Classifications

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  • A61K8/987—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of species other than mammals or birds
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  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
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  • A61K2800/92—Oral administration

Definitions

• the present invention relates to toothpaste formulations comprising allergens and/or allergenic extracts that provide controlled introduction of allergens to the immune system via the oral mucosa and to methods for treating and inhibiting the development of allergies.
• Antigen-specific immunotherapy was developed as a treatment alternative for allergic patients suffering from atopic allergies that are insufficiently controlled by treatments which focus on symptom amelioration, for example anti-histamine and corticosteroid based treatments.
• the aim of allergen immunotherapy is to re-educate the immune system by regular administration of doses of allergens over a sustained period of at least 3 years to a patient's immune system, thereby inducing specific long-term tolerance to those allergens.
• SCIT Subcutaneous immunotherapy
• SLIT sublingual immunotherapy
• SCIT subcutaneous immunotherapy
• SLIT sublingual immunotherapy
• SCIT is related to SCIT in that it refers to the delivery of the same allergens as SCIT, but is differentiated in that delivery is via an oral route rather than via subcutaneous injections.
• SLIT-treated patients are instructed to place an allergen preparation (usually 5 drops of an aqueous solution containing allergens, commonly preserved in 50% v/v glycerin) under the tongue once per day and to hold for approximately 2 minutes before swallowing or spitting.
• a typical exemplary protocol includes daily administration for 3-4 years for SLIT, and weekly or bi-weekly doctor-administered injections for 3-4 years for SCIT.
• Many studies have demonstrated that, in practice, significant numbers of patients fail to comply with AIT regimens for the full treatment course. The reasons for non-compliance vary between the various SCIT and SLIT regimens, but overall patient convenience is most often cited as the common driver for low compliance. The result is an elevated risk of unsatisfactory or poor treatment outcomes for those patients.
• OMIT oral mucosal immunotherapy
• OMIT via oral personal care products further exploits advances in the allergy acquisition and control clinical sciences suggesting that contacting allergens with areas of the oral mucosa other than the sub-lingual mucosa may be more effective in achieving a de-sensitization benefit.
• allergens will necessarily contact a much broader surface of the oral mucosal tissue during daily tooth-brushing than via SLIT, wherein exposure is confined specifically to the area under the tongue.
• toothpaste products are generally formulated to possess certain
• Toothpaste compositions with acceptable physical stability do not readily harden on the shelf and do not exhibit phase separation resulting in water or flavor separation.
• the appearance of the paste as it comes out of the dispenser is also considered an important feature. Consumer studies suggest that the toothpaste should appear smooth and have a pleasant sheen or glossy appearance.
• an OMIT toothpaste formulation should be as similar to the non-OMIT toothpastes familiar to consumers as possible.
• an OMIT toothpaste should have the following properties: (1) homogeneous dispersion of allergen throughout the toothpaste (2) immunologic properties of the allergens conserved over a time frame reasonably commensurate with expectations of toothpaste product life, and (3) a consumer phenomenological experience profile of appearance, flavor, consistency, texture, and mouth feel that is similar to known products and encourages daily use.
• an OMIT toothpaste comprises a food introduction technology (FIT) toothpaste adapted for introduction of food allergens to children generally below the age of 6.
• FIT food introduction technology
• pro-toothpaste compositions formulated to be combinable with an allergen or allergen extract suspended in a solution comprising a sugar alcohol, the pre- toothpaste composition comprising: a sugar alcohol selected to correspond to a sugar alcohol present in the suspension solution, and a viscosity modifier.
• Embodiments of toothpaste compositions formulated by combining a pro-toothpaste according to the invention with an allergen or allergen extract suspended in a solution comprising a sugar alcohol, wherein the toothpaste composition comprises between about 25% and about 75% sugar alcohol by volume and about 20% silica-based viscosity modifier by weight, are also provided.
• kits comprising at least one vial of pro- toothpaste according to embodiments of the invention, and at least one vial of solution comprising at least one allergen or allergen extract.
• at least one allergen or allergen extract is selected to accommodate a food introduction technology regimen.
• the methods comprise: providing a first volume of solution comprising an allergen or allergen extract and a concentration of sugar alcohol; formulating a second volume of pro-toothpaste comprising a reduced concentration of vehicle and an increased concentration of thickener when compared to a conventional toothpaste, the vehicle comprising a sugar alcohol corresponding to the sugar alcohol of the first volume in a concentration substantially corresponding to the concentration of sugar alcohol of the first volume, the first and second volumes being combinable in a ratio such that a concentration of sugar alcohol in the combined volume is between about 45% and 55% by volume, and mixing the first volume and second volume in the ratio.
• kits for reducing an immune response to an allergen in a subject comprise delivering an amount of one or more allergens to a target area of the oral mucosa of the subject by contacting the target area of the oral mucosa with a toothpaste formulation according to the invention at least once daily.
• the methods accommodate a food introduction technology regimen, wherein the subject is a human between the ages of 4 months and 6 years.
• Another embodiment provides methods for diagnosing propensity to developing a food allergy in a human between the ages of 4 months and six years.
• the methods comprise (a) formulating a toothpaste according to claim 29 to include an allergenic protein from one food product and (b) contacting an area of the human's oral mucosa with the toothpaste formulated in step (a) in a daily regimen for a time frame; (c) monitoring for symptoms of an immune response in the oral mucosa during or after the time frame; (d) repeating steps (a), (b) and (c) until practiced with at least 1, 2, 3, up to 8 or more toothpaste formulations, one for each independent food product, and diagnosing a propensity to developing an allergy to a food product where symptoms of an immune response are observed in (c).
• Figure 1 A bar graph comparing stability of dust mite allergen extract Der 1 f over 180 days when formulated into a toothpaste according to the invention versus Der 1 f extract in glycerol suspension.
• Figure 2 A bar graph comparing stability of cat allergen extract Fel d 1 over 180 days when formulated into a toothpaste according to the invention versus Fel d 1 extract in glycerol suspension.
• abrasive, polishing agent, humectant, binder, thickener, surfactant, surface active agent, flavoring, flavoring agent, sweetener, sweetening agent, buffer, preservative, allergen, allergen extract, antigen, and similar terms also include mixtures of like materials. Unless otherwise specified, all percentages are percentages by weight. These terms should be construed to comport with their ordinary meaning in the art.
• a "Pro-toothpaste” as used herein is a toothpaste comprising an ingredient profile substantially similar to conventional toothpaste compositions; however certain ingredients may be eliminated and vehicle is reduced to provide a composition that mixes with one or more allergens and/or allergen extracts to provide an end-product toothpaste with desired stability, efficacy and consumer profiles are achieved upon combination.
• Toothpaste occasionally also referred to as dentifrice, is commonly used with a toothbrush as an accessory to clean and maintain the aesthetics and health of teeth. Toothpaste is used to promote oral hygiene: it serves as an abrasive that aids in removing the dental plaque and food from the teeth, assists in suppressing halitosis, and delivers active ingredients (mainly fluoride) to help prevent tooth and gum disease (gingivitis).
• active ingredients mainly fluoride
• the present investigators have developed Pro- toothpaste compositions which may be combined with allergens suspended in particular solutions to form a suitable consumer toothpaste product such that the allergens are brought into contact with the oral mucosa during tooth-brushing.
• administration of AIT to treat allergic conditions can be effectuated during the ritual of daily dental care as "oral mucosal
• toothpaste compositions should possess certain acceptable physical properties to which the consumer is accustomed. These properties provide toothpaste that has appealing taste, has good cleansing effect, is easy to rinse, has excellent mouth feel, and has physical stability. Moreover, toothpaste compositions must possess an acceptable physical stability profile such that they do not readily harden on the shelf and do not exhibit phase separation such as water or flavor separation. The appearance of the paste as it comes out of the dispenser is also considered important. Studies show that consumers prefer a toothpaste that appear smooth and has a pleasant sheen or glossy appearance.
• Embodiments of the instant invention provide Pro-toothpaste compositions, and methods of formulating such compositions, that are suitable for combining with allergens, preferably suspended in aqueous solution or 50% v/v glycerin.
• Other embodiments provide the constituted toothpaste product, referred to herein as "OMIT toothpaste,” that possesses stability, efficacy and consumer characteristics substantially similar to those of conventional toothpastes.
• kits comprising Pro-toothpaste contained separately from one or more compositions comprising allergen or allergen extract.
• a kit may comprise one or more optional items such as mixing vessels, metered dose-dispensers, and a toothbrush.
• the toothbrush is adapted to optimize exposure of target oral mucosa cells to allergen, for example, gum massaging or stimulating extensions.
• allergen for example, gum massaging or stimulating extensions.
• Other embodiments provide methods for preventing, treating, diagnosing and managing allergic conditions in both humans and other mammals susceptible to development of allergy.
• a Pro-toothpaste is a portion of the toothpaste product comprising typical ingredients of a
• a typical vehicle may comprise humectant and water.
• formulating the composition of the Pro-toothpaste comprises retaining the amounts of binder, surface active agent, and abrasive in a typical toothpaste composition, while decreasing the total percentage of vehicle (water and/or humectant) by an amount that corresponds to the predetermined volume of allergens to be added to the Pro-OMIT toothpaste, such that the Pro-toothpaste is concentrated.
• allergens suspended in aqueous or 50% v/v glycerin solution are combined with a Pro-toothpaste such that the toothpaste may be reconstituted by, for example, a clinician, a pharmacist or a consumer, to a usable form as a finished allergen-containing OMIT toothpaste product.
• One embodiment is directed to a pro-toothpaste composition formulated to be combinable with an allergen or allergen extract suspended in a solution comprising a sugar alcohol, the pre- toothpaste composition comprising: a sugar alcohol selected to correspond to a sugar alcohol present in the suspension solution, and a viscosity modifier.
• the sugar alcohol comprises glycerol and the viscosity modifier comprises a silica-based viscosity modifier in an amount of between about 12% and about 30% by weight, and according to more specific embodiments, the composition comprises between about 40% and 60% by weight glycerol.
• the pro-toothpaste composition comprises about 50% by volume glycerol and about 20% silica-based viscosity modifier by weight.
• the method of formulating the composition of OMIT toothpaste comprises retaining the amounts/relative percentages of binder, surface active agent, abrasive, and humectant in a typical toothpaste composition, while decreasing the percentage of water by an amount that corresponds to the predetermined volume of allergens to be added to the Pro- toothpaste.
• formulating the composition of the OMIT toothpaste comprises
• the predetermined volume of allergens to be combined with a Pro-toothpaste composition may correspond to a volume ratio of about 2 parts Pro-toothpaste to about 1 part allergen, or 3 parts Pro-toothpaste to about 1 part allergen, or about 4 parts Pro-toothpaste to about 1 part allergen, or about 5 parts Pro-toothpaste to about 1 part allergen, or about 6 parts Pro-toothpaste to about 1 part allergen.
• formulating the composition of the Pro-toothpaste comprises retaining the relative amounts of binder, surface active agent, and abrasive, and other ingredients in a typical toothpaste composition, while decreasing the percentage of vehicle (water and/or humectant) by about 20%, wherein the predetermined volume of allergens to be added to the Pro-toothpaste composition is in a volume ratio of about 4 parts Pro-toothpaste to about 1 part allergen.
• compositions of Pro-toothpaste are provided.
• the Pro-toothpaste comprises a binder; a surface active agent; an abrasive; a humectant; and water; in which;
• the binder comprises about 10% - 22% (w/w),
• the surface active agent comprises about 1.0% - 2.0% (w/w),
• the abrasive comprises about 5% - 10% (w/w)
• the humectant comprises 40% - 55% (w/w),
• the water comprises about 18% - 25% (w/w)
• the sweetener comprises about 0.2% - 0.4% (w/w),
• the preservative comprises about 1.5% - 3% (w/w),
• the flavoring agent comprises about 0.5% - 1.5% (w/w)
• the opacifier and/or coloring agent comprises about 0.1% - 0.2% (w/w), and
• the anti-caries agent comprises about 0.2% - 0.5% (w/w).
• the formulation of Pro-toothpaste comprises a binder; a surface active agent; an abrasive; a humectant; water; a sweetener; a preservative; a flavoring agent; an opacifier or coloring agent, and an anti-cavity agent; in which;
• the binder comprises about 0.35% - 0.45% (w/w) Carbomer 940TM or similar binding agent; about 0.75% - 1.0% (w/w) sodium carboxymethylcellulose (CMC) or similar binding agent; and about 10% - 20% (w/w) Zeodent 153TM or similar silica thickener,
• the surface active agent comprises about 1.0% - 2.0% (w/w) sodium lauryl sulfate (SLS) or other similar agent,
• the abrasive comprises about 5.0% - 10.0% (w/w) Zeodent 113TM or other similar abrasive
• the humectant comprises about 40% - 55% (w/w) polyol, such as glycerin or sorbitol (in 70% w/v solution), or other humectant
• the water comprises about 18% - 25% (w/w)
• the sweetener comprises about 0.2% - 0.4% (w/w) sodium saccharine, or other similar sweetener
• the preservative comprises about 1.0% - 2.0% (w/w) sodium phosphate tribasic (Na3P04), and about 0.5% - 1.0% sodium phosphate monobasic (NaH2P04), or other similar preservative,
• the flavoring agent comprises about 0.1% - 1.5% (w/w) of natural peppermint oil or other similar flavor agent
• the opacifier and/or coloring agent comprises about 0.1% - 0.2% (w/w) of titanium dioxide and/or other opacifier or coloring agent
• the anti-cavity agent comprises about 0.2% - 0.5% (w/w) sodium fluoride (NaF) or other similar anti-cavity agent.
• the Pro-toothpaste formulation comprises a binder; a surface active agent; an abrasive; a humectant; water; a sweetener; a preservative; a flavoring agent; an opacifier agent, and an anti-cavity agent; in which;
• the binder comprises about 0.43% (w/w) Carbomer 940TM; about 0.935% (w/w) sodium carboxymethylcellulose (CMC); and about 12.3% (w/w) Zeodent 153TM,
• the surface active agent comprises about 1.41% (w/w) sodium lauryl sulfate (SLS) or other similar agent,
• the abrasive comprises about 6.15% (w/w) Zeodent 113TM or other similar abrasive
• the humectant comprises about 53.1% (w/w) glycerin
• the water comprises about 22.9% (w/w),
• the sweetener comprises about 0.246% (w/w) sodium saccharine
• the preservative comprises about 1.23% (w/w) sodium phosphate tribasic (Na 3 P0 4 ) and about 0.614% (w/w) sodium phosphate monobasic (NaH 2 P0 4 ),
• the flavoring agent comprises about 0.254% (w/w) natural peppermint oil
• the opacifier agent comprises about 0.123% (w/w) titanium dioxide
• the anti-cavity agent comprises about 0.254% (w/w) sodium fluoride (NaF).
• Pro-toothpaste compositions are formulated to comprise reduced percentages of, and/or to eliminate particular conventional toothpaste ingredients. Consequently the concentration of thickening agents and viscosity and/or rheology modifiers is increased.
• the vehicle of a toothpaste composition typically comprises water and/or humectant.
• the instantly inventive OMIT toothpaste product compositions are formulated from a "base" toothpaste composition referred to herein as a Pro-toothpaste.
• a Pro-toothpaste Following manufacture of a Pro-toothpaste, it is intended that one or more allergens can be added to, and homogeneously mixed with, the Pro-toothpaste (i.e., by an appropriate agent such as a drug manufacturer, a compounding pharmacy, an allergy clinician, etc, or in accordance with other embodiments by a consumer or other party at the site of intended use).
• Mixing in accordance with embodiments of the invention comprises generally hand-mixing or low-speed mixing without the use of shearing elements and without imparting a substantial increase in energy to the formulation resulting in a temperature increase.
• Allergens in accordance with specific embodiments are suspended in a water and/or glycerin solution such that when the solution is combined with the Pro-toothpaste, the allergen solution mixes readily and homogeneously with vehicle components to provide an OMIT toothpaste product. More specifically, the addition of a defined volume of allergen solution will complete an OMIT toothpaste composition, resulting in texture, consistency, mouth-feel, and other important properties of the composition being comparable to those of a known toothpaste products usable for daily dental care.
• Pro-toothpaste compositions are mixed with allergens suspended in aqueous and/or glycerin solutions in a specific volume ratio of 4 parts Pro- toothpaste to 1 part allergen solution to form an OMIT toothpaste.
• the formulation of 8ml of the Pro-toothpaste comprises percentage weight amounts of ingredients, such as an abrasive or polishing agent, a binder, a surface active agent, that are intended for 10ml of final OMIT toothpaste, but about 20% less toothpaste vehicle volume.
• volume ratios between Pro-toothpaste and allergen solutions may be about 2 parts Pro-toothpaste to about 1 part allergen solution, or 3 parts Pro- toothpaste to about 1 part allergen solution, or about 5 parts Pro-toothpaste to about 1 part allergen solution, or about 6 parts Pro-toothpaste to about 1 part allergen solution.
• Typical commercial toothpaste ingredients include one or more of an abrasive or polishing agent, humectant, binder, surface active agent, water, and, optionally, other materials that are typical components of toothpaste compositions, such as flavors, coloring agents, sweeteners, preservatives, and, optionally, agents that prevent caries, tooth decay, and gum disease.
• the humectant and water ingredients of are often referred to collectively as the toothpaste "vehicle”. Specific ingredients may also vary from country to country according to local legislation on use of ingredients.
• the sugar alcohol of the allergen extraction suspension corresponds to a sugar alcohol humectant present in the Pro-toothpaste formulation such as illustrated in Example 5, both with respect to specific sugar alcohol and with respect to weight percentage of each formulation.
• an OMIT toothpaste composition of the invention is formulated to
• cellulose gums such as carboxymethyl cellulose (CMC), methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and mixtures thereof;
• polyvinyl pyrrolidone polyvinyl pyrrolidone
• xanthan carrageenans such as iota-carrageenan, kappa-carrageenan, kappa2-carrageenan, lambda-carrageenan, and mixtures thereof
• guar gum iota-carrageenan, kappa-carrageenan, kappa2-carrageenan, lambda-carrageenan, and mixtures thereof
• guar gum gum karaya
• gum arabic gum tragacanth
• Other suitable thickeners include Carbomer 910, Carbomer 934, Carbomer 940, and Carbomer 980 and similar polymers of acrylic acid which are cross-linked with polyalcohol allyl ethers. Hydrated silica and colloidal silica may be used as thickeners.
• Silica thickeners suitable for invention embodiments such as Zeodent 153®, Zeodent 163®, and Zeodent 165®, (J.M. Huber Co., Edison, N.J. USA) are disclosed, for example, in Niemi, U.S. Pat. No. 6,342,205, the entire disclosure of which is incorporated herein by this reference).
• the present investigators surprisingly found that Pro-toothpaste formulations comprising one or more silica thickeners combine with allergen extract suspended in solutions comprising glycerol to provide an enhanced stability effect.
• the toothpaste compositions of the invention may also comprise an abrasive, sometimes referred to as a polishing agent.
• Suitable abrasives, or polishing agents include finely divided water- insoluble powdered materials having no or very low water solubility, typically having a particle size of about 1 to 40 microns in diameter, more typically about 2 to 20 microns in diameter, with normal particle size distributions. These materials have polishing activity without being overly abrasive.
• Typical abrasives include: calcium-based polishing agents, such as dicalcium phosphate dihydrate (generally known as dicalcium phosphate), tricalcium phosphate, calcium carbonate (such as limestone, natural chalk, or precipitated chalk), calcium pyrophosphate, calcium silicate, and calcium aluminate; magnesium carbonate; magnesium phosphate; sodium metaphosphate; amorphous silica; crystalline silica; precipitated silica such as Zeodent 113®, Zeodent 115®, Zeodent 124®, or Zeodent 623® (J.M. Huber Co., Edison, N.J.
• calcium-based polishing agents such as dicalcium phosphate dihydrate (generally known as dicalcium phosphate), tricalcium phosphate, calcium carbonate (such as limestone, natural chalk, or precipitated chalk), calcium pyrophosphate, calcium silicate, and calcium aluminate
• magnesium carbonate magnesium phosphate
• sodium metaphosphate amorphous si
• complex aluminosilicate aluminum hydroxide; aluminosilicates, bentonite, talc, aluminum oxide, silica xerogels, and mixtures thereof. More typical abrasives are dicalcium phosphate, calcium carbonate, and silica.
• a vehicle component comprises water and a humectant.
• the total vehicle volume of a Pro-toothpaste [water + humectant] may be varied over conventional toothpaste compositions in terms of its percentage composition (w/w) in order to adjust for addition of allergens.
• Allergens may be suspended in a solution formulated to readily combine with the vehicle aspect of a Pro-toothpaste.
• the allergen solutions comprise aqueous and/or glycerin in percentage amounts substantially similar , to a vehicle component of a Pro-toothpaste.
• Commercially available allergens vary from country to country based on regulatory scheme and other legal concerns.
• Typical commercially available allergen extract solutions comprise allergen suspended in aqueous or glycerin solutions.
• an allergen extract solution comprises at least about 50% glycerin v/v, and in very specific embodiments an allergen extract comprises about 50% glycerin v/v.
• a humectant provides mouth feel and also prevents a toothpaste composition from drying out.
• Toothpastes are typically formulated with humectants comprising polyols of three to six carbons in which each carbon is hydroxylated, and mixtures thereof.
• Specific non-limiting examples include glycerin (glycerol), sorbitol, polyethylene glycol, polyoxy ethylene glycol, mannitol, xylitol, and other sugar alcohols. It should be appreciated that since glycerin, sorbitol, and xylitol also have sweetening properties, their inclusion in toothpaste compositions can limit the need to include additional sweeteners, such as sodium saccharine.
• Pro-toothpaste is formulated with glycerol as the sole or predominant sugar alcohol.
• Toothpaste compositions of the invention may also comprise a surface active agent, often with surfactant properties, to emulsify or otherwise uniformly disperse toothpaste components.
• the surface active agents are typically anionic or nonionic surface active agents, or mixtures thereof.
• Suitable surface active agents include water-soluble salts of higher fatty acid monoglyceride monosulfates; higher alkyl sulfates; higher alkyl aryl sulfonates; higher alkyl sulfoacetates; higher fatty acid esters of 1,2 dihydroxy propane sulfonate; substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbon atoms in the fatty acid, alkyl or acyl radicals; higher olefin sulfonates, higher alkyl poly-lower alkoxy (of 3 to 100 alkoxy groups) sulfates, and fatty acid soaps.
• anionic surface active agents examples include sodium lauryl sulfate (SLS), sodium hydrogenated coconut oil fatty acids monoglyceride monosulfate, sodium dodecyl benzene sulfonate, sodium lauryl sulfoacetates, sodium N-lauryl sarcosinate, and sodium cocate.
• Suitable types of nonionic surface active agents include chains of lower alkyene oxides such as ethylene oxide and propylene oxide.
• a preferred surface active agent for invention embodiments is sodium lauryl sulfate (SLS).
• the toothpaste compositions of the invention may comprise a number of other ingredients.
• Agents that provide therapeutic or cosmetic benefits may be present, such as enamel hardening agents, tartar control agents, whitening agents, and antibacterial agents.
• One or more sweeteners and flavorings may be added for consumer satisfaction.
• Other materials that are conventional components of toothpaste compositions, such as opacifers and colorants, may also be present.
• flavorings examples include: menthol; carvone; anethole; methyl salicylate; and the oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, kumquat, tangerine, and orange.
• Preferred flavoring oils, such as peppermint oil may be exracted and purified from natural sources or synthesized.
• sweeteners examples include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, L-aspartyl-L-phenylalanine methyl ester (aspartame), and saccharine.
• Specific embodiments comprise saccharine, which may be included as sodium saccharine.
• an amount of artificial sweetener typical in conventional toothpaste formulations may be reduced by reliance predominantly or solely on glycerol as a humectant.
• pyrophosphate salts such as Na 4 P 2 0 7 (TSPP), K 4 P 2 0 7 , Na 2 K 2 P 2 0 7 , Na 2 K 2 H 2 0 7 , and K 2 H 2 P 2 0 7 , long chain polyphosphates such as sodium hexametaphosphate, and cyclic phosphates such as sodium trimetaphosphate may be present in the toothpaste composition.
• hardening agents are fluoride salts such as sodium fluoride, potassium fluoride, calcium fluoride, zinc fluoride, stannous fluoride, zinc ammonium fluoride, sodium
• Preservatives or stabilizers may also be included in the toothpaste compositions of the invention.
• non-cationic antibacterial agents that are based on phenolic and bisphenolic compounds, halogenated diphenyl ether, benzoate esters and carbanilides, such as sodium benzoate; 4-chlorophenol, 2,2'-trichloro-2-hydroxy-diphenyl ether (triclosan); esters of p- hydroxybenzoic acid, especially the methyl, ethyl (ethyl parasept), propyl (propyl parasept), butyl (butyl parasept), and benzyl esters; 3,4,4'-trichlorocarbanalide and 3,3',4- trichlorocarbanilide.
• a preferred antimicrobial agent is triclosan.
• Nonionic antimicrobial agents such as sesquiterpene alcohols such as merolidol and bisabolol are also useful.
• Preferred preservatives of the invention are sodium phosphate monobasic (NaH 2 P0 4 ) and sodium phosphate tribasic (Na 3 P0 4 ) and similar agents, which additionally have useful pH buffering properties.
• Whitening agents may be present in the toothpaste composition.
• Useful whitening agents are oxidizing agents such as calcium peroxide, urea peroxide, peracetic acid, and sodium percarbonate.
• the toothpaste composition may also comprise other ingredients that are conventional
• opacifier agents such as titanium dioxide
• Other ingredients may be orally acceptable colorants such beta-carotene, chlorophyllin, FD&C Yellow #5, FD&C Yellow #6, FD&C Blue #2, FD&C Red #4, FD&C Green #6, FD&C Yellow #10, FD&C Red #40, D&C Green #5, D&C Red #30 lake, and FD&C Blue #1 lake; healing agents, such as rose-seed oil; chelating/sequestering agents, such as citrates; vitamins, such as vitamin C and vitamin E; amino acids; proteins; antibiotics; anti-enzymes; enzymes; pH control agents (buffers); antioxidants; and preservatives.
• Allergens according to the invention may include any agent which triggers a measurable immune response.
• an allergen may include any agent which triggers measurable production of IgE in at least some individuals exposed to the allergen (e.g., at least some atopic individuals).
• an allergen comprises an agent that triggers an allergic reaction (type I hypersensitivity reaction) in at least some individuals exposed to the allergen (e.g., at least some atopic individuals).
• the allergen is an air-borne allergen.
• the main route by which subject are exposed to such allergens is though inhalation.
• the allergen is one to which subjects are mainly exposed by skin contact with the allergen.
• the allergen is one to which subjects are mainly exposed by ingesting the allergen.
• the allergen is one to which subjects are mainly exposed by injection.
• allergens according to the invention include allergens of plant, animal or fungal origin.
• Plant allergens include pollen, sap, leaves and plant toxins, while examples of fungal allergens include polypeptides produced by molds, Aspergillus and others.
• Animal allergens include polypeptides produced by insects, fecal allergens of dust mites and mammals, in particular of cats, and animal keratinacious dander. Specific examples include ragweed pollen, dust mite and dust mite excrement, animal dander and mold.
• Other examples of allergens include food allergens, various insect venoms, and a number of industrial chemicals and pharmaceutical agents (e.g., penicillins, cephalosporins, cancer chemotherapy drugs, etc).
• allergen may refer to one or more allergens, and may refer to any combination of allergens within and/or between the major classes of animal, plant, and fungi/mold.
• Food allergens in particular, may be from any class or any combination of classes.
• Plant pollens are major sources of airborne allergy throughout many areas of the world.
• an allergen comprises grass pollen.
• Grasses include members of the family Poaceae (sometimes termed "true grasses"), rushes (Juncaceae) and sedges (Cyperaceae). Grasses are distributed widely throughout many regions of the world, with different species having variable importance in different geographical areas.
• grass species common in at least some regions of Europe and/or the US include Dactylis glomerata (orchard grass), Poa pratensis (Kentucky bluegrass), Lolium perenne (ryegrass), Anthoxantum odoratum (sweet vernal), Phleum pratense (timothy), Festuca eliator (meadow fescue), Agrostis alba (redtop), and Cynodon dactylon (Bermuda grass).
• Grass allergens include, e.g., Poa a 1 (UniProtTM acc. no. Q9ZP03) and Poa p 5 (UniProtTM acc. no. Q9FPR0).
• an allergen is from a grass within the Dactylis, Poa, Lolium, Anthoxantum, Phleum,, Festuca, Agrostisi or Cynodon genus, e.g., any of the afore-mentioned species.
• an allergen can comprise a Poa a, Poa p, or Phi p protein.
• a plant allergen is pollen (or an extract or component thereof) of a tree or shrub that is a member of the Cupressaceae family.
• the Cupressaceae (cypress) family includes a number of species whose common name includes the word "cedar”.
• the allergen is pollen from a species in the subfamily Cupressoideae, e.g., a member of the genus Chamaecyparis or Juniperus ("juniper").
• the allergen is pollen from Cryptomeria japonica (family Cupressaceae, subfamily Taxodioidea), commonly referred to as Sugi or Japanese cedar.
• allergenic molecules e.g., particular proteins
• allergens such as pollens, dusts, danders, molds, foods, etc.
• allergen encompasses allergens in natural forms such as pollens, dusts, danders, molds, foods, or venoms, extracts of such natural forms of allergens, and allergenic molecules (e.g., particular proteins) that are at least partially purified or substantially purified or isolated from natural sources or produced using, e.g.,recombinant DNA technology.
• allergenic molecules e.g., particular proteins
• allergens and/or allergen extracts are selected as part of a Food Introduction Technology (FIT) regimen, in particular for children.
• FIT Food Introduction Technology
• an OMIT toothpaste comprises a FIT toothpaste.
• Food allergies are most likely to occur during the first few years of life in genetically- susceptible individuals. While food allergies are often outgrown by later childhood, exposure to certain foods may initiate a cascade of inflammatory conditions, known as the "atopic march", typically starting with atopic dermatitis (AD) and allergic rhinitis (AR), then leading to asthma and other allergic co-morbidities such as sinusitis and ear disease. Inferential evidence for early childhood as a critical period for exposure sufficient to de- sensitize an immune response abounds. With delayed introduction of solid foods, Australia saw a 5-fold increase in food anaphylaxis in children under 4 years of age.
• a FIT- suitable OMIT toothpaste according to the invention comprises at least one food allergen, for example, an allergen sourced from one or more of the food-types that represent common food allergies that can develop in humans, including but not limited to milk, egg, soy, wheat, peanuts, tree nuts, fish and shellfish.
• the OMIT toothpaste is formulated for appeal in particular to pediatric subjects.
• pediatric subjects of different ages between 4 months and 6 years of age may have varying preferences and toothpaste formulations may be designed to reflect age biases/restrictions. For example, it is recommended to avoid the use of fluoride-containing toothpaste until at least 2 years of age.
• Some embodiments of the invention provides methods for diagnosing or detecting the emergence of food allergies, preferably in pediatric subjects who are not yet determined to have a food allergy or have no known clinically manifested allergy.
• a subject who is not yet determined to have allergic food sensitivities benefits from an OMIT toothpaste containing a single food allergen which introduces the allergen to the subject's oral mucosa during regular oral care. If allergic symptoms are noted after use of the toothpaste, then the subject is suspected of having an allergic sensitivity to that allergen. The subject would stop using the toothpaste and seek additional counseling and diagnosis from a healthcare professional. The specific knowledge of the identity of the food allergen responsible for triggering the symptoms is helpful in clinical verification that an allergic sensitivity is present.
• the methods comprise (a) formulating a toothpaste according to claim 29 to include an allergenic protein from one food product and (b) contacting an area of the human's oral mucosa with the toothpaste formulated in step (a) in a daily regimen for a time frame; (c) monitoring for symptoms of an immune response in the oral mucosa during or after the time frame; (d) repeating steps (a), (b) and (c) until practiced with at least 1, 2, 3, up to 8 or more toothpaste formulations, one for each independent food product, and diagnosing a propensity to developing an allergy to a food product where symptoms of an immune response are observed in (c).
• kits designed to effectuate practice of methods of detecting emergence of food allergies on subjects with no current determination of clinical food allergies.
• a kit comprises a set of different toothpastes, each toothpaste containing a single food allergen, and each toothpaste in the series containing servings for about 1, 2, 3, or more weeks of use.
• a kit comprises a series of 8 toothpastes, each containing a single allergen from the group of 8 allergens that correspond to the 8 most common food allergies: milk, egg, soy, wheat, peanuts, tree nuts, fish and shellfish.
• a kit comprises a series of 8 toothpastes, each containing a single allergen from the group of 8 allergens that correspond to the 8 most common food allergies: milk, egg, soy, wheat, peanuts, tree nuts, fish and shellfish.
• Subjects, as described herein, may be people who are not known to have any specific food
• Subjects may be considered to be at risk of developing food allergies.
• a person who is at risk of developing food allergies may have a sibling, parent, or other family member with food allergies.
• a person who has exhibited other non-food allergies, for example hayfever, atopic dermatitis, or respiratory allergies may also be considered to be at risk of developing food allergies.
• subjects are pediatric subjects age 4 months through 6 years.
• a FIT toothpaste is agitated along the teeth and gums of a pediatric patient for approximately 2 minutes, optimally with a toothbrush, bathing the vestibular mucosa with about 5, 10, 20, 30 or more mg of a single food antigen source, or alternatively as many as 8 or more food antigen sources.
• Smaller doses of each allergen may be appropriate for infants of 4 months to 1 year of age, for example about lmg, or about 5 mg, or about lOmg, or more may be appropriate for the youngest users of FIT toothpaste.
• amounts of each food allergen are determined as a proportion to bodyweight.
• different formulations of FIT toothpaste may be appropriate for different age periods of subjects, with dosing of allergens corresponding to average bodyweight of subjects at those ages.
• a FIT toothpaste or gel may be applied by either massaging or wiping the gums in edentulous children, or by brushing the teeth. This routine may help subjects gain tolerance to foods at a critical early stage of development, and thus help to avoid or reduce the risk of developing specific food allergies.
• Food allergens comprise proteins from food sources that, in the event of contact or ingestion by an allergic individual, can trigger allergic reactions.
• Food allergens can also be manufactured by extraction and purification from food sources and used in various modes of AIT discussed herein and elsewhere, such as allergy shots, SLIT, and OMIT.
• Methods suitable for allergen processing e.g., production of allergen extracts, purification of allergen molecules, etc., are well known in the art.
• source allergen material e.g., pollen, insect, dander
• Centrifugation can be used, e.g., to separate solid or particulate matter.
• Resulting material can be incubated in an aqueous medium (e.g., water or suitable buffered solution, e.g., ammonium bicarbonate, phosphate buffered saline, etc.) for a suitable period of time to at least partly solubilize proteins.
• Crude extract can be processed using, e.g., dialysis, filtration, fractionation, chromatography, etc.
• one or more steps is performed to at least partly remove low molecular weight components, concentrate the extract, etc.
• Extracts can be sterilized, e.g., using filtration and/or irradiation. Other processing steps can be applied as known in the art. Numerous specific protocols are available.
• Extracts of allergens specifically processed for safe use in human immunotherapy are available commercially.
• Allergy and Immunotherapy division publishes a brochure entitled "Human Allergy Products and Services" available on-line at the company website currently at
• Allergen extracts typically contain multiple proteins, e.g., multiple allergenic proteins, present in the natural form of the allergen. Extracts can be prepared from, e.g., pollens (e.g., of trees, shrubs, grasses, other plants such as those often termed "weeds"), animal epithelia, feathers, fungal mycelia or spores, smuts, mites, insects, insect venoms, foods, dusts, etc.
• pollens e.g., of trees, shrubs, grasses, other plants such as those often termed "weeds”
• animal epithelia feathers
• fungal mycelia or spores smuts
• mites insects, insect venoms, foods, dusts, etc.
• Allergens according to the invention are generally any allergen preparations, or combination of allergen preparations, that are suitable for AIT in allergic patients.
• AIT often involves the development of a specific, personalized mixture of allergens to treat an individual patient's specific allergies, according to their clinical allergy profile. This mixture is often referred to as a specific patient's "treatment set".
• a treatment set may comprise a single allergens or a multiplicity of different allergens, combined together.
• allergen in this disclosure can refer to a treatment set of multiple allergens or allergen extracts.
• an allergen extract is provided in a liquid form, such as water, glycerin, or a combination thereof. Allergen extracts prepared for AIT are commonly provided as about 50% glycerin v/v.
• AIT -type treatment can be used to prevent the potential development of allergies and atopic sensitivities in subjects who do not currently have allergies or allergy symptoms.
• introduction of some food or other allergens preferably at an early stage in life, has been shown to lower the risk of developing allergic sensitivities in some individuals.
• methods and inventions described herein can be intended for preventative use, as well as for therapeutic use.
• Subjects who benefit from the technology disclosed herein may be adult or pediatric humans who are in need AIT to treat allergic sensitivities or who may be in need of ensuring introduction of allergens to their immune systems as a way to assure development of immunotolerance and reduce the risk of developing allergies.
• AIT both as SCIT and SLIT has been shown to be an effective tool in veterinary medicine for treating allergies in animals as well as humans. A discussion of veterinary use of AIT is available here at
• SCIT and SLIT products are available for AIT treatment of allergies and atopic disorders in animals, such as ALLERCEPT products (Heska, Inc., Loveland CO) which can be reviewed at
• Pro-toothpaste compositions for animal-targeted applications comprises compositions of commercially available animal toothpaste products comprising about 50% glycerin by volume. Allergens and allergen extracts may be mixed directly into the composition. Generally, animals do require the same profile of texture, rinsability, visual appearance oral sensory experience as human toothpaste consumers. Commercially available animal toothpastes contain some common elements with toothpaste compositions designed for humans, such as abrasive or polishing agents, humectants, binders, water, and flavoring.
• PETRODEXTM products Sentry Pet Care Products, Inc., Omaha, NE
• a typical ingredient list for pet toothpaste is: sugar alcohol, purified water, dicalcium phosphate, hydrated silica, artificial beef or chicken flavor, poultry digest, dextrose, xanthan gum, and sodium benzoate.
• methods for reducing allergic symptoms in an animal comprise formulating an OMIT toothpaste comprising allergens or extracts of allergens suspected as the cause of the animal's symptoms, and brushing the animal's oral mucosa according to a regimen.
• the regimen may be weekly, daily, twice daily, or more frequently depending on the allergy.
• allergens and/or allergen extracts may be formulated into an abrasive "tooth-brushing" toy or food-stuff as known in the art.
• Non-limiting examples of commercially available "chew-toys" and food-stuffs for dogs and cats may be found at
• Example 1 The following Example illustrates that conventional toothpaste formulations may not be mixed with allergen extract solutions without severely compromising an end-product profile, and further illustrates preliminary mixing and stability performed to provide preliminary formulation guidance.
• Product 1 A well-known non-fluoridated children's toothpaste product (Product 1) was combined with white oak extract suspended in 50% glycerin v/v (Antigen Laboratories, Inc, Liberty, MO) at a ratio of 30ml toothpaste and 0.6ml of allergen extract (2% v/v).
• Product 1 comprised the following listed ingredients: Purified water, sorbitol, propylene glycol, glycerin, cellulose gum, poloxamer 407, flavor, simethicone, methylparaben, potassium sorbate, sodium saccharine, propyl paraben, and citric acid.
• the allergens mixed into Product 1 initially, but the combination lost the texture and consistency of the original Product 1, eventually also losing its color and becoming a clear syrup over 1 week.
• Product 1 combined with allergens as described was unsatisfactory as toothpaste.
• Product 2 A commercially available fluoridated toothpaste product was combined with white oak extract in 50% glycerin v/v in the same manner and ratio (2% v/v) as previously with Product 1. According to the label, Product 2 comprised the following listed ingredients: Sodium monofluorophosphate, dicalcium phosphate dehydrate, water, glycerin, SLS, cellulose gum, flavor, tetrasodium pyrophosphate, and sodium saccharine. The allergen solution mixed with Product 2 initially, but the combination was runny and unstable, eventually separating into a solid white and a liquid phase over 48 hours. Product 2 combined with allergens was unsatisfactory as toothpaste.
• Product 3 A different commercially available toothpaste product was combined with white oak extract in 50% glycerin v/v in the same manner and ratio (2% v/v) as previously with Product 1 and Product 2. According to the label, Product 3 was selected as a representative silica-based composition and comprised the following listed ingredients: Sorbitol, water, hydrated silica, SLS, trisodium phosphate, flavor, sodium phosphate, cellulose gum, carbomer 956, sodium saccharine, titanium dioxide, and "Blue 1" coloring. The white oak allergen appeared to mix well with Product 3 and formulation stability was superior to other products investigated.
• the listed ingredients of Product 3 provided an initial formulation template and several specific compositions of a Pro-toothpaste formulation, each with varying percentages of ingredients and vehicle, were prepared (see Examples 2-4). 079] The following Examples 2-4 illustrate characteristic profiles for several preliminary Pro- toothpaste formulations.
• PT-5 exhibited a thick, paste-like consistency. Upon addition and thorough mixing of 1 part allergen (in 50% glycerin) to 4 parts PT-5, the consistency changed to a texture and consistency similar to that of typical toothpaste. [0081 ] Example 3. Formulation of PT-7
• PT-7 exhibited a thick, paste-like consistency. Upon addition and thorough mixing of 1 part allergen (in 50% glycerin) to 4 parts PT-7, the consistency changed to a texture and consistency similar to that of typical toothpaste. Four volunteers were given PT-7 with allergen and asked to brush their teeth. All subjects remarked that the toothpaste was suitable as toothpaste, with consistency, texture, and flavor consistent with a typical toothpaste.
• PT-16 exhibited a thick, paste-like consistency. Upon addition and thorough mixing of 1 part allergen (in 50% glycerin) to 4 parts PT-16, the consistency and texture sifted to that which is consistent a typical toothpaste. Four volunteers were given PT-16 with allergen and asked to brush their teeth. All subjects commented that the toothpaste was usable as toothpaste, with consistency, texture, and flavor consistent with that of typical toothpastes. Example 5. The following Example demonstrates that a toothpaste formulated with a pro- toothpaste comprising a sugar alcohol (sorbitol, see, e.g.
• Example 3 PT-7) that did not correspond to the sugar alcohol aspect of the allergen extract suspension (glycerol) was unstable with respect to detectable allergen after a 1 month time frame when compared to a toothpaste formulated with a pro-toothpaste comprising a sugar alcohol corresponding to the sugar alcohol present in the allergen extract suspension (Example 4, PT-16).
• the exemplary allergen extracts were Der f 1 , a house mite allergen extract, and Fel d 1 , a cat dander extract.
• Each of the four aliquots of PT-7 and PT-16 was mixed with allergen extract or glycerin at a 1:4 ratio (0.5ml allergen extract in 2ml pre -toothpaste). Results of preliminary initial interference tests determined that the best analytical method was the Multiplex Array for Indoor Allergens (MARIA®).
• MARIA® Multiplex Array for Indoor Allergens
• MARIA® is an allergen detection technology based on fluorescent microspheres coupled with monoclonal antibodies which allows the simultaneous detection of multiple allergens in a single test. Following extraction procedures described above, each sample was measured for Der f 1 , Fel d 1 and Phi p 5 content using MARIA®. All 7 samples were loaded onto the plate at dilutions 1/10, 1/100 and 1/10,000. Results showing a substantial decline in concentration of allergen after one month in PT-7 versus substantial retention of allergen concentration after one month in PT-16 formulation are set forth below in Tables 1 and 2. Table 1
• Example 6 The following Example illustrates that toothpaste formulated with allergens
• PT-16 formulated 4 1 with Der f 1 and PT-16 formulated 4: 1 with Fel dl provided the test formulation specimens and were compared to stability of the extract alone. Results are depicted in Figure 1 and Figure 2. No statistical difference was observed in stability of allergens across 365 days when formulated in accordance with aspects of the invention, versus when present in allergen extract suspensions in glycerol as available for SLIT applications.
• Example 7 Case Report #1 of a 42 year old female with a 25 year history of allergic rhinitis with a symptom profile of sneezing, nasal itching, and rhinorrhea in the spring, along with perennial itching in the mouth when eating apples or raw vegetables.
• Use of oral antihistamines only partially controlled her symptoms.
• SPT skin-prick testing

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