Methylbutyl isovalerate
79

400 μM
51608-18-5
Jasminone B
51

400 μM
5461-08-5
Piperonyl Isobutyrate
63

400 μM
23495-12-7
Phenoxyethyl Propionate
60

400 μM
68527-74-2
Vanillin Propylene Glycol Acetate
50

400 μM
65737-52-2
Octenyl Cyclopentanone
50

400 μM
97-87-0
Butyl Isobutyrate
58

400 μM
8016-23-7
Guaiacwood Oil
60

400 μM
16409-43-1
Tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2H
53



pyran










































Example 5
The compounds listed in TABLE 5 below have been found to be antagonists of the TRPV1 receptor, in that they reduce the level of TRPV1 receptor activation when activated by L-Menthol. 100 μM of antagonist was tested against 1 mM of L-Menthol to determine the level of reduced TRPV1 receptor activation by L-Menthol. Each antagonist compound was run with 1 mM of L-Menthol as a control and the antagonist activity of each compound was determined by comparing the Ca 2+ levels of the control with the antagonist compound being tested.








TABLE 5






% Reduction of



Average
L-Menthol

Dose of

Ca2+
TRPV1

Antagonist
Compounds
Counts
Activation










100 μM
copper(i) iodide
651.5
89.8

100 μM
butyl 4-hydroxybenzoate
319.0
77.2

100 μM
diphenyl disulfide
1630.5
64.9

100 μM
2,3-butanedithiol
586.0
64.8

100 μM
2,5-dimethyl-1,4-dithiane-2,5-
713.7
58.9


diol

100 μM
cellulose acetate
2742.5
57.1

100 μM
ethyl 3-phenylglycidate
1987.0
50.8

100 μM
phenylacetaldehyde
919.3
49.4

100 μM
3-phenyl-2-propen-1-yl 3-
3377.0
47.2


phenylacrylate

100 μM
2,3,5,6-tetramethylpyrazine
972.0
47.0

100 μM
piperazine
3405.0
46.8

100 μM
2-pyrazinylethanethiol
992.0
46.0

100 μM
2-methyltetrahydro-3-furanone
993.7
46.0

100 μM
methyl 3-
998.7
45.7


(methylthio)propionate

100 μM
ethyl 2,4-dioxohexanoate
1000.3
45.7

100 μM
3-mercapto-2-butanol
1008.3
45.3

100 μM
allyl caprylate
2572.0
44.6

100 μM
2,5-dimethylpyrazine
1040.0
43.8

100 μM
succinic acid
1045.0
43.6

100 μM
hexadecyl lactate
1047.0
43.5

100 μM
2-methoxybenzaldehyde
1050.3
43.3

100 μM
1,4-dimethoxybenzene
3633.0
43.2

100 μM
ethyl hexanoate
3655.5
42.9

100 μM
3-mercaptobutyl acetate
1061.3
42.8

100 μM
2′-hydroxyacetophenone
1083.3
41.8

100 μM
ethyl 5-hexenoate
1084.0
41.8

100 μM
gamma-caprolactone
1084.3
41.8

100 μM
(+−)-1-phenylethanol
1087.7
41.6

100 μM
d-(−)-lactic acid
1093.7
41.3

100 μM
2-ethyl-3-hydroxy-4h-pyran-4-
1095.3
41.3


one

100 μM
citronellyl formate
1097.0
41.2

100 μM
ethyl trans-2-hexenoate
1102.7
40.9

100 μM
propyl pyruvate
2386.5
40.9

100 μM
o-methylanisole
1107.3
40.7

100 μM
1-isopropyl-4-methylbenzene
1112.7
40.5

100 μM
trans-2-hexenyl acetate
1119.0
40.2

100 μM
methyl n-octyl sulfide
1120.3
40.1

100 μM
propionic acid trans-2-hexen-1-
1128.3
39.7


yl ester

100 μM
choline bitartrate
1141.3
39.1

100 μM
2-methyl-3-furanthiol
2835.5
38.9

100 μM
crotonic acid cis-3-hexen-1-yl
1150.0
38.7


ester

100 μM
manganese chloride
3922.0
38.7

100 μM
4′-methoxyacetophenone
1162.0
38.2

100 μM
empg
1164.0
38.1

100 μM
zinc gluconate
3963.5
38.1

100 μM
trans-2-hexen-1-al diethyl acetal
1169.0
37.9

100 μM
1-decanol
1175.7
37.5

100 μM
methyl 2-(acetylamino)benzoate
1178.3
37.4

100 μM
2-isobutyl-3-methoxypyrazine
4020.0
37.2

100 μM
methyl laurate
1199.7
36.4

100 μM
4-ethoxybenzaldehyde
1200.0
36.4

100 μM
2-benzoylamino-benzoic acid
1207.7
36.1

100 μM
phenylpropanol,
1218.3
35.6


phenylpropanol (1-phenyl 1-


propanol)

100 μM
4-methyl-5-vinylthiazole
1227.7
35.1

100 μM
butyl 2-methylbutyrate
1233.7
34.9

100 μM
edta
1236.0
34.8

100 μM
ocimene quintoxide
1236.3
34.7

100 μM
ferulic acid
1242.0
34.5

100 μM
2-methyl-1,3-dithiolane
2650.5
34.3

100 μM
2-acetyl-1-methylpyrrole
1254.0
33.9

100 μM
2,4-dimethylanisole
1255.3
33.9

100 μM
tetrahydrofurfuryl acetate
1269.3
33.2

100 μM
4-methyl-1-phenyl-2-pentanone
2707.0
32.9

100 μM
ethyl propionate
2712.0
32.8

100 μM
2-undecanone
1282.3
32.6

100 μM
4-methyl-2,6-dimethoxyphenol
1292.3
32.1

100 μM
diallyl sulfide
1293.3
32.1

100 μM
beta-caryophyllene
2744.5
32.0

100 μM
iron naphthenate
2748.5
31.9

100 μM
octanal
2759.0
31.6

100 μM
2-chloroacetophenone
1313.0
31.2

100 μM
beta-resorcylic acid
1317.3
31.0

100 μM
ethyl 3-(2-furyl)propionate
4446.5
30.5

100 μM
(1r)-(+)-camphor
2807.0
30.5

100 μM
thymol
1331.3
30.3

100 μM
dextrin from potato starch
1336.0
30.1

100 μM
2,3,6-trimethylphenol
1339.3
30.0

100 μM
isopropyl tiglate
4497.5
29.7

100 μM
2-sec.-butylcyclohexanone
1352.3
29.4

100 μM
2,6-dimethoxyphenol
1365.0
28.8

100 μM
phloretin
4616.5
27.9

100 μM
benzyl formate
2923.5
27.6

100 μM
dibutyl sebacate
1398.0
27.3

100 μM
4-methoxybenzyl formate
1399.0
27.2

100 μM
(+)-sodium 1-ascorbate
2961.0
26.6

100 μM
hexanedioic acid, dipropyl ester
2964.0
26.6

100 μM
(r)-(+)-2-phenyl-1-propanol
1414.0
26.5

100 μM
5-methyl-2,3-hexanedione
2968.5
26.4

100 μM
1-stearoyl-rac-glycerol
4708.0
26.4

100 μM
4-methoxyphenylacetone
1421.7
26.2

100 μM
cis-3-octen-1-ol
1424.7
26.0

100 μM
cis-3-hexenyl butyrate
2987.5
26.0

100 μM
3-(methylthio)propyl
1426.7
25.9


isothiocyanate

100 μM
isobutyl hexanoate
3443.5
25.8

100 μM
ethyl oleate
1431.3
25.7

100 μM
2-ethyl-3-methoxypyrazine
1432.7
25.7

100 μM
2-methoxybenzoic acid
1441.7
25.2

100 μM
1-octanol
1442.3
25.2

100 μM
2,5-dimethylfuran-3-thiol
1443.0
25.2

100 μM
6,6-dimethylbicyclo[3.1.1]hept-
1448.3
24.9


2-ene-2-methyl acetate

100 μM
isopentyl formate
1451.7
24.8

100 μM
ethyl trans-4-decenoate
1454.3
24.6

100 μM
allyl cyclohexanepropionate
4895.5
23.5

100 μM
2-(1-
1480.7
23.4


propoxyethoxy)ethylbenzene

100 μM
methyl nicotinate
1483.7
23.3

100 μM
2-acetylthiazole
3569.5
23.1

100 μM
(+−)-beta;-citronellol
1501.3
22.5

100 μM
pyruvic aldehyde
1504.0
22.3

100 μM
quinine hydrochloride dihydrate
1505.3
22.3

100 μM
sec-butyl disulfide
3652.0
21.3

100 μM
methyl 2-methylpentanoate
1529.3
21.2

100 μM
methyl trans-2-octenoate
1538.7
20.7

100 μM
3,4-dihydroxybenzoic acid
1539.7
20.7

100 μM
ethyl 2-benzylacetoacetate
1548.3
20.3

100 μM
3-methylthio-2-butanone
1554.0
20.0





















































































































































As demonstrated in EXAMPLES 6 and 7 described below, the negative attributes of menthol and hydrogen peroxide can be reduced using TRPA1 and TRPV1 antagonists. These reductions translate into a user noticeable signal from the personal care product.
For EXAMPLES 6 and 7 sensory evaluation studies of menthol and hydrogen peroxide activity were conducted using a methodology patterned after the techniques described in M. C. Meilgaard, et al., Sensory Evaluation Techniques, 4th Ed. (2007). In one study, a panel of 8-15 trained sensory experts evaluated the menthol or peroxide sensations experienced after brushing with a dentifrice containing the menthol or hydrogen peroxide and the respective TRPA1 or TRPV1 antagonists. Panelists brushed teeth with 1.5 grams of a dentifrice (containing coolant) or control (no coolant) and then expectorated. After brush expectoration, panelists evaluated the burn intensity, assigning a number between 0 (no burning) to 60 (intense cooling). After rinse expectoration, panelists evaluated burning intensity according to the same 0 to 60 scale. Evaluations were conducted at 5, 15, 30, 45, 60 minute, etc. time points. At each evaluation, panelists were instructed to breathe in through pursed lips and evaluate overall burning sensation. In this test, a numerical score difference from the control of 7.5 indicates user significant differences or definite reduction in burning at the specified time point. Measures between 4.0 to 7.5 indicate a noticeable trend in the specified parameter, which is not statistically significant, but noticeable.
Example 6
For EXAMPLE 6 (TABLES 8 and 9), a panel of 14 trained sensory experts evaluated the sensory profile experienced after brushing with the dentifrice sample formulations shown in TABLES 6 and 7 containing high levels of menthol followed by rinsing with water. Panelists brushed teeth with 1.5 grams of a test dentifrice (containing high menthol levels) or control (no menthol) for 36 seconds and then expectorated. The dentifrice sample formulations (control and high L-Menthol) are shown below in TABLE 6 (with peppermint flavor) and TABLE 7 (with spearmint flavor). The dentifrices were made using conventional methods and are shown below with component amounts in weight % of total composition.














TABLE 6



Ingredient
A (Control)
B
C
D
E
F
G
H
I



FD&C Blue #1
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%

Color Solution










Sodium
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%

Fluoride










CARBOMER
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%

956










Sodium
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%

Saccharin










Sodium
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%

Phosphate,










Monobasic,










Monohydrate










Titanium
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%

Dioxide










Carboxymethycellulose
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%

Sodium










Peppermint
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%

Flavor










Spearmint
0%
0%
0%
0%
0%
0%
0%
0%
0%

Flavor










Added L-
0%
0.25%
0.5%
0.75%
1.0%
1.25%
1.5%
1.75%
2.0%

Menthol










Tribasic
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%

Sodium










Phosphate










Dodecahydrate










Sodium Lauryl
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%

Sulfate 28%










Solution










Silica, Dental
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%

Type, NF










(Zeodent 119)










SORBITOL
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%

SOLUTION










LRS USP










Water Purified,
QS*
QS*
QS*
QS*
QS*
QS*
QS*
QS*
QS*

USP, PhEur,










JP, JSCI



*QS refers to the term quantum sufficit, meaning as much as suffices, where the remainder of the formula hole is filled with this substance



































































TABLE 7



Ingredient
J (Control)
K
L
M
N
O
P
Q
R



FD&C Blue #1
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%
0.045%

Color Solution










Sodium Fluoride
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%
0.243%

CARBOMER
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%

956










Sodium
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%
0.300%

Saccharin










Sodium
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%
0.419%

Phosphate,










Monobasic,










Monohydrate










Titanium Dioxide
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%
0.525%

Carboxymethycellulose
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%
0.800%

Sodium










Peppermint
0%
0%
0%
0%
0%
0%
0%
0%
0%

Flavor










Spearmint Flavor
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%
1.000%

Added L-
0%
0.25%
0.5%
0.75%
1.0%
1.25%
1.5%
1.75%
2.0%

Menthol










Tribasic Sodium
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%
1.100%

Phosphate










Dodecahydrate










Sodium Lauryl
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%
4.000%

Sulfate 28%










Solution










Silica, Dental
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%
15.000%

Type, NF










(Zeodent 119)










SORBITOL
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%
54.673%

SOLUTION LRS










USP










Water Purified,
QS*
QS*
QS*
QS*
QS*
QS*
QS*
QS*
QS*

USP, PhEur, JP,










JSCI



*QS refers to the term quantum sufficit, meaning as much as suffices, where the remainder of the formula hole is filled with this substance

















































TABLES 6 and 7 contain the formulations for toothpastes with added menthol going from 0% (control toothpaste for each flavor type) to 2.0% additional menthol for a 1% peppermint toothpaste (Samples A-1-TABLE 6) and for a 1% spearmint toothpaste (Samples J-R—TABLE 7).
Trained panelists separately brushed their teeth with each of the toothpastes (A-R) and rated them separately according to perceived burn. After expectoration, the panelists rinsed their mouth with 15 mls of tap water at room temperature (average temperature of 20° c.). The 14 panelists began the rating the burn sensation measurement in-mouth during brushing and after expectoration &water rinse over the course of 20 minutes. They assessed the burn sensation in their mouth and on their lips at 0 minutes after expectoration, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after expectoration. They assigned a burn sensation of 0 (no sensation) to 60 (highest intensity sensation). At each evaluation, panelists were instructed to breathe in through pursed lips and evaluate overall sensation. In this test, a numerical score of 7.5 indicates a significant user noticeable sensation. Differences less than 7.5, but greater than 5.0 indicate the trending of the data on a specific attribute. Results are shown in TABLE 8 for peppermint toothpaste (Samples A-1-TABLE 6) and 9 for spearmint toothpaste (Samples J-R—TABLE 7) below.






TABLE 8




Burn sensation rating for peppermint


Sample













6A
6B
6C
6D
6E
6F
6G
6H
6I














In-
6.3
14.3
17.6
15.9
21.8
22.6
21.5
23.9
29.9

mouth










After
13.7
17.6
24.2
25.7
34.3
33.9
37.5
33.7
42.0

Ex-










pecto-










ration










0 min
10.3
13.9
20.5
20.7
28.4
31.9
33.3
32.2
38.0

after










rinse










5 min
3.5
2.3
9.5
7.2
10.2
11.2
15.7
11.2
17.5

after










rinse










10 min
1.0
0.0
2.1
1.3
3.6
4.5
7.2
5.3
7.0

after










rinse










15 min
0.8
0.0
0.7
0.6
2.3
2.1
3.3
1.5
3.8

after










rinse










20 min
0.5
0.0
0.4
0.4
0.6
1.3
1.5
0.8
1.5

after










rinse



















































TABLE 9




Burn sensation rating for spearmint


Sample #













7J
7K
7L
7M
7N
7O
7P
7Q
7R














In-
31.1
33.0
37.1
36.9
40.9
40.0
42.5
40.4
44.4

mouth










0 min
33.3
33.6
38.0
38.2
41.9
40.5
44.1
42.3
46.1

after










rinse










5 min
21.3
22.1
31.0
28.3
32.0
31.8
35.1
35.1
38.1

after










rinse










10 min
7.4
13.3
21.0
12.8
21.6
20.4
25.9
26.9
29.9

after










rinse










15 min
2.8
6.0
10.0
6.3
14.5
10.9
12.1
14.7
19.5

after










rinse










20 min
1.8
2.9
7.1
3.3
5.8
4.5
7.2
7.5
8.8

after










rinse









































As shown in TABLE 8, the burn sensation increases significantly for dentifrices which contain >0.25% added menthol (Samples B-I). The burn sensation was significant for the 0.5% added menthol and higher formulations (Samples C-I) for peppermint when compared to the control (Sample A)which contained the flavor without the additional menthol. The burn sensation for the peppermint formulations with >0.25% (Samples B-I) added menthol was significantly high for 5-10 minutes after the water rinse.
As shown in TABLES 8 and 9 the burn sensation for Samples having spearmint (Samples J-R) was higher than that of Samples having peppermint (Samples A-I). This is exemplified in the Samples having no menthol, Sample A for peppermint and Sample J for spearmint. When >0.25% menthol was added (Samples K-R), the burn sensation was significantly higher. The burn sensation was significantly higher for the 0.5% added menthol and higher formulations (Samples L-R) for spearmint when compared to the control formulation (Sample J) which contained the flavor without the additional menthol. The burn sensation for the spearmint formulations was significantly high for 5-20 minutes after the water rinse.
TABLES 8 and 9 demonstrate the need to add burn sensation antagonists when adding high levels of menthol to the formulations.
For TABLE 10 all the Samples had the same formulation as Sample E from TABLE 6, except for the Control which lacked menthol. After brushing or mouthwash expectoration, panelists evaluated the burning sensation, assigning a number between 0 (no sensation) to 60 (highest intensity sensation). Evaluations were conducted at 5, 10, 20 and 30 minute time points, following expectoration. At each evaluation, panelists were instructed to breathe in through pursed lips and evaluate overall sensation. In this test, a numerical score of 7.5 indicates a significant user noticeable sensation. Differences less than 7.5, but greater than 5.0 indicate the trending of the data on a specific attribute. Results are shown in TABLE 10 below.






TABLE 10




Burning Sensation Rating













10 Min
20 Min
30 Min


After
After
5 Min After
After
After
After

Sample
Expectoration
Rinse
Rinse
Rinse
Rinse
Rinse











Control (no menthol)
14.3
10.6
1.2
0.0
0.0
0.0

Control + 1% Menthol
25.6
20.8
12.2
3.9
0.8
0.1

200 ppm Apritone
27.4
24.0
13.3
5.3
0.0
0.0

6 ppm Dihydrojasmone
24.1
21.3
11.3
2.5
0.0
0.0

100 ppm Isobornyl Isobutyrate
25.4
22.8
12.8
5.6
0.6
0.0

100 ppm Isobornyl Isobutyrate +
23.9
20.6
6.6
1.9
0.0
0.1

200 ppm Apritone







100 ppm Isobornyl
25.6
22.4
10.0
0.9
0.0
0.0

Isobutyrate + 6 ppm







Dihydrojasmone







100 ppm α-heptyl-γ-
25.4
21.5
13.8
1.3
0.0
0.0

valerolactone







100 ppm α-heptyl-γ-
21.8
19.1
9.3
2.8
0.0
0.0

valerolactone + 200 ppm







Apritone







100 ppm α-heptyl-γ-
26.1
21.7
10.2
2.5
0.0
0.0

valerolactone + 6 ppm







Dihydrojasmone











































The data in TABLE 10 was from panel testing of a dentifrice (Sample E from TABLE 6) containing TRPV1 and/or TRPA1 antagonists. As shown in TABLE 10, overall, the combination of apritone plus isobornyl isobutyrate showed significant reductions in perceived burning sensation from 1% menthol, as compared to the control- 1% menthol, at 5 min after brushing (6.6 for isobornyl isobutyrate+apritone compared to 12.2 for control+menthol) and 10 min after brushing (1.9 for isobornyl isobutyrate+apritone compared to 3.9 for control+menthol) with the dentifrice and rinsing with 15 mls room temperature water. This combination with menthol showed the trend of reducing the burning sensation.
Example 7
For EXAMPLE 7, a panel of 10 trained sensory experts evaluated the sensory profile experienced after rinsing with 30 grams of a test mouthwash (containing hydrogen peroxide and TRPA1 or TRPV1 antagonist) or control (containing hydrogen peroxide and no TRPA1 or TRPV1 antagonist) for 30 seconds and then expectorated. After expectoration, panelists evaluated the sensorial profile (cooling, warming, burning, numbing, and astringency), assigning a number between 0 (no sensation) to 60 (highest intensity sensation). Evaluations were conducted at 2.5, 5, 10, 20, and 30 minute time points, following expectoration at each evaluation, panelists were instructed to breathe in through pursed lips and evaluate overall burning or numbing sensation. The hydrogen peroxide containing mouthwash formulations are shown below in TABLE 11. The mouthwash samples tested comprised a control having the components listed in TABLE 11 by weight % of the composition or the control formulation plus TRPA1 or TRPV1 antagonist, as shown in TABLE 12. The mouthwashes were made using conventional methods and are shown below with amounts in weight % of total composition. Results are shown in TABLE 12 below.








TABLE 11





Ingredient
Control





35% H 2 O 2 solution
4.286


Sensate**
0.0-0.1


Flavor
0.01-0.3


Poloxamer 407
0.05-0.2


Glycerin
11-25


Propylene Glycol
0.01-3.00


Sodium Saccharin
0.01-0.1


Cetyl Pyridinium Chloride
0.1025%


Phosphoric Acid
0.0-0.02


Water, Purified, USP
QS*





*QS refers to the term quantum sufficit, meaning as much as suffices, where the remainder of the formula hole is filled with this substance


**Sensates can be chosen from the non-limiting examples of cooling agents, warming agents, tingle agents, numbing agents, or combinations thereof.






































TABLE 12




Initial

2 Min 30 SEC
5 Min
10 Min
20 Min
30 Min


in
After
After
After
After
After
After


Mouth
Expectoration
Expectoration
Expectoration
Expectoration
Expectoration
Expectoration









Burning Sensation










Control Mouthwash
18.2
24.9
17.6
11.7
3.6
1.7
0.0

200 ppm Apritone
12.6
21.9
20.8
16.0
8.6
3.3
1.3

100 ppm Isobornyl
12.7
20.9
17.6
11.4
5.1
0.0
0.0

Isobutyrate








200 ppm Apritone +
10.7
17.4
14.1
5.3
2.8
0.3
0.0

100 ppm








Isobornyl








Isobutyrate








200 ppm Apritone +
12.6
19.1
14.1
8.9
1.7
0.0
0.0

6 ppm








Dihydrojasmone








6 ppm
12.5
16.9
13.1
8.9
2.8
0.8
0.6

Dihydrojasmone








100 ppm
12.9
22.4
20.6
15.4
5.6
0.0
0.0





Numbing Sensation










Control Mouthwash
NR
11.8
10.9
9.8
5.6
3.1
0.0

200 ppm Apritone
NR
11.6
12.4
10.1
6.0
4.2
0.8

100 ppm Isobornyl
NR
8.4
7.9
5.8
2.5
0.0
0.0

Isobutyrate








200 ppm Apritone +
NR
7.3
6.1
2.5
0.0
0.0
0.0

100 ppm








Isobornyl








Isobutyrate








200 ppm Apritone +
NR
8.4
7.5
5.7
0.6
0.0
0.0

6 ppm








Dihydrojasmone








6 ppm
NR
6.9
6.9
6.3
0.8
0.0
0.0

Dihydrojasmone








100 ppm
NR
7.9
8.5
6.9
3.3
0.6
0.0





























































As shown in TABLE 12, the mouthwash compositions provide a pleasant high-impact minty taste during use and noticeable long-lasting fresh breath with a reduction in burning and numbing sensations from hydrogen peroxide in mouthwash.
Example 8
For EXAMPLE 8, 50 panelists evaluated the sensory profile experienced after brushing with a zinc based dentifrice containing 0.4% menthol for 2 minutes, expectorating the dentifrice, then rinsing with 15 ml tap water at room temperature and then expectorating. The high menthol containing dentifrice formulations (control and with antagonist) are shown below in TABLE 13.
The dentifrices were made using conventional methods and are shown below with amounts in weight % of total composition. The commercial product was purchased at a local store and evaluated as shown.







TABLE 13





Samples






Ingredient
A
B
C



Mica, Titanium Dioxide coated
0.4%
0.4%
0.4%

Sodium Fluoride
0.243%
0.243%
0.243%

Polyethylene Specks, Blue
0.35%
0.35%
0.35%

Carrageenan
0.7%
0.7%
0.7%

Sodium Saccharin
0.300%
0.300%
0.300%

Titanium Dioxide
0.525%
0.525%
0.525%

Carboxymethycellulose Sodium
1.3%
1.3%
1.3%

Hydroxyethylcellulose
0.3%
0.3%
0.3%

Peppermint Flavor
1.000%
1.000%
1.000%

Added Menthol
0%
0.25%
0.25%

Sodium Lauryl Sulfate 28% Solution
1.0%
1.0%
1.0%

Silica, Dental Type, NF (Zeodent 119)
17%
17%
17%

Sorbitol Solution LRS USP
40.5%
40.5%
40.5%

Zinc Citrate Dihydrate
0.788%
0.788%
0.788%

Stannous Chloride Dihydrate
0.209%
0.209%
0.209%

Apritone
0%
0.03%
0%

Isobornyl Isobutyrate
0%
0.005%
0%

G180 coolant
0.025%
0.010%
0.010%

Vanillyl Butyl Ether
0%
0%
0%

Zingerone
0%
0%
0%

Frescolat MGA coolant
0.0225%
0.010%
0.010%

WS5 coolant
0.007%
0.010%
0%

Sucralose
0.2%
0.2%
0.2%

Water Purified, USP
QS*
QS*
QS*



*QS refers to the term quantum sufficit, meaning as much as suffices, where the remainder of the formula hole is filled with this substance

















































TABLE 14



n = 50


Avg. Scores
Samples






Significance level = 90%
A
B
C



Overall Flavor Rating
62
67
61

Pleasant after taste in mouth
64
68
62

Overall Acceptance Rating
62
64
60

Overall Acceptance Rating at 30 minutes post brushing
59
62
60

























TABLE 14 shows the panelists' response to the formulations in TABLE 13. Sample B had the higher menthol plus the apritone plus isobornyl isobutyrate and it scored the highest overall flavor rating, and also had the highest pleasant aftertaste in mouth. After 30 minutes, Sample B had the highest overall acceptance rating.
Example 9
The compounds listed in TABLE 15 below have been found to be antagonists of the TRPA1 receptor, in that they reduce the level of TRPA1 receptor activation when activated by hydrogen peroxide or L-Menthol. 100 μM of antagonist was tested against 1 mM of L-Menthol or 500 μM hydrogen peroxide to determine if they impeded TRPA1 receptor activation by hydrogen peroxide, L-Menthol, or both. TABLE 15 below illustrates the antagonists specific to either L-Menthol or hydrogen peroxide and those that antagonize both L-Menthol and hydrogen peroxide. Intracellular Ca ++ levels were measured using cell based assays as described for EXAMPLES 1, 2, and 3.







TABLE 15





Dose









BLOCK ONLY H2O2/TRPA1


2-Hexyl-4-methyl-1,3-dioxolane
100 μM

Fenchone
100 μM

2-methyl-3-ethoxypyrazine
100 μM

Isopropyl Hexanoate
100 μM

2-Methyl-1-Butanethiol
100 μM

Desoxycholic acid
100 μM

n-Butyl Alcohol
100 μM

Sodium Erythorbate
100 μM

1-Undecanol
100 μM

6-Undecanone
100 μM

3-acetylpyridine, 98%
100 μM

Amyl Alcohol
100 μM

dl-Verbenone
100 μM

Methyl Linoleate
100 μM

Acetic acid isopropenyl ester
100 μM

3-Mercapto-2-Pentanone
100 μM

3-Hydroxybenzoic Acid
100 μM

Phenylethyl Isovalerate
100 μM

2-Acetyl-5-methylfuran
100 μM

2-Nonanol
100 μM

Isoamyl Pyruvate
100 μM

Ethyl Methyl Beta-Phenylethyl Carbinol
100 μM

Ferric Chloride
100 μM

Alpha, Alpha-dimethyl hydrocinnamyl acetate
100 μM

1-Octen-3-yl acetate
100 μM

gamma-Terpinene
100 μM

2-Undecanol
100 μM

3-Methyl-1,2-cyclopentanedione
100 μM

P-Cymen-8-ol
100 μM

Quinoline
100 μM

2-Methyl butyl 2-methylbutyrate
100 μM

4′-Methylacetophenone
100 μM

3-Hexanone
100 μM

Isobutyl isobutyrate
100 μM

2-Phenyl-2-Butenal
100 μM

Alpha-p-dimethylstyrene
100 μM

Isopentyl Alcohol
100 μM

Methylbenzoate
100 μM

2-Methyl-3-heptanone
100 μM

3,7-Dimethyl-1-octanol
100 μM

2,4,6-Trithiaheptane
100 μM

5-Methylhexanoic acid
100 μM

Acetoin
100 μM

2-Propionylthiazole
100 μM

Benzothiazole
100 μM

Butyl lactate
100 μM

2-Ethyl-1-hexanol
100 μM

But-2-enoic acid
100 μM

1-hexanol
100 μM

4-Benzo[1,3]dioxol-5-yl-butan-2-one
100 μM

Phenyl-methanol
100 μM

malic acid
100 μM

Methyl 4-hydroxybenzoate
100 μM

Butyraldehyde
100 μM

2-Methyl-2-pentenoic acid
100 μM

2,5-Dimethylphenol
100 μM

7-Hydroxycitronellal
100 μM

Urea
100 μM

Benzyl Tiglate
100 μM

γ-Dodecalactone
100 μM

Vanillic Acid
100 μM

γ-Methyl Decalactone
100 μM

2-Methoxy-4-propyl-phenol
400 μM

Methyl 2-methoxy-benzoate
400 μM

1-Methyl-2-pyrole carboxaldehyde
400 μM

Strawberry Furanone Acetate
400 μM

3,3,5-Trimethylcyclohexanol
400 μM

N-(2-Hydroxyethyl) lactamide
400 μM

2-(3-Phenylpropyl) tetrahydrofuran
400 μM

Methyl-4-phenyl butyrate
400 μM

3-Heptyldihydro-5-methyl-2(3H)-furanone
400 μM

3-acetylsulfanylhexyl acetate
400 μM

Isobornyl Isobutyrate
400 μM

Bornyl Valerate
400 μM

Citronellyl acetate
400 μM

Trans-2-hexenal
400 μM

(2-Cyclohexen-1-one, 3-methyl-5-propyl-) Celery Ketone
400 μM

(1-Oxaspiro[4.5]decan-6-ol, 2,6,10,10-tetramethyl-,
400 μM

(2S,5S,6S)-6-)Hydroxydihydrotheaspirane

BLOCK ONLY MENTHOL/TRPA1

Ethyl Hexanoate
100 μM

1,4-Dimethoxybenzene
100 μM

Cellulose acetate
100 μM

3-phenyl-2-propen-1-yl 3-phenylacrylate
100 μM

Isopropyl Tiglate
100 μM

Ethyl 3-(2-Furyl)Propionate
100 μM

Iron Naphthenate
100 μM

Beta-Caryophyllene
100 μM

(+)-Sodium L-ascorbate
100 μM

5-Methyl-2,3-Hexanedione
100 μM

Ethyl propionate
100 μM

Ethyl 3-phenylglycidate
100 μM

Propyl Pyruvate
100 μM

Octanal
100 μM

4-Methyl-1-Phenyl-2-Pentanone
100 μM

Benzyl formate
100 μM

cis-3-hexenyl butyrate
100 μM

(1R)-(+)-Camphor
100 μM

Hexanedioic acid, Dipropyl ester
100 μM

trans-2-Hexenyl acetate
100 μM

Ethyl 2,4-Dioxohexanoate
100 μM

o-Methylanisole
100 μM

Methyl N-Octyl Sulfide
100 μM

(+−)-beta; -Citronellol
100 μM

3-Mercaptobutyl acetate
100 μM

2,5-Dimethylpyrazine
100 μM

2-Benzoylamino-benzoic acid
100 μM

Angelic Acid Isobutyl Ester
100 μM

2,3,6-Trimethylphenol
100 μM

Ethyl 2-benzylacetoacetate
100 μM

1-isopropyl-4-methylbenzene
100 μM

2,3,5,6-Tetramethylpyrazine
100 μM

trans-Cinnamaldehyde
100 μM

Diallyl sulfide
100 μM

Pyruvic Aldehyde
100 μM

1-octanol
100 μM

Choline bitartrate
100 μM

3,4-Dihydroxybenzoic acid
100 μM

4-Methyl-2,6-Dimethoxyphenol
100 μM

Ethyl trans-2-Hexenoate
100 μM

beta-Resorcylic acid
100 μM

2-sec-butylcyclohexanone
100 μM

Dibutyl sebacate
100 μM

4-Methyl-5-Vinylthiazole
100 μM

Tridecanoic acid
100 μM

Isopentyl formate
100 μM

1-phenyl 1-propanol
100 μM

4-Methoxybenzyl Formate
100 μM

2-Methyl-3-Furanthiol Acetate
100 μM

2-Methyltetrahydro-3-furanone
100 μM

Citronellyl Formate
100 μM

Ethyl oleate
100 μM

EDTA
100 μM

2-(1-propoxyethoxy)ethylbenzene
100 μM

Ethyl 5-Hexenoate
100 μM

trans,trans-2,4-Decadienal
100 μM

2-Methoxybenzaldehyde
100 μM

Dextrin from potato starch
100 μM

Tetrahydrofurfuryl acetate
100 μM

Oleic acid
100 μM

Farnesylacetone
100 μM

2-Ethyl-3-methoxypyrazine
100 μM

cis-3-Octen-1-ol
100 μM

(1R)-6,6-Dimethylbicyclo[3.1.1]hept-2-ene-2-methyl acetate
100 μM

Hexadecyl Lactate
100 μM

Methyl 3-(methylthio)propionate
100 μM

methyl 2-(acetylamino)benzoate
100 μM

3-Methylthio-2-butanone
100 μM

Ethyl trans-4-decenoate
100 μM

Propionic acid trans-2-hexen-1-yl ester
100 μM

Citral dimethyl acetal, mixture of cis and trans
100 μM

Methyl nicotinate
100 μM

2-Isopropenyl-5-Methyl-5-Vinyltetrahydrofuran
100 μM

2′-Hydroxyacetophenone
100 μM

2-Methoxybenzoic Acid
100 μM

4-Methoxyphenylacetone
100 μM

Ferulic acid
100 μM

Methyl 2-Methylpentanoate
100 μM

Quinine hydrochloride dihydrate
100 μM

sec-Butyl disulfide
100 μM

Isobutyl Hexanoate
100 μM

2-Methyl-3-furanthiol
100 μM

Allyl Caprylate
100 μM

2-Acetylthiazole
100 μM

BLOCK BOTH MENTHOL AND H2O2 ON TRPA1

2-Isobutyl-3-Methoxypyrazine
100 μM

Piperazine
100 μM

Allyl Cyclohexanepropionate
100 μM

Furfuryl Alcohol
100 μM

Block menthol, H2O2, and AITC on TRPA1
100 μM

Manganese Chloride
100 μM

Phloretin
100 μM

1-Stearoyl-rac-glycerol
100 μM

Copper(I) iodide
100 μM

2-Methyl-1,3-Dithiolane
100 μM

Butyl 4-hydroxybenzoate
100 μM

2,5-Dimethyl-1,4-Dithiane-2,5-Diol
100 μM

Phenylacetaldehyde
100 μM

2,3-Butanedithiol
100 μM

2-Pyrazinyl ethanethiol
100 μM

2-Chloroacetophenone
100 μM

2-Ethylbenzenethiol
100 μM

2-Undecanone
100 μM

Diphenyl Disulfide
100 μM

Block both H2O2 and AITC on TRPA1
100 μM

Ethyl acetoacetate ethylene ketal
100 μM

1,2-Propanedithiol
100 μM

Isobutyric Acid Isopropyl Ester
100 μM

2-hydroxy-4-Methylbenzaldehyde
100 μM

Benzyl cinnamate
100 μM

Phenyl salicylate
100 μM

Benzothiazole
100 μM

Ethyl acetoacetate
100 μM

Cinnamon Bark Oil
100 μM

Anisyl Butyrate
400 μM

trans, trans-2,4-Nonadienal
400 μM

4-Allyl-2,6-dimethoxyphenol
400 μM

o-Methoxycinnamaldehyde
400 μM

4-Methyl-2-phenyl-2 Pentenal (mixture of cis and trans isomers)
400 μM

BLOCK BOTH MENTHOL AND AITC ON TRPA1

Zinc Gluconate
100 μM

Erucin
100 μM

Succinic acid
100 μM

delta-Octanolactone
100 μM

2,5-Dimethylfuran-3-thiol
100 μM

3-(Methylthio)propyl Isothiocyanate
100 μM

2-Methyl-3-furanthiol
100 μM




































































































































































































































Example 10
In an attempt to demonstrate the selective reduction in hydrogen peroxide activation of the TRPV1 receptor, antagonists were tested to determine if they failed to significantly reduce the activation of the TRPV1 receptor by capsaicin (TRPV1 agonist), but yet still reduced TRPV1 receptor activation by hydrogen peroxide. Intracellular Ca ++ levels were measured using cell based assays as described for EXAMPLES 1, 4, and 5.












TABLE 16





Ca ++ counts

% inhibition
Ca ++ counts

% inhibition



for activation

of TRPV1
for activation

of TRPV1



of TRPV1 by

activation by
of TRPV1 by

activation by



(500 uM
Ca ++
500 uM
(350 nM)
Ca ++
350 nM

Dose
Name
H2O2)
counts
H2O2
Capsaicin
counts
Capsaicin














1000
*(−)-Bornyl Acetate
1867
877
53
15029
13976
7

1000
Hydroxycitronellal
1650
627
62
15029
14728
2

1000
Apritone
1673
66
96
15029
13526
10

1000
Methyl N,N-
1129
451
60
15029
15329
−2


Dimethylanthranilate







1000
2-Ethoxy-3-
1129
474
58
15029
14878
1


ethylpyrazine







1000
L-Piperiton
1129
361
58
15029
13225
12

1000
***Isobornyl
1129
541
52
15029
14803
1.5


Isobutyrate







1000
***4-Acetoxy-2,5-
1129
451
60
15029
14578
3


dimethyl-3(2H)-








furanone







4000
Tripropylamine
1935
715
63
11872
11278
−5

4000
Dihydrojasmone
1935
38
98
11872
11397
4

4000
***1-Methyl-2-
1811
380
79
11872
11516
3


pyrole








carboxaldehyde







4000
3-Octyl Acetate
1811
181
90
11872
12109
−2

4000
2-Methylbutyl
1811
380
79
11872
11278
−5


isovalerate







4000
Jasminone B
1844
903
51
11872
11635
2

4000
**Piperonyl
1844
682
63
11872
10804
9


Isobutyrate







4000
*Phenoxyethyl
1844
737
60
11872
10922
8


Propionate







4000
Vanillin Propylene
1844
922
50
11872
11516
3


Glycol Acetate







4000
Octenyl
1844
922
50
11872
9378
1


Cyclopentanone







4000
Butyl Isobutyrate
1844
774
58
11872
11278
0.5

4000
*Guaiacwood Oil
1844
737
60
11872
10922
8

4000
Tetrahydro-4-
1844
866
53
11872
11041
7


methyl-2-(2-methyl-








1-propenyl)-2H








pyran



*Also TRPA1 agonist

**TRPA1 enhancer

***Also reduced H2O2 activation by TRPA1 and TRPA1V1





























































TABLE 16 shows compounds that reduce hydrogen peroxide activation of TRPV1, but do not reduce capsaicin activation of TRPV1. The compounds (Bornyl Acetate, Phenoxyethyl Propionate, Vanillin Propylene Glycol Acetate, and Guaiacwood Oil) are TRPA1 agonists, yet reduce hydrogen peroxide activation of TRPV1. The compound (Piperonyl Isobutyrate) is an enhancer of TRPA1, yet reduces hydrogen peroxide activation of TRPV1. Further, compounds (Isobornyl Isobutyrate, 4-Acetoxy-2,5-dimethyl-3(2H)-furanone, 1-Methyl-2-pyrole carboxaldehyde) reduced hydrogen peroxide activation of TRPA1, in addition to hydrogen peroxide reduction of TRPV1.
For EXAMPLES 11 and 12 a 0.1% sodium lauryl sulfate (SLS) aqueous solution was prepared to contain either 1 ppm or 10 ppm of 1-propanethiol. SLS solution was added to the sample and control solutions to assist in solubilization of the more hydrophobic compounds. Control solutions contained surfactant and 1-propanethiol, while sample solutions contained these components plus a protectant compound added at either 0.01% or 0.05%. 100 μL aliquots of control or test solutions were aliquotted into a 22 mL headspace vial, vortexed for 30 seconds, and incubated for 30 minutes at 60 C in an oven. After that period, 1 mL of head space was sampled and injected into an Agilent 7890 gas chromatograph equipped with a sulfur chemiluminescence detector (GC-SCD). Peak areas of the 1-propanethiol control sample (no protectant compound added) were established by triplicate injection of the control sample. The area of the propanethiol peak produced from samples containing selected protectant molecules were then determined and ratioed to the 1-propanethiol control peak area, subtracted from 1, and multiplied by 100 to calculate percent reduction of the thiol peak, thus indicating the effectiveness of each protectant at reducing the level of thiol.
Example 11
The samples in TABLE 17 were prepared by combining 1 ppm 1-propanethiol with 0.1% sodium lauryl sulfate with 1% of the test compounds. The volatile sulfurs were measured with headspace GC/MS using a SPEME column to capture the volatile sulfur. The results in TABLE 17 below show the efficacy of the dihydrojasmone on the initial screen, as well as the effectiveness of other cyclopentenones for their effectiveness in the reduction of propyl mercaptan.
















TABLE 17














Propanethiol;



Sample












Isophorone
Acetylpyrrole



isobutyrate
M.H. prep.)
Ethyl maltol
isobutyrate



% Thiol
100
69.5
50.2
45.7
43.1
37.3
22.6
9.6
0.0
−17.2
−25.7

Reduction



indicates data missing or illegible when filed


















The results from TABLE 17 demonstrate most compounds tested reduced sulfur production, but Dihydroj asmone significantly or completely reduced sulfur production.
Example 12
The samples in TABLE 18 were prepared by combining either 1 or 10 ppm 1-propanethiol with 0.1% sodium lauryl sulfate with either 0.01% or 0.05% of the test compounds. The volatile sulfurs were measured with headspace GC/MS using a SPEME column to capture the volatile sulfur.









TABLE 18







Propyl



1-
Percent Thiol
disulfide


1-Propanethiol
Propanethiol
Reduction vs.
Peak

Sample
Concentration
Peak Area
Control
Area











Blank (0.1% SLS)
na
0.0
na
0.0

1 ppm 1-Propanethiol in 0.1%
1 ppm
2,555.3
na
1,039.5

SLS

1 ppm 1-Propanethiol in 0.1%
1 ppm
2,848.0
na
1,043.8

SLS

1 ppm 1-Propanethiol in 0.1%
1 ppm
2,970.9
na
1,021.8

SLS


Average
2,791.4
na
na


Std Dev.
213.5
na
na


% RSD
7.6
na
na

0.01% Cinnamic aldehyde
1 ppm
1,764.0
36.8
719.2

0.05% Cinnamic aldehyde
1 ppm
1,328.5
52.4
763.3

0.01% Anisaldehyde
1 ppm
1,354.7
51.5
607.7

0.05% Anisaldehyde
1 ppm
1,094.5
60.8
802.3

0.01% cis-Jasmone
1 ppm
1,783.7
36.1
1,034.2

0.05% cis-Jasmone
1 ppm
1,246.5
55.3
1,220.2

0.01% Dihydrojasmone
1 ppm
587.4
79.0
1,633.1

0.05% Dihydrojasmone
1 ppm
221.4
92.1
1,836.1

0.01% Methyl jasmonate
1 ppm
996.3
64.3
675.5

0.05% Methyl jasmonate
1 ppm
773.2
72.3
800.7

0.01% delta-Damascone
1 ppm
623.2
77.7
344.3

0.05% delta-Damascone
1 ppm
495.2
82.3
1,564.1

10 ppm 1-Propanethiol in
10 ppm
28,575.3
na
23,521.0

0.1% SLS

10 ppm 1-Propanethiol in
10 ppm
26,691.8
na
22,177.3

0.1% SLS

10 ppm 1-Propanethiol in
10 ppm
27,628.9
na
22,738.4

0.1% SLS


Average
27,632.0
na
na


Std Dev.
941.8
na
na


% RSD
3.4
na
na

Blank (0.1% SLS)
na
107.5
na
166.9

0.01% Cinnamic aldehyde
10 ppm
30,403.7
−10.0
6,936.6

0.05% Cinnamic aldehyde
10 ppm
29,201.1
−5.7
8,281.6

0.01% Anisaldehyde
10 ppm
25,275.0
8.5
10,477.5

0.05% Anisaldehyde
10 ppm
16,178.2
41.5
4,387.2

0.01% cis-Jasmone
10 ppm
20,614.0
25.4
15,135.5

0.05% cis-Jasmone
10 ppm
25,378.8
8.2
22,392.7

0.01% Dihydrojasmone
10 ppm
16,233.8
41.3
16,939.8

0.05% Dihydrojasmone
10 ppm
9,210.2
66.7
24,082.8

0.01% Methyl jasmonate
10 ppm
23,259.5
15.8
15,226.2

0.05% Methyl jasmonate
10 ppm
12,831.5
53.6
8,446.4

0.01% delta-Damascone
10 ppm
5,252.7
81.0
5,400.0

0.05% delta-Damascone
10 ppm
5,193.0
81.2
3,839.7



































































The screening in TABLE 18 below shows the equivalence of dihydrojasmone to delta damascone. The results showed the comparison of low and high levels of propane thiol and how the Michael Acceptors reduce its levels. At the higher thiol levels (10 ppm), delta damascone had higher activity at its lower concentration (0.01%) than any of the other michael acceptor's. Dihydrojasmone at its higher concentration (0.05%) was close to delta damascone's thiol reduction. At the lower levels of thiol (1 ppm), the levels of dihydrojasmone tested showed better reduction in thiol than delta damascone. This data illustrated the need to range find on levels to suit the desired application, as the more sulfur that is present, the more of the Michael Acceptor that is needed, hence the two concentrations of Michael Acceptor tested (0.01% and 0.05%).
Example 13
As shown in TABLE 19 Quantitative structure-activity relationship models (QSAR models) were used to find molecular structures built off a target compound to identify new structures that are predicted to be more efficacious Michael Acceptors based on the data the tested structures. The molecular structure was generated in the computer software Discovery Studio (Accelrys Inc., San Diego, Calif.), followed by descriptor generation in the computer software CAChe (Developed by Cache Group, Beaverton, Oreg. Cache and Discovery Studio software were run on a HP 8540w Laptop Computer. All descriptors including logP, Balaban J Index reversed, nucleophilic, electrophilic and radical susceptibility descriptors were calculated in the CAChe software. The electrophilic, nucleophilic and radical susceptibility descriptors estimate how vulnerable a molecule is to an attack by either electrophiles, nucleophiles, or radicals respectively and exact methods of computation are documented in the CAChe User Guides and Quick Start manuals. All default values in the program for both CAChe and Display Studio were used for the computations.”










TABLE 19






highest






nucleo-
highest


Balaban
highest
philic
radical


J Index
electrophilic
suscep-
suscep-

QSAR Properties
Reversed
susceptibility
tibility
tibility
LogP












Cinnamic_aldehyde
1.1361
0.3751
0.4736
0.2807
1.949

Anisaldehyde
1.1177
0.4827
0.4937
0.3415
1.573

cis-Jasmone
1.5372
0.4793
0.6395
0.3973
3.108

Dihydrojasmone
1.6259
0.6129
0.6533
0.5226
3.552

Methyl_jasmonate
1.3367
0.6458
0.7053
0.3528
2.356

delta-Damascone
1.7559
0.6149
0.8042
0.411
3.387






























The QSAR computed properties in TABLE 19 indicate that the highest electrophilic susceptibility most directly separated these three from the others. Other influencers were LogP and highest nucleophilic susceptibility. Indicating that the electrophilic susceptibility, LogP, and nucleophilic susceptibility are the values that best describe the current set of molecules and could be used to create new structures.
Example 14
TABLES 20 and 21 outline shave prep compositions and methods of making. The water soluble polymers (polyethylene oxide, hydroxyethylcellulose) are added to water and mixed until the polymers are completely dissolved (about 30 min.). The aqueous mixture is then heated and the glyceryl oleate, sorbitol and fatty acids are added at about 60 deg. C. and well mixed while the heating continues. At 80-85 deg. C. the triethanolamine is added and mixed for about 20 minutes to form the aqueous soap phase. After cooling the aqueous soap phase to room temperature, the remaining components (i.e., Lubrajel, glycerin, fragrance, colorant, botanicals) are added to the aqueous soap phase and mixed well to form the gel concentrate. (Water may be added if required to bring the batch weight to 100%, thereby compensating for any water loss due to evaporation.) The concentrate is then combined with the volatile post-foaming agent under pressure within the filling line and filled into bottom-gassed aerosol cans with shearing through the valve under nitrogen pressure. Note, Iso E Super can be added the same time as the fragrance.







TABLE 20





Samples








Ingredient
1
2
3
4
5



Sorbitol 70% Solution
0.97%
0.97%
0.97%
0.97%
0.97%

Glycerin
0.49%

0.49%

0.49%

Water
QS
QS
QS
QS
QS

hydroxyethyl cellulose 18
0.49%
0.49%
0.49%
0.49%
0.49%

PEG-90M 19
0.06%
0.06%
0.06%
0.06%
0.06%

PEG-23M 20
0.05%
0.05%
0.05%
0.05%
0.05%

PTFE 21
0.15%
0.15%
0.15%
0.15%
0.15%

Palmitic acid
7.53%
7.53%
7.53%
7.53%
7.53%

Stearic Acid
2.53%
2.53%
2.53%
2.53%
2.53%

Glyceryl Oleate
1.94%
1.94%
1.94%
1.94%
1.94%

Triethanolamine (99%)
5.88%
5.88%
5.88%
5.88%
5.88%

Lubrajel Oil 22
0.49%
0.97%
0.49%
0.97%
0.49%

Apritone
0.05%
0.05%

Isobornyisolbutyrate

0.05%
0.05%

Phloretin




0.1%

Dihydrojasmone



0.05%

Menthol
0.15
0.2%
0.15%
0.2%
0.25%

Fragrance
0.87%
0.87%
0.87%
0.87%
0.87%

Other (e.g. Vit E, Aloe , etc.)
0.10%
0.10%
0.10%
0.10%
0.10%

Dye
0.10%
0.10%
0.10%
0.10%
0.10%

Isopentane (and) Isobutane
2.8500%
2.8500%
2.8500%
2.8500%
2.8500%



18 Available as Natrosol 250 HHR from Hercules Inc., Wilmington, DE

19 Available as Polyox WSR-301 from Amerchol Corp., Piscataway, NJ

20 Available as Polyox WSR N-12K from Amerchol Corp., Piscataway, NJ

21 Available as Microslip 519 from Micro Powders Inc., Tarrytown, NY

22 Available from Guardian Laboratories, Hauppauge, NY

*QS refers to the term quantum sufficit, meaning as much as suffices, where the remainder of the formula hole is filled with this substance













































The pre-shave prep samples shown in TABLE 21 are made by weighing out the water in a vessel sufficient to hold the entire batch. Insert an overhead mixer with impeller into the vessel and increase agitation to create a vortex. Pre-blend the thickener and polymer powders. Sprinkle the polymer blend into the vortex until incorporated. Begin heating batch to 70 C to hydrate the polymers. Once the batch is at 70 C, add the oil and mix until uniform and dispersed. Add the liquid dispersion polymer to the batch and mix until uniform and hydrated, increasing rpms to maintain good mixing. Add the surfactant and mix until uniform and dispersed. Begin cooling batch to below 45 C. Once below 45C, add the perfume, preservatives and other temperature-sensitive additives. Cool to below 35C and QS with water. Iso E Super can be added after the sample is cooled to 35 C or along with the perfume.







TABLE 21





Samples








Ingredient
1
2
3
4
5



Water
QS
QS
QS s
QS s
QS s

Sepigel 305
2.00
2.00
2.00
2.00
2.00

(Polyacrylamide &

C13-14 Isoparaffin &

Laureth-7)

Polyox N12K (PEG-23M)
0.50
0.50
0.50
0.50
0.50

Natrosol 250 HHR (HEC)
0.80
0.80
0.80
0.80
0.80

Glycerin 99.7% Usp/Fcc
5.00
5.00
5.00
5.00
5.00

Brij 35 (Laureth-
2.00
2.00
2.00
2.00
2.00

23)

Disodium EDTA
0.10
0.10
0.10
0.10
0.10

Perfume
0.15
0.15
0.15
0.15
0.15

Glydant Plus
0.20
0.20
0.20
0.20
0.20

Apritone
0.05%
0.05%

Isobornyisolbutyrate

0.05%
0.05%

Phloretin




0.1%

Dihydrojasmone



0.05%

Menthol
0.00
0.05
0.05
0.04
0.02






































TABLE 22 illustrates shampoo compositions containing menthol and burn sensation blockers (TRPA1/TRPV1 antagonists). The shampoo compositions may be made by mixing the ingredients together at either room temperature or at elevated temperature, e.g., about 72° C. Heat only needs to be used if solid ingredients are to be incorporated into the composition. The ingredients are mixed at the batch processing temperature. Additional ingredients, including electrolytes, polymers, fragrance, menthol, and particles, may be added to the product at room temperature.






TABLE 22




Samples










Ingredient
1
2
3
4
5
6
7



Water
QS
QS
QS
QS
QS
QS
QS

Polyquaterium 76 1
0.25
—
—

0.01



Guar, Hydroxylpropyl Trimonium
—
0.25
—

0.3
0.4
0.5

Chloride 2








Guar, Hydroxylpropyl Trimonium



0.25




Chloride 3








Polyquaterium 6 4
—
—
0.25





Sodium Laureth Sulfate (SLE3S) 5
6
10.5
6

6.0

10.0

Sodium Laureth Sulfate (SLE1S) 6



10.5

12


Sodium Lauryl Sulfate (SLS) 7
6
1.5
6
1.5
7.0

6

Silicone 8
0.75
1.00
0.5
1.00


1.00

Gel Network 9



27.3




Cocoamidopropyl Betaine 10
1.0
1.0
1.0
2.00
1.0
1.0


Cocoamide MEA 11
0.85
0.85
0.85
0.85

1.0


Ethylene Glycol Distearate 12
1.50
1.50
1.50
1.50
2.5
1.5
1.5

Zinc Pyrithione 13




1.0
1.0
1.0

Zinc Carbonate 14




1.6
1.6
1.6

Sodium Benzoate
0.25
0.25
0.25
0.25
0.25
0.25
0.25

Disodium EDTA
0.13
0.13
0.13
0.13




5-Chloro-2-methyl-4-isothiazolin-3-
0.0005
0.0005
0.0005
0.0005
0.0005
0.0005
0.0005

one, Kathon CG








Sodium Chloride/Ammonium
Visc.
Visc.
Visc.
Visc.
Visc.
Visc.
Visc.

Xylene Sulfonate
QS
QS
QS
QS
QS
QS
QS

Citric Acid/Sodium Citrate
pH
pH
pH
pH




Dihydrate
QS
QS
QS
QS




Hydrochloric Acid 6N solution




pH to 7
pH to 7
pH to 7

Menthol
0.3
0.5
0.2
0.4
0.3
0.5
0.4

Fragrance
0.7
0.7
0.7
0.7
0.7
0.8
0.9





1 Mirapol AT-1, Copolymer of Acrylamide(AM) and TRIQUAT, MW = 1,000,000; CD = 1.6 meq./gram;

Supplier Rhodia

2 Jaguar C500, MW - 500,000, CD = 0.7, supplier Rhodia

3 Jaguar C17 available from Rhodia

4 Mirapol 100S, supplier Rhodia

5 Sodium Laureth Sulfate, supplier P&G

6 Sodium Laureth Sulfate, supplier P&G

7 Sodium Lauryl Sulfate, supplier P&G

8 Dimethicone Fluid, Viscasil 330M; 30 micron particle size; supplier Momentive Silicones

9 Gel Networks; See Composition below. The water is heated to about 74° C. and the Cetyl Alcohol,

Stearyl Alcohol, and the SLES Surfactant are added to it. After incorporation, this mixture was passed

through a heat exchanger where it was cooled to about 35° C. As a result of this cooling step, the Fatty

Alcohols and surfactant crystallized to form a crystalline gel network.





Ingredient
Wt. %


Water
86.14%


Cetyl Alcohol
3.46%


Steary Alcohol
6.44%


Sodium laureth-3 sulfate
3.93%


(28% Active)



5-Chloro-2-methyl-4-isothiazolin-
0.03%


3-one, Kathon CG





10 Tegobetaine F-B, supplier Evonik

11 Monamid CMA, supplier Evonik

12 Ethylene Glycol Distearate, EGDS Pure, supplier Evonik

13 ZPT from Arch Chemical

14 Zinc carbonate from the Bruggeman Group

















































































The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “40 mm” is intended to mean “about 40 mm.”
Every document cited herein, including any cross referenced or related patent or application and any patent application or patent to which this application claims priority or benefit thereof, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it alone, or in any combination with any other reference or references, teaches, suggests or discloses any such invention. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.