Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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  • A61K31/075—Ethers or acetals
  • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
  • A61K33/10—Carbonates; Bicarbonates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/40—Peroxides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/42—Phosphorus; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/20—Halogens; Compounds thereof
  • A61K8/21—Fluorides; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/24—Phosphorous; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
  • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

• the present application relates to compositions and methods for preventing dental caries.
• the present application relates to aqueous compositions and methods for improving the mechanical strength of teeth.
• Dental caries are one of the most common preventable diseases plaguing humans and non- human animals worldwide.
• Dental caries teeth decay, cavity
• bacterial processes which damage hard tooth structure ⁇ e.g., enamel, dentin, and cementum). These tooth structures break down progressively, producing holes in teeth (dental caries).
• Teeth which are comprised primarily of minerals, are constantly subjected to demineralization and remineralization between teeth and the surrounding saliva.
• Hydroxylapatite a crystalline calcium phosphate— is the primary mineral of a tooth's enamel surface and has the general formula Ca 5 (P0 4 ) 3 (OH), but is usually written Ca 10 (PO 4 ) 6 (OH) 2 to denote that the crystal unit cell comprises two entities.
• pH at the tooth surface drops below 5.5, demineralization proceeds faster than remineralization ⁇ i.e. a net loss of
• Fluoride assists in the prevention of caries by binding to hydroxylapatite surfaces in the tooth enamel, forming fluorapatite and making the enamel more resistant to demineralization (and thus more resistant to decay). Fluoride is also commonly added to municipal water supplies to prevent tooth decay, yet the National Research Council (functioning under the auspices of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine) recently concluded that the levels of fluoride found in municipal water supplies and the levels of fluoride known to cause toxic effects are dangerously close to one another.
• Theobromine (IUPAC name: 3,7-dimethyl-2,3,6,7-tetrahydro-lH-purine-2,6-dione ; also known as 3,7-dimethylxanthine) is a white (or colorless) bitter-tasting crystalline powder with a sublimation point of 290-295 °C, a melting point of 357 °C, and a molecular weight of 180.16 g/ mol.
• the solubility of theobromine in water is 1.0 g/2 L; in boiling water, it is 1.0 g/ 150 mL, and in 95% ethanol it is 1.0 g/ 2.2 L.
• Theobromine is related chemically to caffeine and theophylline, and is found in numerous foods including chocolate, cocoa, tea leaves, and acai berries.
• the chemical structures of theobromine, theophylline (1,3-dimethylxanthine), and caffeine (1,3,7-trimethylxanthine) are given below as formulae I, II, and III, respectively.
• Theobromine is found naturally in cacao beans Theobroma cacao) at a concentration of from about 1.5% to about 3%, and in the husk of the bean at a concentration of from about 0.7% to about 1.2%, or about 15 to about 30 g/Kg (Winholdz, 1983).
• Caffeine acts relatively quickly, and its main effect on humans is increased mental alertness; theobromine's effect is subtler, and causes a mood elevation that is milder longer- lasting than that of caffeine.
• Theobromine's plasma half-life (t 1/2 ) in the bloodstream is six hours, while caffeine's is only two hours. Another difference is that theobromine is not physiologically addictive, producing no withdrawal symptoms after prolonged regular consumption, while caffeine has been proven to be physiologically addictive and linked with many cases of proven withdrawal.
• Theobromine can also be isolated or produced as an amine salt e.g., the ethylene diamine salt thereof) or a double salt thereof ⁇ e.g., with alkali metal salts or alkaline earth metal salts of organic acids, for example alkali or alkaline earth metal salts of acetic, gluconic, benzoic, or 15 salicylic acid) .
• the double salts may be prepared either to make the theobromine more water souble, or to make insoluble complexes.
• cocoa powder washed with water possessed considerably less anti-cariogenic effect than unwashed cocoa powder.
• Stralfors still observed a considerable anti- caries effect in the washed cocoa powder group, "indicating an existence of a non-water soluble cariostatic factor," and alluded to the existence of "two caries-inhibitory substances in cocoa: one water-soluble, and another which is sparingly soluble in water” (Stralfors, A., 1966).
• Hall-Petch relationship dictates that the resistance of a solid material to permanent deformation (e.g., its indentation hardness) increases as the particle size decreases. Consequently, the increased hydroxylapatite crystallinity observed after exposure to
• the present disclosure provides a composition, the composition comprising isolated theobromine, at least one source of calcium, at least one source of phosphate, and a pH of about 6.0 to about 8.5.
• the at least one source of calcium may be selected from the group consisting of calcium chloride, calcium carbonate, calcium gluconate, calcium phosphate, and combinations thereof.
• the at least one source of phosphate may be selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof.
• the composition may further comprise at least one isotonic agent.
• the isotonic agent may be a polyhydric alcohol.
• the polyhydric alcohol may be selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, arabitol, glycerol, and combinations thereof.
• the composition may further comprise at least one thickener.
• the thickener may be selected from the group consisting of methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
• composition may further comprise an antibacterial agent.
• the antibacterial agent may be triclosan, hydrogen peroxide (H ⁇ O ⁇ , methyl- 4-hydroxybenzoate, clove oil, benzalkonium chloride, or combinations thereof.
• a composition for enhancing the hardness of at least one tooth, wherein said composition enhances said hardness more than a dentifrice containing 0% to about 1.1% of either sodium fluoride or sodium monofluorophosphate.
• the composition enhances said hardness more than a dentifrice containing 0% to about 0.5% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate.
• the composition enhances said hardness more than a dentifrice containing 0% to about 0.25% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate.
• the composition enhances said hardness more than a dentifrice containing 0% to about 0.15% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate.
• the present disclosure provides a method of treating dental surfaces in a mammal in need thereof, said method comprising: providing a composition comprising isolated theobromine, theobromine salt, or theobromine double salt, at least one source of calcium, and at least one source of phosphate, wherein the pH of said composition is about 6.0 to about 8.5; and administering said composition to said mammal.
• the least one source of calcium may be selected from the group consisting of calcium chloride, calcium carbonate, calcium gluconate, calcium phosphate, and combinations thereof.
• the at least one source of phosphate may be selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof.
• the composition of said method may further comprise at least one isotonic agent.
• the isotonic agent may be a polyhydric alcohol.
• the polyhydric alcohol may be selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, arabitol, glycerol, and combinations thereof.
• the composition of said method may further comprise at least one thickener.
• the thickener may be selected from the group consisting of methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and combinations thereof.
• the composition may further comprise an antibacterial agent, an antimicrobial agent, or combinations thereof.
• the antibacterial agent may be selected from the group consisting of triclosan, hydrogen peroxide, methyl-4- hydroxybenzoate, clove oil, and combinations thereof.
• a composition for treating a dental surface of at least one tooth, wherein said composition treats said dental surface better than a dentifrice containing 0% to about 1.1% of either sodium fluoride or sodium monofluorophosphate.
• the composition treats said dental surface better than a dentifrice containing 0% to about 0.5% of sodium fluoride or 0% to about 0.76% sodium
• the composition treats said dental surface better than a dentifrice containing 0% to about 0.25% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate. In one aspect of said method, the composition treats said dental surface better than a dentifrice containing 0% to about 0.15% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate. In one aspect, said dental surface is scratched, chipped, eroded, abraded, pitted, damaged by dental caries, and/ or damaged by other trauma.
• the present disclosure provides a method of enhancing the indentation hardness of at least one tooth, said method comprising providing a composition comprising isolated theobromine, theobromine salt, or theobromine double salt, at least one source of calcium, and at least one source of phosphate, wherein the pH of said composition is about 6.0 to about 8.5; and administering said composition to said mammal.
• the at least one source of calcium may be selected from the group consisting of calcium chloride, calcium carbonate, calcium gluconate, calcium phosphate, and combinations thereof.
• the at least one source of phosphate may be selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof.
• the composition of said method may further comprise at least one isotonic agent.
• the isotonic agent may be a polyhydric alcohol.
• the polyhydric alcohol may be selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, arabitol, glycerol, and combinations thereof.
• the composition of said method may further comprise at least one thickener.
• the thickener may be selected from the group consisting of methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and combinations thereof.
• the composition of said method may further comprise an antibacterial agent, an antimicrobial agent, or combinations thereof.
• the antibacterial agent may be selected from the group consisting of triclosan, hydrogen peroxide, methyl-4-hydroxybenzoate, clove oil, and combinations thereof.
• the enhancing may further comprise deposition of new hydroxylapatite and/ or calcium phosphate onto said tooth.
• a composition for enhancing the indentation hardness of at least one tooth, wherein said composition enhances said indentation hardness more than a dentifrice containing 0% to about 1.1% of either sodium fluoride or sodium monofluorophosphate.
• the composition enhances said indentation hardness more than a dentifrice containing 0% to about 0.5% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate.
• the composition enhances said indentation hardness more than a dentifrice containing 0% to about 0.25% of sodium fluoride or 0% to about 0.76% sodium monofluorophosphate.
• the composition enhances said indentation hardness more than a dentifrice containing 0% to about 0.15% of sodium fluoride or 0% to about 0.76% sodium
• FIG. 1 shows indentations in tooth enamel following microhardness testing.
• the dashed line indicates the length (L) of the long diagonal, used in calculating the Knoop hardness number (HK).
• FIG. 2 shows scanning electron micrographs of a control tooth at different magnifications.
• FIG. 3 shows indentations in tooth enamel of a tooth exposed to 0.15% NaF (750x mag.).
• FIG. 4 shows indentations in tooth enamel of a tooth exposed to 0.25% NaF (750 x mag.).
• FIG. 5 shows indentations in tooth enamel of a tooth exposed to 5 mg/L theobromine (750 x mag.).
• FIG. 6 shows indentations in tooth enamel of a tooth exposed to 10 mg/L theobromine (250 x 5 mag.) .
• FIG. 7 shows indentations in tooth enamel of a tooth exposed to 200 mg/L theobromine (750 x mag.).
• FIG. 8 shows indentations in tooth enamel of a tooth exposed to 500 mg/L theobromine (250 x mag.).
• the dashed box within FIG. 8 indicates the area shown in FIG. 9 at 750 x magnification.
• FIG. 9 shows the area bounded by the dashed square in FIG. 8, and shows indentations in tooth enamel of a tooth exposed to 500 mg/L theobromine (750 x mag.).
• FIG. 10 is a bar graph showing the effects of different concentrations of NaF and theobromine on microhardness.
• FIG. 11 is a semi-log scatterplot showing the effects of different concentrations of NaF and 15 theobromine on microhardness.
• FIG. 12 shows three scanning electron micrograph of three different tooth samples scratched with a diamond scribe.
• FIG. 12A shows such a tooth incubated in control solution (artificial saliva);
• FIG. 12B shows such a tooth incubated in a solution containing 0.25% NaF;
• FIG. 12C shows such a tooth incubated in a solution containing 200 mg/L theobromine.
• FIG. 13 is a bar graph showing the change in Vickers microhardness of tooth samples subjected to a caries model, then incubated for 14 days to artificial saliva, 0.25% NaF toothpaste, or 200 mg/L theobromine.
• FIG. 14 is a bar graph showing the change in Vickers microhardness of tooth samples subjected to an erosion model, then incubated for 14 days to artificial saliva, 0.25% NaF toothpaste, or 25 200 mg/L theobromine.
• the present disclosure comprises a theobromine composition, useful for enhancing the mechanical resistance of teeth, as well as a method of enhancing the mechanical resistance of teeth, the method comprising administering the theobromine composition of the present
• the theobromine of the instant composition and method may be isolated or produced as an amine salt e.g., the ethylene diamine salt thereof) or a double salt thereof ⁇ e.g., with alkali metal salts or alkaline earth metal salts of organic acids, for example alkali or alkaline earth metal salts of acetic, gluconic, benzoic, or salicylic acid).
• the double salts may be prepared either to make
• Suitable acid addition salts of theobromine include the acid addition salts including pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, a-keto glutarate, a-glycerophosphate
• the acid addition salt is a hydrochloride salt.
• the compounds of the theobromine composition are preferably in pharmaceutically acceptable form.
• pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
• a pharmaceutically acceptable 30 level of purity will generally be at least 50% excluding normal pharmaceutical additives,
• the theobromine concentration may be from about 0.1 to about 1000, from about 0.25 to about 900, from about 0.5 to about 800, from about 0.5 to about 700, from about 0.75 to about
• 600 from about 1 to about 500, from about 5 to about 500, from about 10 to about 450, from about 25 to about 400, from about 50 to about 350, from about 100 to about 300, from about 150 to about 250, from about 175 to about 225, and preferably about 200 mg/L.
• the present disclosure provides a theobromine composition
• a theobromine composition comprising isolated theobromine, or a salt or double salt thereof, at least one source of calcium, and at least one source of phosphate, where the pH of the composition is from about 5 to about 10, from about 5.5 to about 9.5, from about 6.0 to about 9.0, from about 6.0 to about 8.5, from about 6.5 to about 8.5, from about 6.8 to about 8.2, from about 7.0 to about 8.0, from about 7.2 to about 7.8, and preferably from about 7.4 to about 7.6.
• the theobromine composition is formulated for oral or topical oral administration, and may be formulated for slow or rapid release of the active ingredients.
• the theobromine composition may be in the form of tablets (including orally-disintegrating tablets), gums ⁇ e.g., chewing gum), sachets, powders, granules, lozenges, reconstitutable powders, and liquid, gel, or paste preparations such as oral solutions or suspensions.
• Topical oral formulations are also envisioned, where appropriate ⁇ e.g., toothpaste, mouthwash, dental floss, over-the-counter trays, coated strips, orthodontic and pediatric varnishes, dental cements or adhesives, polishing pastes, tooth bleaching agents, and cavity filling materials and resins (both UV reactive and non-UV reactive)), as well as the incorporation of the theobromine composition into foodstuffs ⁇ e.g., baked goods, beverages, etc.) and endodontic materials ⁇ e.g., gutta percha, etc. containing the theobromine composition), all of which may be used with or without prior acid etching of a dental surface ⁇ see, e.g., EXAMPLE 4 below).
• the composition is provided as a unit dose.
• the formulations may contain conventional excipients such as binding agents ⁇ e.g., syrups such as corn syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, polyethylene glycols (PEG), waxes and other fats, cocoa butter, cocoa butter substitutes, hydrogenated tallow, hydrogenated vegetable oils, hydrogenated cotton seed oil, palm kernel oil, soybean oil, stannol esters, glycerol esters, polyalcohol esters, polyoxyethylene esters of hydrophilic and hydrophobic balances from 0.5 to above 20 and polyethylene glycols, monosaccharides, oligosaccharides (dextrose, dextrose monohydrate, lactose, mannose, fructose, and derivatives and mixtures thereof), polysaccharides, gum solutions, hydrogenated starch hydrolates, glycerine, and mixtures thereof; fillers ⁇ e.g., silicon dioxide, sugars, starches, lacto
• Solid, orally-disintegrable, or chewable oral compositions may be prepared by conventional methods of blending, filling, tabletting, soaking, or the like, and may be in the form of, for example, tablets (including orally-disintegrating tablets), gums, sachets, powders, granules, lozenges, reconstitutable powders, liquid, gel, or paste preparations such as oral solutions or suspensions, and foodstuffs such as mints, gums, candies, and baked goods. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
• the chewable or orally-disintegrable compositions may be produced, inter alia, by subjecting a feedstock containing a carrier material to flashflow processing, thereby producing a shearform matrix, or "floss", as taught by the prior art.
• the shearform matrix can then be mixed by conventional techniques with active ingredients ⁇ e.g., isolated theobromine, a source of calcium, a source of phosphate).
• Active ingredients ⁇ e.g., isolated theobromine, a source of calcium, a source of phosphate.
• Gutta percha the predominant material used to obturate the space inside of a tooth after endodontic therapy ⁇ e.g., after a root canal
• Liquid oral preparations may be in the form of, for example, emulsions, syrups, mouthwashes (rinses), or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use ⁇ e.g., as a sports drink).
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or a
• Topical oral formulations may be presented as, for instance, ointments, creams, lotions, impregnated dressings, gels, gel sticks, sprays, and aerosols, and may contain appropriate conventional additives such as preservatives and/or solvents to assist drug penetration and emollients in ointments and creams.
• the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
• the theobromine compositions and formulations may contain from about 0.01% to about 0.1%, to about 1.0%, to about 2.5%, to about 5%, to about 10%, to about 20%, to about 50%, or to about 99% by weight, preferably from about 0.01% to about 0.1%, to about 1.0%, to about 2.5%, to about 5%, to about 10%, to about 20%, or to about 50% by weight, and more preferably from about 0.1% to about 0.1%, to about 1.0%, to about 2.5%, to about 5%, to about 10%, to about 20%, to about 50% of isolated theobromine, depending on the formulation.
• the resistance of a solid material to deformation depends upon its microdurability (small-scale shear modulus) in any direction, and not upon any rigidity or stiffness properties such as its bulk modulus or Young's modulus. Observers often confuse stiffness and hardness. For example, reports occasionally describe materials as being harder than diamond, but fail to account for the anisotropy of the materials' solid cells (the different values of measured properties, when measured in different directions). This failure accounts for the reported materials' propensity for spalling and flaking in squamose or acicular habits in other dimensions (e.g., osmium is suffer than diamond, but only as hard as quartz).
• the Hall-Petch relationship describes the relationship between a solid material's particle size and its resistance to permanent deformation (e.g., its indentation hardness), and predicts that yield strength increases as the particle size decreases.
• the relationship is based upon the observation that grain boundaries— the interfaces between grains in a polycrystalline material — disrupt the motion of dislocations through a material and that the number of dislocations within a grain affects the ease with which dislocations traverse grain boundaries and travel from grain to grain.
• modifying grain size e.g., via heat treatment, or by altering the rate of solidification
• the yield strength either remains constant or decreases with decreasing particle size.
• - 72 - confounding factor e.g., a factor that ameliorated reduced yield strength, in the face of increased grain size, in females but not males).
• etching the dental surface enhances the deposition of new calcium phosphate and/ or hydroxylapatite.
• a one-step etching process may be employed using any inorganic acid including, but not limited to, HC1
• HN0 3 nitric acid
• H 2 S0 4 sulfuric acid
• H 3 P0 4 phosphoric acid
• organic acid including, but not limited to, lactic acid, pyruvic acid, glycolic acid, chloroacetic acid, dichioroacetic acid, trichloroacetic acid, cyanoacetic acid, tartaric acid, succinic acid, glutaric acid, maleic acid, fumaric acid, malonic acid, citraconic acid, ortho-phthalic acid, meta-phthalic acid, para-phthalic acid, citric acid, tricarballyic acid, 1 ,3,5-pentanetricarboxylic acid, trimellitic acid, 2-acrylamido-2-methyipropane sulfonic acid, benzenesulfonic acid, benzoic acid, bromoacetic acid, 10-camphorquinonesulfonic acid, 10-camphorsulfonic acid,
• dibromoacetic acid 2,4-dinitrophenol, formic acid, fumaric acid, 2-hydroxy-4- methoxybenzophenone-5-sulfonic acid, maleic-acid, 2-naphthalene sulfonic acid, nitric acid, oxalic acid, p-nitrophenol, phenol, phosphorous acid esters (such as 2,2'-bis(a-methacryloxy-b- hydroxypropoxyphenyl)propane diphosphonate (Bis-GMA diphosphonate), dibutyl phosphite, di-2-ethyl-hexyl phosphate, di-2-ethyl-hexyl phosphite, hydroxyethyl methacrylate
• phosphorous acid esters such as 2,2'-bis(a-methacryloxy-b- hydroxypropoxyphenyl)propane diphosphonate (Bis-GMA diphosphonate)
• Bis-GMA diphosphonate dibut
• a two-step etching process may also be used, as described at EXAMPLE 4, using any of the aforementioned acids.
• the concentration of said acid or acids may be (independently) from about 0.01 M to about 2 M, from about 0.025 M to about 1.5 M, from about 0.05 M to about 1 M, from about 0.075 M to about 0.75 M, from about 0.085 M to about 0.5 M, from about 0.09 M to about 0.4 M, from about 0.1 M to about 0.3 M, from about 0.1 M to about 0.25 M, from about 0.1 M to about 0.2 M, and preferably about 0.1 M.
• a two-step etching process comprising irrigation/immersion/ exposure for about 15 seconds in/ to 0.1 M HC1, rinse with distilled water, then irrigation/immersion/ exposure for about 15 seconds to a 0.1 M oxalic acid solution, and then rinse once more with distilled water.
• the applicants present the unexpected and surprising result that human teeth exposed to a theobromine composition demonstrate significantly enhanced indentation hardness despite concomitant increase in grain size. Applicants also present the further unexpected and surprising result that such exposure produces significant deposition of new hydroxylapatite/ calcium phosphate onto dental surfaces, and that such deposition is to a greater degree than that observed in either control situations or with NaF.
• This discovery represents a significant advance in the prevention of dental injuries including tooth fractures (generally), fractures of the enamel, chipping, and caries.
• Samples were immersed in either control solution (artificial saliva, as shown in TABLE 2), control solution containing NaF, or control solution containing theobromine, for thirty minutes daily. Following this daily immersion regimen, samples were rinsed with distilled water and placed in control solution (artificial saliva) for the remainder of the 24-hour period. The only exception to this rinsing regimen occurred on the eighth day, when the rinsing step was omitted in order to avoid disrupting the enamel surfaces prior to subjecting the samples to scanning electron microscopy (SEM).
• SEM scanning electron microscopy
• Sorbitol Solution (70%, aqueous) 0 - 50 g 42.80 g
• Sodium fluoride was examined at concentrations of 0.15% (about 35.7 mM), 0.25% (about 59.5 mM), 0.5% (about 119 mM), and 1.1% (about 262 mM), representing both the lower end of commercially-available (over-the-counter) sodium fluoride concentrations, and the prescription- strength level of 1.1%.
• the effects of theobromine were studied at concentrations of lmg/L (about 0.006 mM), 5 mg/L (about 0.028 mM), 10 mg/L (about 0.056 mM), 25 mg/L (about 0.139 mM), 50 mg/L (about 0.278 mM), 100 mg/L (about 0.556 mM), 200 mg/L (about 1.11 mM), and 500 mg/L (about 2.78 mM).
• concentrations of lmg/L about 0.006 mM
• 5 mg/L about 0.028 mM
• 10 mg/L about 0.056 mM
• 25 mg/L about 0.139 mM
• 50 mg/L about 0.278 mM
• 100 mg/L about 0.556 mM
• 200 mg/L about 1.11 mM
• 500 mg/L about 2.78 mM
• the highest dose of theobromine— 500 mg/L— corresponds to the average level of theobromine found in commercial cocoa powder (about 1.89%), as mentioned above, and represents the upper solubility limit of theobromine in water.
• the 500 mg/L theobromine was made by mixing 1890 mg (1.89g) theobromine per liter of artificial saliva.
• Tri-calcium phosphate Ca 3 (P0 4 ) 2 is the major impurity found in hydroxylapatite and can be detected by x-ray diffraction as a deviation of the Ca:P ratio away from the target ratio of 1.67:1. Tri-calcium phosphate formation is easily minimized by ensuring the presence of sufficient calcium ⁇ e.g., as calcium chloride) in the artificial saliva solution (Van Der Bijl and De Waal (1993), Kelly et al. (2004)).
• the applicants' formulation deviates from the literature in that the artificial saliva solution contains twice the usual amount of calcium chloride (0.32 g/L of CaCl 2 -2H 2 0) so as to minimize TCP formation.
• the addition of an effective threshold level of calcium is also of particular concern for the development of applicants' dentifrice.
• Knoop microhardness tests were performed on each sample, each day, for eight days, using a
• Buehlet Micromet-1 microhardness tester fitted with an elongated diamond-shaped indenter tip.
• the Micromet-1 diamond tip was lowered to make contact with the enamel surface of each
• the microhardness indenter applied 50 grams of force to the enamel surface of each sample, for 5 seconds. The force applied was roughly
• Scanning electron micrographs were taken using an Amray 1820 digital SEM at 15kv acceleration voltage, and 18mm working distance, 25° sample tilt, and a 400 ⁇ final aperture.
• FIG. 11 shows clearly that the theobromine composition is significantly more effective than sodium fluoride, on a molecule-to-molecule basis, at enhancing the indentation hardness of teeth.
• Isolated human teeth were scratched with a diamond scribe on the enamel surface. Each tooth was then etched for 15 seconds in 0.1 M HCl, rinsed with distilled water, then exposed for 15 seconds to a 0.1 M oxalic acid solution, and then rinsed once more with distilled water. The teeth were then placed into a 0.2 M Na 2 HP0 4 solution, to which either theobromine (to a final concentration of 200 mg/L), NaF (to a final concentration of 0.25 %), or water (control) was added. The pH was adjusted to 7.4-7.6, after which a 0.2 M CaCl 2 solution was added with stirring (the solution turns immediately turbid from Ca-phosphate precipitation). The pH was checked and adjusted immediately to between 7.4 and 7.6, as required.
• the final concentrations of theobromine and NaF were 200 mg/L and 0.25%, respectively.
• a volume ratio of about 3:5 Na 2 HP0 4 solution-to-CaCl 2 solution was used to avoid any excess of either Ca or P.
• the teeth were so incubated at room temperature for about 90 minutes, after which they were removed from solution, carefully rinsed several times with distilled water, and then dried in a desiccator for 24 hours. After drying, the teeth were carbon-coated for viewing via scanning electron microscopy (SEM). The SEM results are shown in FIGS. 12-14, and discussed below.
• FIG. 12A shows a scratched tooth that was incubated for 90 minutes in control solution (no theobromine or NaF).
• the scratch produced by the diamond scribe shown by the arrows, proceeds from the top of the figure to the bottom, and is deep and pronounced.
• FIG. 12B shows a scratched tooth that was incubated for 90 minutes in the presence of 0.25% NaF.
• the scratch produced by the diamond scribe appears to be pardy- filled, as shown by the arrows pointing to the shadow on the tooth surface, yet the scratch remains wide.
• the teeth incubated with NaF also demonstrated small, focused mineral deposits over the entire visible surface. In marked contrast to both the control and the NaF experiments, FIG.
• each tooth was cut to enable visualization of the drilled holes and measure the amount of calcium phosphate deposition in said holes.
• the teeth were visualized via SEM, as in EXAMPLE 4, and the amount of calcium phosphate deposition measured for each experimental condition.
• the anticaries potential of theobromine-containing toothpaste formulations was compared to a standard NaF dentifrice by determining the early caries lesion remineraUzation in an established in vitro remineraUzation/ demineraUzation pH cycUng model.
• the gel was prepared by adding 0.10 M sodium hydroxide to 0.10 M lactic acid to give a final pH value of 4.5. To this solution, 6% w/v hydroxyethyl ceUulose was added whilst vigorously stirring. The final consistency of gel achieved exhibited a viscosity in the region of 100 cP. Following lesion formation, the nail varnish was carefully and totally removed with acetone. Thus, a total of 3 lesion-bearing blocks were obtained from each tooth (30 teeth) to be used for the remineralization test (a total of 90 blocks).
• the 30 blocks for each treatment group were distributed into 3 subgroups of 10 blocks each. Using an acid-resistant nail varnish, the 10 blocks for each subgroup were stuck onto a cylindrical rod attached to the cover of a 30-mL color-coded treatment vial, giving a total of three vials for each dentifrice group.
• the remineralization study was conducted using a pH cycling (demineralization/re- mineralization) model, simulating the activities within the oral environment as closely as possible ⁇ see TABLE 4).
• Pooled human saliva was used as the remineralization medium in all treatment regimens, while the acidified gel described above for the development of the early caries lesion was used as the acid challenge medium.
• Fresh, pooled human saliva was used each day.
• Standard slurry of the dentifrices was prepared by mixing 1 part dentifrice and 3 parts pooled human saliva (9 g : 27 mL) using a laboratory stand mixer, until homogenous. Fresh slurry for each group was prepared just prior to each treatment episode.
• the cyclic treatment regimen for each day consisted of three 1-hour acid challenges, three 2-minute dentifrice treatment periods, and then saliva treatment for the rest of the time, as shown in the treatment schedule below at TABLE 4 (Day 1 was an all-day saliva treatment to allow for development of pellicle; treatment on subsequent days was as given in TABLE 4).
• Vickers microhardness tests were performed on each sample (3 groups of 10 blocks each, 30 total), using a diamond indenter having the form of a right pyramid to indent the test material.
• the diamond indenter pyramid had a square base and an angle of 136° between opposite faces, and was subjected to a load of 25 gf (gram-force) for 15 seconds dwelling time. The force applied was roughly perpendicular to the enamel surface. When finished, the diamond tip retracted
• HV Vickers hardness
• a tooth slice (—150 ⁇ thick) will be cut from each lesion-bearing tooth block using a water- cooled diamond wire saw.
• This slice will serve as a baseline to be used to determine the Pre- treatment TMR parameters (mineral loss ( ⁇ ) and lesion depth (LD)) of the lesion before remineralization (pretest parameters).
• the parameters of the control slices will be used to select the lesions that are suitable for the remineralization study.
• the baseline slices will be processed for TMR assessment as follows. First, both sides of the slice will be polished using 5 Adhesive Back lapping film in a MultiPrepTM Precision Polishing machine (Allied High Tech, USA) to achieve planoparallel surfaces as well as reduce the thickness of the slice to 100 ⁇ (the appropriate thickness for TMR). Following this, the slices will be microradiographed on type 1A high resolution glass X-ray plates (Microchrome Technology, CA, USA) using a Phillips x- ray generator system set up for this purpose. The plates will be exposed
• the microradiographs will be subjected to visualization and image analysis using a computer program (TMR2006 version 3.0.0.6).
• the hardware will be a Leica DMR optical microscope linked via a Sony model XC-
• the enhanced image of the microradiograph will be analyzed under standard conditions of light intensity and magnification and processed, along with data from the image of the step wedge, by the TMR program.
• the parameters of integrated mineral loss ( ⁇ , ⁇ 1%. ⁇ ) and lesion depth (LD, ⁇ ) will be quantified for each carious lesion.
• a tooth slice (—150 ⁇ thick) will be cut from each of the 60 blocks and processed for microradiography as described above for the control specimen.
• control slices will have been microradiographed and analyzed for selection of the appropriate lesions, they will be microradiographed again together with the post-test slices and both will be
• This process will yield the following information: 1) the pre-test TMR parameters (A j and LDl) of the lesions; 2) the post- test TMR parameters ( ⁇ 2 and LD2) of the lesions; and 3) the pre-test and post- test TMR images of the lesions.
• the following examinations will be carried out with the data and the images: A) using the TMR images, the pattern and the extent of remineralization produced within the internal structure of each lesion by each treatment method will be examined and
• the power analysis will be performed using nQuery Advisor software (Statistical Solutions,
• the anticaries potential of theobromine-containing toothpaste formulations will be compared to a standard NaF dentifrice by determining the early caries lesion remineralization in an
• Teeth without caries or enamel malformations were selected and cleaned with pumice to remove the remnants of pellicle from the buccal surface. Using a water-cooled
• each block-bearing glass slide was immersed in a 50 mL beaker containing freshly prepared 1% citric acid (1.0 g of powdered citric acid anhydrous dissolved in 100 mL of deionized distilled water under constant agitation with magnetic stirrer) for 10 minutes with continuous agitation with magnetic stirrer. After immersion for the designated time, specimens were removed from the solution and rinsed thoroughly with distilled water for 10 seconds. Specimens were then dried carefully with paper towels and removed from the glass slide, providing a total of 3 lesion-bearing blocks from each tooth for the
• EXAMPLE 6 ten blocks from each of three treatment groups (control, NaF toothpaste, and theobromine toothpaste) were removed after immersion for 14 days and subjected to Vickers microhardness testing as described above in EXAMPLE 6.
• TMR Baseline Transverse Microradiographic
• blocks subjected to the erosion model and then treated for 14 days with theobromine toothpaste demonstrated dramatically improved HV (surface hardness gain of 43.9%) compared to blocks treated for 14 days with either artificial saliva (control) or NaF toothpaste (surface hardness gains of 4.6% and 4.9%, respectively).

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