Oral wound healing antioxidant compositions and methods of use thereof

Abstract

The disclosure provides a method of facilitating oral wound healing in a patient's mouth by preventing, reducing, or eliminating at least one negative effect of inflammation in the patient's mouth by applying to a soft oral tissue having an oral wound in the patient an oral wound healing antioxidant composition including: between 0.3% w / w and 0.05% w / w dihydrochalcone, such as phloretin; between 0.2% w / w and 0.4% w / w phenylpropanoid, such as ferulic acid; optionally between 0.02% w / w and 0.1% w / w essential oil, such as between 0.02% w / w and 0.04% w / w menthol and / or between 0.04% w / w and 0.06% w / w thymol; optionally, between 10% w / w and 14% w / w xylitol; and between 65% w / w and 70% w / w water. The oral antioxidant composition does not include chlorhexidine.

Description

[0001] ORAL WOUND HEALING ANTIOXIDANT COMPOSITIONS AND METHODS OF USE THEREOF

[0002] TECHNICAL FIELD

[0003] The current invention, according to some embodiments, relates to methods of using oral wound healing compositions that include antioxidants to facilitate healing of oral wounds and / or to prevent, reduce, or eliminate the negative effects of wounds to oral tissue. In particular embodiments, the oral wound healing antioxidant compositions may be used with soft oral tissues, such as the lips, oral mucosa, tongue, soft and hard palates, periodontal ligament, or gingiva.

[0004] BACKGROUND

[0005] Wound damage of soft oral tissues may be caused in a number of ways, but is often a necessary consequence of otherwise beneficial oral procedures, such as dental procedures, oral surgeries, or other procedures or a consequence of procedures related to the teeth such as braces and dental implants. Faster healing of wound damage, particularly with minimal inflammation, reduces the risk of infection at the wound site and also of possible other complications that may occur if healing is too slow. In addition, faster healing lessens overall patient discomfort.

[0006] Currently chlorhexidine is often prescribed to patients immediately before or after oral procedures to facilitate wound healing. Chlorhexidine is an antiseptic and works primarily by decreasing the number of harmful bacteria in an oral wound.

[0007] Chlorhexidine is not known to positively directly affect human cells in a manner that induces wound healing. Chlorhexidine may actually impede wound healing by having unfavorable effects on fibroblasts, such as increasing fibrotic marker expression and myofibroblast differentiation, by generally reducing mammalian cell proliferation and increasing the expression of proapoptotic molecules, by reducing expression of the RACI gene, the expression of which is favorable to wound healing by characterizing keratinocyte migration and proliferation and the ability of oral wounds to respond to stress, and by triggering expression of SERPINE1 and TIMP1, which regulate scar wound healing.

[0008] In addition, chlorhexidine has a bitter taste that often results in poor patient compliance. Furthermore, chlorhexidine may worsen some oral or dental problems, such as periodontitis or tartar buildup and can cause staining of teeth. Teeth staining is the primary reason according to patients as to why they do not use chlorehexidine as directed post surgery.

[0009] Accordingly, alternative forms of care are needed. SUMMARY

[0010] The current invention, according to some embodiments, relates to a method of facilitating oral wound healing in a patient’s mouth comprising applying to a soft oral tissue having an oral wound in the patient an oral wound healing antioxidant composition including: between 0.3% w / w and 0.05% w / w dihydrochalcone; between 0.2% w / w and 0.4% w / w phenylpropanoid; and between 65% w / w and 70% w / w water, wherein the oral antioxidant composition does not comprise chlorhexidine, and wherein the oral antioxidant composition prevents, reduces or eliminates at least one negative effect of inflammation in the patient’s mouth.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Embodiments of the present invention may be better understood through reference to the following figures in which:

[0013] FIGURES 1A, IB, 1C, and ID show the result of treatment with embodiments of the present disclosure.

[0014] FIGURES 2A and 2B show the result of treatment with embodiments of the present disclosure.

[0015] FIGURES 3A and 3B show the result of treatment with embodiments of the present disclosure.

[0016] FIGURES 4A and 4B show the result of treatment with embodiments of the present disclosure.

[0017] FIGURES 5A and 5B show the result of treatment with embodiments of the present disclosure.

[0018] FIGURES 6A, 6B, 6C, and 6D show the result of treatment with embodiments of the present disclosure.

[0019] FIGURES 7A and 7B show the result of treatment with embodiments of the present disclosure.

[0020] FIGURE 8 shows the result of treatment with embodiments of the present disclosure.

[0021] FIGURES 9A and 9B show the result of treatment with embodiments of the present disclosure.

[0022] DETAILED DESCRIPTION

[0023] The current invention, according to some embodiments, relates to methods of using antioxidant compositions to facilitate healing of oral wounds and / or to prevent, reduce, or eliminate the negative effects of wounds to oral tissue. The oral wound healing antioxidant compositions may not include (i.e. may lack or have no detectable amount of) chi orhexi dine.

[0024] Compositions and methods of the present invention may be used in conjunction with beneficial oral procedures, such as dental procedures and oral surgeries. Dental procedures and oral surgeries may include gingival tissue grafting, tooth extractions, gum flap surgery, crown lengthening, crown prep, laser surgery in the oral cavity, dental implants, bone grafting in the oral regions of the face, root canals, fillings, treatment of oral irritation, such as that from filling and adjustment of orthodontic appliances, and treatment of oral ulcers, mouth bums (such as from hot foods), laser recontouring, and laser treatment of gum and other soft tissue. Compositions and methods of the present invention may also be used to facilitate healing after accidental wounding of the oral cavity.

[0025] Some of these oral procedures or treatments are performed by a medical professional, typically in a dental treatment facility, but others, such as treatment of oral irritation or oral ulcers, may be instructed by a medical professional and performed by a patient at home. Other treatments may be initiated by the patient at home as preparation for a subsequent dental procedure or oral surgery, and may, in some cases continue with additional uses by the patient at home.

[0026] Oral Wound Healing Antioxidant Compositions

[0027] Oral wound healing antioxidant compositions of the present disclosure include antioxidants alone or in combination with other materials, to form an oral wound healing composition.

[0028] According to some embodiments, the oral wound healing antioxidant composition includes both a Dihydrochalcone (derivative of 1,3 -diphenyl- 1 -propanone) and a Phenylpropanoid (derivative of cinnamic acid).

[0029] Phenylpropanoids include: Cinnamic acid, Caffeic acid, Ferulic acid, Trans-ferulic acid (including its antioxidant pharmacore 2,6-dihydroxyacetophenome), 5-Hydroxyferulic acid, Sinapic acid, Coumaryl alcohol, Coniferyl alcohol, Sinapyl alcohol, Eugenol, Chavicol, Safrole, P-coumaric acid, and Sinapinic acid. Without limiting the mode of action of the invention, Phenylpropanoids may neutralize free radicals.

[0030] Dihydrochalcones include: Phloretin, Dihydrochalcone phloretin Phlorizin, Aspalathin, Naringin dihydrochalcone, Neohesperidin dihydrochalcone, and Nothofagin. Without limiting the mode of action of the invention, dihydrochalcones may exert an antioxidant effect by reducing reactive free radicals, like reactive oxygen and reactive nitrogen species.

[0031] In a more specific embodiment, the oral wound healing antioxidant composition may include phloretin and ferulic acid. In some embodiments, the oral wound healing antioxidant composition may include only a Dihydrochalcone, specifically phloretin and a Phenylpropanoid, specifically ferulic acid, as antioxidants.

[0032] In other embodiments the oral wound healing antioxidant composition may further include at least one additional antioxidant. The additional antioxidant may be another, additional Dihydrochalcone; another, additional Phenylpropanoid; at least one natural exogenous phytochemical antioxidant, such as a phenolic and a carotenoid; at least one flavonoid, such as a flavanone, a flavanonol, a flavone, a flavonol, a flavan-3-ol, or a flavan-4-ol; at least one anthocyanidin; at least one Curcuminoid; at eleast one Tannin; at least one stilbenoid; at least one Coumarin; at least one Carotenoid; at least one vitamin; at least one of a Xanthone, Butylated Hydroxytoluene, 2,6-Di-tert-butylphenol, 2,4-Dimethyl-6-tert-butylphenol, Gallic acid, Eugenol, Uric acid, alpha -Lipoic acid, Ellagic acid, Chicoric acid, Chlorogenic acid, Rosmarinic acid, Salicylic acid, Acetylcysteine, S-Allyl cysteine, Barbigerone, Chebulagic acid, Edaravone, Ethoxyquin, Glutathione, Hydoxytyrosol, Idebenone, Melatonin, N-Acetylserotonin, Nordihydroguaiaretic acid, Oleocanthal, Oleuropein, Paradol, Piceatannol, Probucol, Propyl gallate, Protocatechuic acid, Pyritinol, Rutin, Secoisolariciresinol diglucoside, Sesamin, Sesamol, Silibinin, Silymarin, Theaflavin, Theaflavin digallate, Thmoquinone, Trolox, Tyrosol, Polyunsaturated fatty acid, or a sulfur-based antioxidants such as Methionine or Lipoic acid, or any a combination, including any possible subcombinations, thereof.

[0033] According to another embodiment, the antioxidants used may include flavonoids. Flavonoids constitute a large group of over 5000 polyphenolic phytochemicals with antioxidant properties that act through direct free radicals scavenging. Flavonoids have anti-inflammatory, anti-bacterial, anti-viral, anti-allergic, anti-mutagenic, anti -thrombotic, anti-neoplastic and vasodilatory action and may prevent, reduce, or eliminate the oxidative damage from dental devices using these methods of action as well. Flavonoids also exhibit chelating properties with metal ions and may reduce the oxidative damage from metal ions by sequestering the ions. Formation and stability of flavonoids-metal-chelates is a structure-dependent function. Flavonoids with a catechol moiety and with hydrogen bonds between hydroxyl group in the 5- and 3- positions have chelating properties. Glycosides of flavonoids may also be used.

[0034] According to a more specific embodiment, the flavonoid may be a flavanone (derivative of 2,3-dihydro-2-phenylchromen-4-one). Flavones include: Butin, Eriodictyol, Hesperetin, Hesperidin, Homoeriodictyol, Isosakuranetin, Naringenin, Naringin, Pinocembrin, Poncirin, Sakuranetin, Sakuranin, and Sterubin.

[0035] According to another specific embodiment, the flavonoid may be a flavanonol (derivative of 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one). Flavanols include: Taxifolin, Aromadedrin, Chrysandroside A, Chrysandroside B, Xeractinol, Astilbin, and Fustin. According to another specific embodiment, the flavonoid may be a flavone (derivative of

[0036] 2-phenylchromen-4-one). Flavones include: Apigenin, Luteolin, Tangeritin, Chrysin, Baicalein, Scutellarein, Wogonin, Synthetic Flavones: Diosmin, and Flavoxate.

[0037] According to another specific embodiment, the flavonoid may be a flavonol (derivative of

[0038] 3-hydroxy-2-phenylchromen-4-one). Flavonols include: 3 -Hydroxyflavone, Azaleatin, Fisetin, Galangin, Gossypetin, Kaempferide, Kaempferol, Isorhamnetin, Morin, Myricetin, Natsudaidain, Pachypodol, Quercetin, Rhamnazin, Rhamnetin, Azalein, Hyperoside, Isoquercitin, Kaempferitrin, Myricitrin, Quercitrin, Robinin, Rutin, Spiraeoside, Xanthorhamnin, Amurensin, Icariin, and Troxerutin.

[0039] According to another specific embodiment, the flavonoid may be a flavan-3-ol (derivatives of 2-phenyl-3, 4-dihydro-2H-chromen-3-ol). Flavan-3-ols include: Catechin, Epicatechin, Epigallocatechin, Epicatechin gallate, Epigallocatechin gallate, Epiafzelechin, Fisetinidol, Guibourtinidol, Mesquitol, and Robinetinidol.

[0040] According to another specific embodiment, the flavonoid may be a flavan-4-ol (derivative of 2-phenylchroman-4-ol). Flavan-4-ols include: Apiforol and Luteoforol.

[0041] According to another specific embodiment, the flavonoid may be an isoflavone (derivative of 3-phenylchromen-4-one). Isoflavones include: Genistein, Daidzein, Biochanin A, Formononetin, and the Equol metabolite from Daidzein.

[0042] According to another embodiment, the antioxidant may be an anthocyanidin (derivative of 2-phenylchromenylium cation). Anthocyanidins include: Aurantinidin, Cyanidin, Delphinidin, Europinidin, Luteolinidin, Pelargonidin, Malvidin, Peonidin, Petunidin, Rosinidin, and Xanthone.

[0043] According to another embodiment, the antioxidant may be a Phenylpropanoid (derivatives of cinnamic acid). Phenylpropanoids include: Cinnamic acid, Caffeic acid, Ferulic acid, Transferulic acid (including its antioxidant pharmacore 2,6-dihydroxyacetophenome), 5-Hydroxyferulic acid, Sinapic acid, Coumaryl alcohol, Coniferyl alcohol, Sinapyl alcohol, Eugenol, Chavicol, Safrole, P-coumaric acid, and Sinapinic acid. Without limiting the mode of action of the invention, Phenylpropanoids may neutralize free radicals.

[0044] According to another embodiment, the antioxidant may be a Chaicone (derivative of 1,3- diphenyl-2-propen-l-one). Chaicones include: Butein, Okanin, Carthamin, Marein, Sophoradin, Xanthohumol, Flavokvain A, Flavokavain B, Flavokavin C., and synthetic Safalcone.

[0045] According to another embodiment, the antioxidant may be a Curcuminoid. Curcuminoids include: Curcumin, Desmethoxycurcumin, bi s-Desm ethoxy curcumin, Tetrahydrocurcumin, and Tetrahydrocurcuminoids. Curcumin and tetrahydrocurcuminoids may be derived from rhizomes of Curcuma longa. Tetrahydrocurcumin, a metabolite of curcumin, has been found to be a more potent antioxidant and more stable compared to curcumin. Tetrahydrocurcumin is available commercially, for example, it is the main component of Tetrahydrocurcuminoids CG™ as sold by Sabinsa Corp. (Piscataway, NJ). Tetrahydrocurcuminoids CG™ contains on a w / w basis tetrahydrocurcumin (75-90%), tetrahydrodemethoxycurcumin (15-20%), and tetrahydrobisdemethoxycurcumin (1-4%). Each of these components is a potent antioxidant. Accordingly, in some embodiments, curcumin or tetrahydrocurcumin may be used in place of tetrahydrocurcuminoids. Further, each component of Tetrahydrocurcuminoids CG™ may be used separately as tetrahydrocurcuminoids. Tetrahydrocurcuminoids CG™ or other useful tetrahydrocurcuminoids are described in WO 00 / 61162. Without limiting the mode of action of the invention, curcuminoids may reduce free radicals.

[0046] According to another embodiment, the antioxidant may be a Tannin. Tannins include: Tannin, Terflavin B, Glucogallin, Dgallic acid, and Quercitannic acid.

[0047] According to another embodiment, the antioxidant may be a stilbenoid. Stilbenoids include: Resveratrol, Pterostilbene, and Piceatannol. Resveratrol may include, but is not limited to, 3,5,4'-trihydroxystilbene, 3,4,3',5'-tetrahydroxystilbene (piceatannol), 2, 3', 4,5'- tetrahydroxystilbene (oxyresveratrol), 4,4'-dihydroxystilbene, and alpha and beta glucoside, galactoside and mannoside derivatives thereof. Other derivatives are recited in U.S. 6,572,882, incorporated by reference herein. Additionally, analogs of resveratrol such as the 3, 4,4', 5- tetrahydroxystilbene of U.S. 6,790,869 (incorporated by reference herein) may also be used. Both cis and trans configurations of resveratrol or its derivatives may be used. Without limiting the mode of action of the invention, stilbenoids may neutralize free radicals.

[0048] According to another embodiment, the antioxidant may be a Coumarin (derivatives of 2H- chromen-2-one). Coumarins include: 4-Hydroxycoumarin, Umbelliferone, Aesculetin, Herniarin, Auraptene, and Dicoumarol.

[0049] According to another embodiment, the antioxidant may be a Carotenoid. Carotenoids include: beta-Carotene, alpha-Carotene, gamma-Carotene, beta-Cryptoxanthin, Lycopene, Lutein, and Idebenone.

[0050] According to another embodiment, the antioxidant may be a vitamin. Vitamins include: Retinol, Ascorbic acid, L- Ascorbic acid, Tocopherol, Tocotrienol, and the Vitamin cofactor: Coenzyme Q10.

[0051] According to another embodiment, the antioxidant may be: a Xanthone, Butylated Hydroxytoluene, 2,6-Di-tert-butylphenol, 2,4-Dimethyl-6-tert-butylphenol, Gallic acid, Eugenol, Uric acid, alpha -Lipoic acid, Ellagic acid, Chicoric acid, Chlorogenic acid, Rosmarinic acid, Salicylic acid, Acetylcysteine, S-Allyl cysteine, Barbigerone, Chebulagic acid, Edaravone, Ethoxyquin, Glutathione, Hydoxytyrosol, Idebenone, Melatonin, N-Acetylserotonin, Nordihydroguaiaretic acid, Oleocanthal, Oleuropein, Paradol, Piceatannol, Probucol, Propyl gallate, Protocatechuic acid, Pyritinol, Rutin, Secoisolariciresinol diglucoside, Sesamin, Sesamol, Silibinin, Silymarin, Theaflavin, Theaflavin digallate, Thmoquinone, Trolox, Tyrosol, Polyunsaturated fatty acids, and sulfur-based antioxidants such as Methionine or Lipoic acid.

[0052] Antioxidants used herein may be synthesized, extracted or purified from natural products, or present in a natural product. The antioxidants may be isolated or partially isolated prior to formulation for use in the wound healing methods described herein or used in a naturally occurring form. In addition, the antioxidants may include plant extracts or combinations containing any of the above-mentioned antioxidants or derivatives thereof.

[0053] According to particular embodiments, the concentration of each individual antioxidant in the antioxidant compositions may be above 0.0001% w / w, above 0.001% w / w, above 0.01% w / w, as high as 0.5% w / w, 1.0%, w / w, 1.5% w / w, 2% w / w, 3% w / w, 4% w / w, 5%, w / w and in ranges between any combinations of these concentration limits. Expressed another way, the molarity of each antioxidant may be on the order of 10'3M or less, 10'4M or less, 10'5M or less, or 10'6M or less.

[0054] In a specific embodiment, the oral wound healing antioxidant composition includes at least 0.2% w / w, 0.3% w / w, or 0.4% w / w, or in a range between 0.1 % w / w and 0.9% w / w, 0.1 % w / w and 0.7% w / w, 0.1% w / w and 0.6% w / w, 0.1% w / w and 0.5% w / w, 0.1% w / w and 0.4% w / w, 0.1% w / w and 0.3% w / w, 0.2% w / w and 0.9% w / w, 0.2% w / w and 0.7% w / w, 0.2% w / w and 0.6% w / w, 0.2% w / w and 0.5% w / w, 0.2% w / w and 0.4% w / w, 0.2% w / w and 1.0% w / w, 0.3% w / w and 0.7% w / w, 0.3% w / w and 0.6% w / w, 0.3% w / w and 0.5%, w / w, 0.3% w / w and 0.4% w / w.

[0055] In some embodiments, the oral would healing antioxidant composition may include both a dihydrochalcone, such as phloretin, and a phenylpropanoid, such as ferulic acid, in the above ranges.

[0056] According to a particular embodiment, the total antioxidant concentration of all antioxidants in an antioxidant composition may be above 0.0001% w / w, above 0.001% w / w, above 0.01% w / w, as high as 0.5% w / w, 1.0%, w / w, 1.5% w / w, 2% w / w, 3% w / w, 5%, w / w, 10% w / w, 15% w / w, or 20% w / w and in ranges between any combinations of these concentration limits.

[0057] The concentration of various antioxidant components may be determined by the amount that achieves a desired effect, such as a cell proliferation effect, increased migration of a cell, or decreased cell death, in a soft oral tissue. For some combinations, upper limits on the concentration of the antioxidant components may apply due to decreases in desired effects at high antioxidant concentrations. In other embodiments, upper limits of antioxidant concentration may be set by acceptable levels to avoid gingival hyperplasia.

[0058] For antioxidant compositions containing mixtures of antioxidants, the ratios of one antioxidant to another may be mole per mole 1 : 1. In other embodiments, the ratios may be adjusted depending on the particular antioxidant compositions used. For example, one antioxidant composition may be in the majority and the other may be in the minority due to various factors including differential therapeutic or preventative effects, differential adverse effects, ease of formulation, or cost. Each antioxidant may be present in sufficient amount to cause some improvement in the therapeutic or preventative effects of the antioxidant composition as compared to an identical composition lacking that antioxidant. In alternative embodiments, antioxidants may be present in at least a minimal amount to cause another desirable effect, such as stabilization of another antioxidant. Other antioxidants may be absent from such compositions or present only in trace amounts, such as a by-product, unable to cause any substantial therapeutic or preventative effect.

[0059] In certain embodiments, synergistic effects may be observed between two or more antioxidants. Many such synergistic effects are observed in the Examples contained herein. Antioxidants exhibiting synergistic effects may allow for improved results as compared to using the antioxidants alone in a given amount. They may allow for the same results to be obtained as with the antioxidants alone, but using lower amounts of one or more of the antioxidants. Synergistic antioxidants may also allow a combination of these two effects, for example by administering a lower amount of one or more of the antioxidants, while still obtaining improved effects as compared to using the antioxidants alone. In selected embodiments, the amount of an antioxidant exhibiting a synergistic effect in an antioxidant composition may be only 25%, only 50%, or only 75% the amount otherwise described herein for use in such a composition. Among a group of antioxidants exhibiting a synergistic effect, the amount of only one, more than one, or all antioxidants in the group may be reduced. Furthermore, in embodiments in which one antioxidant of a group induces a synergistic effect at very low amounts, that antioxidant may be included only in the minimal amount able to cause a measurable synergistic effect.

[0060] Discussed herein are various antioxidants that are components of the oral wound healing antioxidant composition. Although some derivatives of these antioxidants are identified specifically herein, this is not intended to in any way exclude other derivatives of these antioxidants from the scope of the invention. According to embodiments of the invention, any derivatives of the antioxidants discussed herein that also have antioxidant properties may be substituted for the named antioxidant unless it is clear from context that such substitution is not intended. Further, antioxidants as discussed herein may, unless otherwise clear from context, include combinations of the named antioxidant and derivatives or combinations of derivatives alone. Similarly, when groups of antioxidants are discussed, combinations of group members may be used unless otherwise indicated by context. In some embodiments, other therapeutic additives that may be present in the oral wound healing antioxidant composition include other drugs that increase or supplement the antioxidant effect or that are otherwise beneficial to soft oral tissues. For example, a fluoride source beneficial to the teeth may be added. Other wound healing agents, such as polysaccharides and aminopolysaccharides may also be added. Such agents may also help in forming gels, pastes and other formulations. Specific additives may include stannous fluoride, sodium fluoride, triclosan, sodium bicarbonate, chlorhexidine, or a HMG-CoA Reductase Inhibitor, such as a statin or a monocolin.

[0061] In some embodiments, the wound healing oral wound healing antioxidant composition may further include an essential oil. In some embodiments, the essential oil may be present in an amount of at least 0.1 %, w / w, up to 10% w / w, in a range between 0.1% w / w and 10% w / w, in a range between 0.1% w / w and 5% w / w, or in a range between 5% w / w and 10% w / w of the oral wound healing antioxidant composition. In some embodiments, the essential oil may include or may be limited to menthol, thymol, or a combination thereof.

[0062] In specific embodiments, the essential oil may include thymol, menthol, or a combination there of and may be present in an amount of 0.07% w / w, 0.08% w / w, or 0.09% w / w, or in a range between 0.07% w / w and 0.09% w / w, 0.07% w / w and 0.08% w / w, 0.08% w / w and 0.09% w / w, or 0.075% w / w and 0.085% w / w of the oral wound healing antioxidant composition.

[0063] In a more specific embodiment, the essential oil is a combination of menthol and thymol, and menthol is present in an amount of 0.02% w / w, 0.03% w / w, or 0.04% w / w, or in a range between 0.02% w / w and 0.04% w / w, 0.02% w / w and 0,03% w / w, 0.03% w / w and 0.04% w / w, or 0.025% w / w and 0.035% w / w of the oral wound healing antioxidant composition, while thymol is present in an amount of 0.04% w / w 0.05% w / w, or 0.06% w / w, or in a range between 0.04% w / w and 0.06 % w / w, 0.04% w / w and 0.05% w / w, 0.05% w / w and 0.06% w / w, or 0.045% w / w and 0.055% w / w of the oral wound healing antioxidant composition.

[0064] In some embodiments, the oral wound healing antioxidant composition may further include xylitol. In some embodiments, the xylitol may be present in an amount of at least 1% w / w, up to 15% w / w, or in a range between 1% w / w and 15% w / w, 1% w / w and 5% w / w, 1% w / w and 10% w / w, 5% w / w and 15% w / w, 5% w / w and 10% w / w, 10% w / w and 15% w / w, 10% w / w and 14% w / w, 11% w / w and 13% w / w, 11% w / w and 12% w / w, or 12% w / w and 13% w / w of the oral wound healing antioxidant composition.

[0065] The oral wound healing antioxidant composition may optionally further contain additional materials in some embodiments, such as solvents, surfactants, preservatives, viscosity enhancers, therapeutic additives, flavor or color enhancers, and water. These additional components (those that are not an antioxidant or an additional therapeutic additive), excluding water, may be in total up to 5%, 10%, 20%, 30%, 40%, or 50 % w / w of the oral wound healing antioxidant composition. Individually, additional components, excluding water, may be between 0.5% to 2 % w / w of the oral wound healing antioxidant composition or as much as 10% w / w or 20 % w / w of the oral wound healing antioxidant composition.

[0066] The oral wound healing antioxidant compositions of the invention may include various solvents. For example, they may include aqueous solvents, organic solvents, including nonaqueous organic solvents and aqueous organic solvents. In particular embodiments, propylene glycol, polyethylene glycol (PEG), such as PEG 600, glycerine, and ethyl alcohol may be used as solvents.

[0067] Buffers may be used to maintain pH of the oral wound healing antioxidant compositions. In a particular embodiment, a buffer may be used to maintain a pH of at least 5.0 or between 5.5 and 7.4. Buffers suitable for these pH ranges may include sodium citrate and citric acid buffer, which may be present in an amount of between 0.001% w / w to about 0.2% w / w.

[0068] Preservatives may be added to the oral wound healing antioxidant compositions of the invention and include antibacterial compositions or any other preservative used in oral products. Exemplary preservatives include sodium bisulfite, sodium metabisulfite, phenoxyethanol, parabens such as methyl, ethyl, propyl, butyl or isobutyl parabens, 4-hydroxy benzoic acid, benzoic acid, sorbic acid, methyl salicylate, menthol, thymol, eucalyptol, xylitol, and the like.

[0069] Viscosity enhancers may be added to the oral wound healing antioxidant compositions of the invention and include any viscosity enhancers used in oral products. Specifically, gelling polymer is a viscosity enhancer and may include cellulose gum, such as carboxymethylcellulose (e.g. pre-hydrated Ticalose® CMC 2500), xanthan gum, gum arabic, guar gum, polyvinyl alcohol, sodium alginate, polyvinylpirrolidone, sodium hyaluronate, pullulen, carrageenans, and the like. Dextrans, dextran derivatives, or hyaluronic acid may be added to gelling polymers. Thickeners may also be selected to help dissolution of hydrophobic components or stabilize a gel structure. Exemplary thickeners include sugar alcohols such as sorbitol and xylitol, and the like.

[0070] Surfactants may be included if a hydrophobic antioxidant or other agent is present in an oral wound healing antioxidant composition. Suitable surfactants include ionic surfactants such as sodium lauryl sulfate, magnesium sodium lauryl sulfate, or tauranol; and non-ionic surfactants such as polyoxyethylene sorbitan esters, like Polysorbate 80, polyethylene-polypropylene glycols (particularly Poloxamer® 407), and the like. Other suitable surfactants may include cocamidopropyl betaine and plant saponins as natural surfactants. Flavor or color enhancers may be added to the oral wound healing antioxidant composition of the invention and include any such materials used in oral cosmetic formulations or topical oral products. For example, flavors commonly used in toothpaste may be added.

[0071] Other additional ingredients include, but are not limited to: potassium nitrate, sodium monofluorophosphate, sodium benzoate, sodium phosphate, aloe vera, lactoferrin, lysozyme, lactoperoxidase, glucose oxidase, mutanase, and dextranase.

[0072] In some embodiments the total additional ingredients other than antioxidants, essential oils, xylitol, and water may be present in an amount in a range between 15% w / w and 20% w / w, 17% w / w and 19% w / w, 17% w / w and 18% w / w, or 18% w / w and 19% w / w of the oral wound healing antioxidant composition.

[0073] Distilled or deionized water may be used to complete the oral wound healing antioxidant composition. Water may be present in much higher levels than other non-antioxidant components. An oral wound healing antioxidant composition may include up to 95% w / w water, up to 90% w / w water, or between 50% w / w and 90% w / w water.

[0074] In a specific embodiment, the oral wound healing antioxidant composition may include up to 70% w / w water, or an amount of water in a range between 50% w / w and 75% w / w, 50% w / w and 70% w / w, 60% w / w and 75% w / w, 60% w / w and 70% w / w, 65% w / w and 75% w / w, or 65% w / w and 70% w / w of the oral wound healing antioxidant composition.

[0075] In a specific embodiment, the oral wound healing antioxidant composition includes as antioxidants a dihydrochalcone, which in some embodiments may be phloretin, in an amount in a range between 0.3% w / w and 0.5% w / w of the oral wound healing antioxidant composition, and a phenylpropanoid, which in some embodiments may be ferulic acid, in an amount in a range between 0.2% w / w and 0.4% w / w of the oral wound healing antioxidant composition. The composition also includes as essential oils menthol in an amount in a range between 0.025% w / w and 0.035% w / w of the oral wound healing antioxidant composition, thymol in an amount in a range between 0.045% w / w and 0.055% w / w of the oral wound healing antioxidant composition. The composition also includes xylitol in an amount in a range between 10% w / w and 14% w / w of the oral wound healing antioxidant composition. The composition further includes water in an amount between 65% w / w and 70% w / w of the oral wound healing antioxidant composition. Finally, the composition includes other components, such as non-therapeutic additives disclosed herein, in an amount in a range between 15% w / w and 20% w / w of the oral wound healing antioxidant composition.

[0076] According to other embodiments, the oral wound healing antioxidant composition may be in any pharmaceutically acceptable carrier formulated for oral use. Pharmaceutically acceptable carriers commonly include buffers such as citric acid and sodium citrate, and other organic acids, low-molecular weight polypeptides; proteins such as serum albumin, gelatin and immunoglobulin, hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, arginine or lysine; monosaccharides such as mannose, disaccharides, and other carbohydrates; chelating factors such as EDTA; metal ions such as zinc, cobalt or copper; sugar alcohols such as mannitol or sorbitol; and salt-forming counter ions such as sodium. Excipients and diluents may also be present and may include magnesium stearate, calcium carbonate, starch-gelatin paste, talc, aluminum salt, physiological salt solution, lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, polyvinylpyrolidine, methylhydroxy benzoate, and propylhydroxybenzoate.

[0077] Certain additional components that are formulation-specific may also be added. For example, paste formulations may include one or more ingredients used in oral pastes, such as toothpaste. Examples ingredients include thickening agents such as methylcellulose, carboxymethylcellulose, such as pre-hydrated Ticalose® CMC 2500, or hydroxypropyl methylcellulose and humectants, gel carriers such as gelatin, polyethylene glycol, xanthan gum, gum arabic, and guar gum. In some embodiments, paste formulations may include an abrasive agent, such as silicas. In some embodiments, ZEODENT® (Evonik, Germany) silicas may be used, or any other silica as is known in the art.

[0078] Other embodiments of the invention relate to products containing oral wound healing antioxidant compositions. The products may contain concentrations of the antioxidants identified for oral wound healing antioxidant compositions above. Products may be sold containing these concentrations, or they may be made by adding antioxidants to achieve the above concentrations after sale. For example, one embodiment of the invention relates to antioxidant compositions intended for addition to other products to achieve the antioxidant concentrations described above. These concentrated antioxidant additives may have higher concentrations of antioxidants than described above to allow for their dilution when added to a product.

[0079] The oral wound healing antioxidant compositions may preferably have a pH higher than skin antioxidant preparations. This provides the added benefit of avoiding lower pHs, which may damage enamel on the teeth. Example oral wound healing antioxidant compositions have a pH of 5.5, the normal lower limit of salivary pH, or higher. In some examples, the pH may be as high as 6.0 to further avoid demineralization of the teeth. Oral wound healing antioxidant composition according to some embodiments may have a pH of up to around 7.4, the upper normal limit of salivary pH, or lower. Saliva is a buffer, so small quantities of materials, such as oral wound healing antioxidant compositions, introduced into the mouth may adjust to salivary pH or near salivary pH. Accordingly, some oral wound healing antioxidant compositions may have a pH near, but outside of salivary pH range. In some compositions, the upper pH limit may be set by the pH at which one of the antioxidants in the composition becomes predominantly its salt, typically around pH 8. According to one specific embodiment, oral wound healing antioxidant compositions may have a pH of between 5.5 and 7.4, similar to salivary pH. In another embodiment, the antioxidant composition may have a pH of between 5.5 and 8.0, between 5.5 and 7.0, between 5.5 and 6.5, between 5.5 and 6.0, between 6.0 and 8.0, between 6.0 and 7.0, or between 6.0 and 6.5.

[0080] In one embodiment, the oral wound healing antioxidant composition may include phloretin, ferulic acid, menthol, and xylitol. In a further embodiment, the oral wound healing composition may include only phloretin and ferulic acid as antioxidants.

[0081] In one embodiment, the oral wound healing antioxidant composition may include phloretin, ferulic acid, thymol, and xylitol. In a further embodiment, the oral wound healing composition may include only phloretin and ferulic acid as antioxidants.

[0082] In one embodiment, the oral wound healing antioxidant composition may include phloretin, ferulic acid, methnol, thymol, and xylitol. In a further embodiment, the oral wound healing composition may include only phloretin and ferulic acid as antioxidants.

[0083] Any oral wound healing antioxidant composition as described herein may be formulated for topical oral use. Topical oral use includes application topically to any soft oral tissue, including, but not limited to, the lips, oral mucosa, gingiva, tongue, other oral epithelium, including, but not limited to, the oral epithelium, oral sulcular epithelium and junctional epithelium, periodontal ligament, soft palate, hard palate, and the like. Topical application may, in some embodiments, provide the antioxidants to both the oral epithelium and underlying tissues such as the periodontal ligament, lamina propria and submucosal layers, including mesenchymal and periodontal ligament cells, and gingival fibroblasts. Formulations suitable for oral use include, but are not limited to, pastes, gels, rinses, sprays, including aerosol sprays, syrups, powders, including reconstitutable powders, tablets, gums, lipsticks or balms, lozenges, dental trays or other teeth whitening delivery methods, pharmaceutical delivery vehicles such as liposomes, nanoparticles, polymer-based delivery systems, including antioxidant-infused wound dressings, and other cellular delivery vectors, particularly vehicles able to penetrate the oral epithelium, and in dissolvable strips. Example dissolvable strips and edible films in which the antioxidant composition may be incorporated are described in U.S. 6,923,981, incorporated by reference herein.

[0084] In a specific embodiment, the oral wound healing antioxidant composition is in a topical oral gel, such as a viscous oral gel, such as, for example, may be used in a dental tray. More specifically, the oral gel may contain a flavoring agent, such as mint. Effects of Oral Wound Healing Antioxidant Compositions

[0085] According to specific embodiments, the oral wound healing antioxidant compositions may generally promote healing. Without limiting these embodiments to a specific mechanism of action, healing may be carried out primarily through mobile cells able to migrate to different locations to participate in healing. Such cells may include juvenile cells such as precursor cells or pluripotent stem cells, as well as mobile adult cells, such as fibroblasts. Specifically, mobile cells may include human gingival fibroblasts or human periodontal ligament cells.

[0086] Some embodiments of the present invention may address excessive or exuberant inflammation. The inflammatory response is an important pathway employed by the body. However, in excessive inflammation, healthy cells are destroyed as collateral damage. Most damage is host derived because of reactive oxygen species, cytokines, chemokines, matrix metalloproteases, and other factors. Antioxidant compositions have been shown to inhibit or modulate inflammatory markers and mediators, as well as markers in the bone resorptive pathway. Further, this has had a minimal effect on tissue health. Accordingly, oral wound healing antioxidant compositions of the invention may be able to modulate, inhibit, or regulate the inflammatory pathway. In addition, compositions may be able to modulate, inhibit, or regulate the bone resorption pathway. This may be accomplished, in particular, by affecting IL-1, IL-6, and TNF-a.

[0087] Oxidative damage can affect all cell types. Accordingly, the treatment or preventative effects of the oral wound healing antioxidant compositions are not limited to gingival fibroblasts or periodontal ligament cells in all embodiments of the invention. For example, similar effects regarding apoptosis, proliferation, or migration may be seen in other oral cells, particularly other oral cells involved in wound healing, such as fibroblasts and fibroblast precursors. As a consequence, the site of therapeutic or preventative benefit provided by oral wound healing antioxidant compositions may not be fixed to the cells of the epithelial layer that actually contact the oral wound healing antioxidant compositions. Therapeutic or preventative benefit may also be provided to underlying cells in addition to the fibroblasts and fibroblast precursors, for example, the periodontal ligament, lamina propria and submucosal layers, including mesenchymal and periodontal ligament cells, and gingival fibroblasts.

[0088] In order to achieve therapeutic or preventative effects, antioxidants may be absorbed from the oral wound healing antioxidant composition into the internal regions of oral soft tissues in some embodiments. However, in many cases of periodontal disease, it may be sufficient for the oral wound healing antioxidant composition to merely contact an oral surface or a wound surface and be absorbed the cells located at or near that surface. On a cellular level, oral wound healing antioxidant compositions may act by preventing, reducing, stabilizing, or reversing oxidative damage resulting from a wound. In one specific embodiment, exogenous antioxidants of the current invention may decrease or prevent the damaging effects of free radicals on dental tissues by supporting endogenous antioxidants, such as glutathione, CoQlO, and lipoic acid, and / or endogenous defense enzymes such as superoxide dismutase, catalase and glutathione peroxidase.

[0089] The oral wound healing antioxidant composition may be applied regularly, for example at least every 4 hours, every 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours. Time between applications may vary depending on the antioxidant or antioxidant combinations used, but may be approximately the duration for which the oral wound healing antioxidant composition causes a desirable effect, such as a cell proliferation effect, increased migration of a cell, or decreased cell death, in a soft oral tissue to which the oral wound healing antioxidant composition is applied. Oral wound healing antioxidant composition may be administered repeatedly, for example until the wound shows sufficient improvement, or on a regularly occurring basis. Oral wound healing antioxidant composition may also be administered on a prophylactic ore pre-treatment basis prior to planned oral procedures.

[0090] The duration of administration may vary depending on the formulation of the oral wound healing antioxidant composition. For example, the composition may be allowed to dissipate naturally, or it may be applied for a set period of time. For example, a more viscous formulation may be applied for a set time in a professional setting, such as immediately after an oral procedure. According to a particular embodiment, the oral wound healing antioxidant composition may be formulated in a topical composition that remains in the mouth for a length of time appropriate for the use. For example, in many uses the patient may retain the gel for 2 minutes or less, 1 minute or less, 30 seconds or less, or in a range between 10 seconds and 2 minutes, 10 seconds and 1 minute, 10 seconds and 30 seconds, 30 seconds and 2 minutes, 30 seconds and 1 minute, or 1 minute and 2 minutes.

[0091] However, for some uses, such as in dental trays, the oral wound healing antioxidant composition, particularly when formulated as a topical composition, such as a gel, may remain in the patient’s mouth for much longer such as 60 minutes or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, or in a range between 1 minute and 60 minutes, 1 minute and 30 minutes, 1 minute and 15 minutes, 1 minute and 10 minutes, 1 minute and 5 minutes, 5 minutes and 60 minutes, 5 minutes and 30 minutes, 5 minutes and 15 minutes, 5 minutes and 10 minutes, 10 minutes and 60 minutes, 10 minutes and 30 minutes, or 30 minutes and 60 minutes.

[0092] The oral wound healing antioxidant composition may simply be spat out by the patient at the end of the relevant time period, or may be rinsed from the mouth. In some embodiments, the patient may be instructed to refrain from rinsing, eat, or drinking for a time after removal of the oral wound healing antioxidant composition, such as 10 minutes or less, 30 minutes or less, or 60 minutes or less.

[0093] In other uses in which the oral wound healing antioxidant composition is formulated in another composition or device that remains in the oral cavity for an extended period of time, such as longer than one hour or longer than one day. Such embodiments may include oral wound dressings that include the oral wound healing antioxidant composition.

[0094] The disclosure further provides the following specific embodiments, which may be combined with one another as indicated or with any of the rest of the disclosure herein, unless clearly mutually exclusive.

[0095] Embodiment 1. A method of facilitating oral wound healing in a patient’s mouth comprising applying to a soft oral tissue having an oral wound in the patient an oral wound healing antioxidant composition including: between 0.3% w / w and 0.05% w / w dihydrochalcone; between 0.2% w / w and 0.4% w / w phenylpropanoid; and between 65% w / w and 70% w / w water, wherein the oral antioxidant composition does not comprise chlorhexidine, and wherein the oral antioxidant composition prevents, reduces or eliminates at least one negative effect of inflammation in the patient’s mouth.

[0096] Embodiment 2. The method of embodiment 1, wherein the oral wound healing antioxidant composition further comprises between 0.02% and 0.1% w / w essential oil.

[0097] Embodiment 3. The method of embodiment 2, wherein the oral wound healing antioxidant composition further comprises between 0.02% w / w and 0.04% w / w menthol.

[0098] Embodiment 4. The method of any one of embodiment 2 or embodiment 3, wherein the oral wound healing antioxidant composition further comprises between 0.04% w / w and 0.06% w / w thymol

[0099] Embodiment 5. The method of any one of embodiments 1-4, wherein the oral wound healing antioxidant composition further comprises between 10% w / w and 14% w / w xylitol.

[0100] Embodiment 6. The method of any one of embodiments 1-5, wherein the oral wound healing antioxidant composition further comprises between 0.0001% and 5.0% w / w of at least one additional antioxidant.

[0101] Embodiment 7. The method of any one of embodiments 1-6, wherein the oral wound healing antioxidant composition does not comprise additional antioxidants other a dihydrochalcone, and a phenylpropanoid.

[0102] Embodiment 8. The method of any one of embodiments 1-6, wherein the oral wound healing antioxidant composition further comprises citric acid and wherein the oral wound healing antioxidant composition does not comprise additional antioxidants other a dihydrochalcone, and a phenylpropanoid, and citric acid.

[0103] Embodiment 9. The method of any one of embodiments 1-8, wherein the dihydrochalcone is phloretin.

[0104] Embodiment 10. The method of any one of Claims 1-9, wherein the phenylpropanoid is ferulic acid.

[0105] Embodiment 11. The method of any one of embodiments 1-10, wherein the oral wound resulted from an accident.

[0106] Embodiment 12. The method of any one of embodiments 1-10, wherein the oral wound resulted from an oral procedure.

[0107] Embodiment 13. The method of embodiment 13, wherein the oral procedure included at least one of gingival tissue grafting, tooth extractions, gum flap surgery, crown lengthening, crown prep, laser surgery in the oral cavity, dental implants, bone grafting in the oral regions of the face, root canals, fillings, treatment of oral irritation, such as that from filling and adjustment of orthodontic appliances, treatment of oral ulcers, mouth burns, laser recontouring, and laser treatment of gum and other soft tissue.

[0108] Embodiment 14. The method of any one of embodimentl2 or embodiment 13, wherein the oral wound healing antioxidant composition is applied within 60 minutes of completion of the oral procedure.

[0109] Embodiment 15. The method of any one of embodiments 12-14, wherein the oral wound healing antioxidant composition is applied for at least one day subsequent to the oral procedure.

[0110] Embodiment 16. The method of any one of embodiments 12-15, further comprising applying the oral wound healing antioxidant composition every 2 hours.

[0111] Embodiment 17. The method of any one of embodiments 12-16, further comprising applying the oral wound healing antioxidant composition at least one day prior to the oral procedure.

[0112] Embodiment 18. The method of embodiment 17, further comprising applying the oral wound healing antioxidant composition every 2 hours until the commencement of the oral procedure.

[0113] Embodiment 19. The method of embodiment 17, further comprising applying the oral wound healing antioxidant composition twice a day until the commencement of the oral procedure.

[0114] Embodiment 20. The method of any one of embodiments 1-19, wherein the oral wound healing antioxidant composition is a topical oral gel.

[0115] Embodiment 21. The method of any one of embodiments 1-20, wherein the oral wound healing antioxidant composition is an oral rinse. EXAMPLES

[0116] The present invention may be better understood through reference to the following examples. These examples are included to describe exemplary embodiments only and should not be interpreted to encompass the entire breadth of the invention.

[0117] Example 1 - Oral Wound Healing Antioxidant Gel

[0118] An oral wound healing antioxidant gel having the following composition was prepared for use in Examples 2-8:

[0119] AO Oral Gel

[0120] Phloretin - 0.4 % w / w

[0121] Ferulic Acid - 0.3% w / w

[0122] Menthol - 0.03% w / w

[0123] Thymol - 0.05% w / w

[0124] Xylitol - 12% w / w

[0125] Water - 68.3% w / w

[0126] Non-therapeutic additives (solvents, surfactants, preservatives, viscosity enhancers, and flavor or color enhancers) - 18.92% w / w

[0127] Example 2 - Treatment of Patients with AO Oral Gel

[0128] The objective of the clinical study was to verify the safety of a topical oral gel prepared according to the present disclosure containing the antioxidants phloretin and ferulic acid as well as menthol, thymol and xylitol, ingredients with demonstrated antimicrobial properties, used twice daily for six weeks. Professional dentists examined each patient at the outset, after two weeks of product usage, and after six weeks. In addition, a subset of patients used the product twice daily for 12 weeks. Observations included probing deaths, gingival color and gingival form, as well as several other clinical parameters; plus participants’ assessment of the product along with dentists’ assessment of the product. Thirty-seven dentists expressed an interest in the study and signed a study site contract. Only 19 dentists had at least one patient with complete six-week records for each observation category. Out of 134 patients enrolled in the study, 119 patients completed six weeks of use. However, not all 119 patients had complete records. The following grid shows the amount of complete records for each observation category. Table 1 - Number of patients with complete records at 6 and 12 weeks

[0129] All data was calculated on complete data records for each category.

[0130] The gel was shown to be well tolerated and considered generally safe for daily use. Only three patients in the study reported they would not use the product in the future and had an adverse response during and after use. Moreover, clinical observations showed significant improvements in gingival color, gingival form and probing depths, particularly baseline probing depths greater than 7 mm.

[0131] Methods and Materials

[0132] The topical oral gel was as described above in Example 1, which was a viscous, minty, aqueous gel. The ingredients include the antioxidants phloretin and ferulic acid as well as essential oils menthol and thymol, plus xylitol, which have antimicrobial properties. The gel is intended to produce a clean and refreshing feeling in the mouth. It acts by creating a barrier between oral soft tissue and environmental elements. In addition, the antioxidants and essential oils safely interact with free radicals and bacteria. The product is believed to improve the appearance of soft oral tissue in and around the oral cavity that are subjected to free-radical oxidation and bacteria attack, and to freshen breath odor.

[0133] The purpose of this study was two-fold: 1) to substantiate that the product is well tolerated and safe for daily use; and 2) to determine if there are any side effects, beneficial or non-beneficial, resulting from daily use of the product. The study did not involve any invasive procedures or the use of any drugs or other medications.

[0134] Study participants, adults with moderate to good oral health, were instructed to use the gel twice daily as part of their oral hygiene routine for a total of either six or 12 weeks. After the initial office visit and baseline examination, study participants returned for observations in the second week and in the sixth week. In addition, a select group of the original study participants were asked to continue participation for an additional six weeks. For these participants an additional examination was made in the twelfth week.

[0135] Patients were asked to complete an ease-of-use survey at baseline, then after two weeks and again after six weeks. Upon completion of six weeks, patients were asked to complete an additional survey on future use and any adverse reaction to the gel during the six weeks of use. At the conclusion of six weeks, those dental offices that had one or more patients complete six weeks of use were asked to report on their observations of patient use and compliance as well as their assessment of the product.

[0136] Patients were instructed to report any and all allergic reactions immediately to their dentist. Each participating dentist was instructed to report any adverse reactions immediately to the study chair. All adverse reactions were documented by the study chair and PerioSciences management.

[0137] Enrollment of Participants

[0138] Individual dentists from 19 different offices enrolled study participants from their existing patient population.

[0139] The criteria for patient inclusion included:

[0140] (a) Age range 18-60 years

[0141] (b) Assessed to have acceptable dental hygiene habits

[0142] (c) Minimal to moderate gingival inflammation (either localized or generalized)

[0143] (d) Ability to individually provide informed consent

[0144] Patients were excluded from the study by these criteria:

[0145] (a) Unacceptable oral hygiene habits

[0146] (b) Oral surgical procedure within most recent 60 days or need for oral surgical procedure anticipated during the six-week study

[0147] (c) Presence of significant calculus deposits (minimal supragingival deposits were acceptable)

[0148] (d) Breast-feeding, pregnant or intending to become pregnant during the term of the study

[0149] (e) Since the product contains sodium citrate, no history of Addison’s disease, heart disease, kidney disease, high blood potassium, dehydration or an allergic reaction to sodium citrate or citric acid.

[0150] Altogether, an initial 134 patients were enrolled in the study. One hundred and nineteen patients used the product for six weeks. Complete records varied as per the chart above. The study population was 59 percent male, with an average age of 46 years, and 41 percent female, with an average age of 51. Study Procedures

[0151] Dental office investigators explained the study to each participant and answered any questions. Participants signed Consent to Participate forms as well as authorization for the use of individually identifiable medical information.

[0152] Following enrollment and consent procedures, the dental investigators:

[0153] (a) Conducted a baseline examination with complete medical and dental history at initial visit.

[0154] (b) Also, at initial visit investigators (i) applied the product and observed for any immediate adverse effects and (ii) advised the study participants to make self-observation in one to two hours after initial office visit and immediately report any adverse effects.

[0155] (c) Conducted an observation-only office visit during the second week interval to update medical and dental history

[0156] (d) Conducted an examination at an office visit during the sixth week of study

[0157] (e) For selected study participants, investigators conducted office examinations during the twelfth week and updated medical and dental history.

[0158] The full oral and periodontal examination included observing and charting these standard parameters of oral health:

[0159] (a) Probing depths and bleeding points

[0160] (b) General appearance of gums

[0161] (c) Abnormalities or irritation of gingiva and mucosa

[0162] (d) Participant oral hygiene assessment

[0163] (e) Participant environmental exposures such as nicotine, bleaching, alcohol, etc.

[0164] (f) Clinical photographs

[0165] (g) Participant assessment of product.

[0166] Records of the examinations were maintained in the participant dental records of the investigator. Investigators monitored the compliance of each participant and discontinued any study participant that failed to follow recommended uses of the product, had poor oral hygiene habits or required a dental surgical procedure.

[0167] A study participant could discontinue participation in the research study at any time without adverse consequences.

[0168] Results

[0169] Clinical observations focused on oral health parameters and periodontal health parameters. Surveys from both patients and dentists were collected as well. Oral health results

[0170] Oral health was measured on a five-point numerical scale (1= best, 5 = worst) in the following categories: oral hygiene (i.e., visible plaque), calculus deposits, tooth staining, gingival color, gingival form, oral mucosa and breath odor. In all oral health categories when comparing baseline to six weeks there was a clear improvement in oral health as evidenced by patients’ scores elevating over the six weeks.

[0171] Part of the analysis calculated the odds ratios for the improvements. The statistical odds ratio analysis suggests the improvements are due to use of the gel, particularly in the category of gingival color and gingival form. These clinical observations not only substantiate the product is safe but also suggest that daily use of the product for a period of six weeks can improve the appearance of oral soft tissue.

[0172] It should be noted that in all the oral health measurements, the odds ratios exceeded 1.0 at both the six-week and 12-week analysis. The odds ratios for improved gingival color and gingival form were especially high: 6.2 and 5.0 respectively after six weeks.

[0173] Periodontal health results

[0174] Periodontal health was measured by pocket depths and bleeding points upon probing. Probing was completed on distal, mesial and middle for both anterior and posterior. The overall mean score of pocket depth for all measurements at baseline was 2.636 mm and at six weeks was 2.393 mm, revealing an overall probing depth mean reduction of 0.243 mm.

[0175] A more detailed analysis shows the mean scores of pocket depth for anterior distal, mesial and middle at baseline to be 2.484 mm, 2.504 mm, and 1.764 mm; while at six weeks those measurements were respectively 2.256 mm, 2.269 mm, and 1.568 mm. This represents reductions in anterior distal of 0.228 mm, anterior mesial of 0.235 mm, and anterior middle of 0.196 mm.

[0176] The mean scores of pocket depth for posterior distal, mesial and middle at baseline were 3.309 mm, 3.305 mm, and 2.450 mm; while at six weeks those measurements were respectively 3.007 mm, 3.019 mm, and 2.238 mm. This represents reductions in posterior distal of 0.302 mm, posterior mesial of 0.286 mm, and posterior middle of 0.212 mm.

[0177] It is worth noting that when examining all patients with complete records in the periodontal exam probing depths, there were a total of 912 probing depths greater than 4mm at baseline. In that same patient population at the 6 week point there were only 502 probing depths greater than 4mm. This reduction in probing depths represents a 45 percent decrease after using the gel two times per day over six weeks. Furthermore, bleeding points were measured at baseline and six weeks for 59 patients along with baseline and twelve weeks for 26 patients. The odds ratio again suggests significance in the reduction in bleeding points after use of the gel.

[0178] Patients ’ opinions

[0179] As patients participated in the study they were given an ease-of-use survey at two weeks and six weeks. A select few patients also completed an ease-of-use survey at 12 weeks. The results of the ease-of-use survey at the six-week point follows:

[0180] Question 1 - Did you like the taste of the gel? Answer: 89% Yes

[0181] Question 2 - What is your method of application? Answer: 85% use fingertip

[0182] Question 3 - Rate the Ease of Use between (a) Easy, (b) Neutral, or (c) Difficult. Answer: 90% report Easy.

[0183] Question 4 - Rate the Consistency of the gel between (a) just right, (b) too thin, or (c) too thick. Answer: 79% report consistency is Just Right.

[0184] Question 5 - Identify which benefits the gel provided (select all that apply)

[0185] 52% report gums look better

[0186] 17% report teeth appear whiter / brighter

[0187] 16% report teeth less stained

[0188] 29% report reduction of tartar deposits

[0189] 55% report gums feel better

[0190] 67% report mouth feels fresher

[0191] 38% report breath improved

[0192] At the conclusion of the study (six weeks) patients were asked to complete a continued use / adverse reaction survey. The summary of results follows here:

[0193] Question 1 - Would you continue to use the gel on a daily basis? Answer: 82% Yes.

[0194] Question 2 - Did you use the gel 2X per day? Answer: 54% Every day; 32% Most days; 8 % Some days; 6 % No days.

[0195] Question 3 - Did you have any irritation of oral tissues? Answer: 89% No.

[0196] Question 4 - Did you experience any ill effects following the use of the gel? Answer: 96 % No.

[0197] Dentists ’ observations

[0198] At the conclusion of the study (six weeks) participating dentists were asked to complete an observational survey. Seventeen dentists responded, all of whom had at least one patient that completed six weeks of use. The top two clinical observations made in patients who used the gel were 1) improvement in the general appearance of the gingiva; and 2) improvement of oral hygiene. 94% of dentists said the overall response was favorable. 65 % of dentists said they feel patients benefited from using the gel. 94 % of dentists said they would recommend the use of the gel to patients.

[0199] Discussion

[0200] The two-fold objective of the safety study of the topical oral gel was accomplished. Sufficient data was compiled to substantiate that the product is generally safe when used as directed. The assessments of oral health and periodontal condition showed no deterioration. Only four patients in the study reported a mildly negative response during and after use of the gel. The professional opinions of the participating dentists revealed no significant ill effects.

[0201] As for the second part of the two-fold objective of the study, there were no significant negative side effects reported. However, the study results do suggest that there were beneficial effects of using the oral gel as directed. In particular, the observations on gingival color and gingival form showed significant improvement following product use for six weeks. Similarly, the comparison of probing depths and bleeding points between baseline and six weeks showed a significant improvement. As noted when reviewing the periodontal exam probing depth data there were 912 depths greater than 4mm at baseline. At six weeks there was a 45 % reduction in probing depths greater than 4mm.

[0202] Example 3 - AO Oral Gel as Treatment for Gingivitis in Orthodontic Patients

[0203] A study was performed to evaluate the treatment effect of an antioxidant-essential oil gel on orthodontic patients with generalized gingivitis. See Martin, et al., Angle Orthod. 2016 May; 86(3): 407-412, which is incorporated herein by reference.

[0204] In short, thirty orthodontic patients were screened for gingivitis and randomly allocated into treatment and placebo-control groups. Each patient was evaluated at three orthodontic treatment visits (Tl, T2, and T3) where a periodontal examination, including probing depth (PD), bleeding on probing (BOP), gingival index (GI), and plaque index (PI) was performed. Between Tl and T2, patients were instructed to apply a topical gel (active or placebo) to their gingiva twice daily after brushing. From T2 to T3, patients were instructed to discontinue use of the gel.

[0205] The treatment group showed statistically significant (P < .05) reductions of BOP (-13.6 percentage points) and GI (-0.14) between Tl and T2, and significant increases in BOP (13.3 percentage points) and GI (0.14) between T2 and T3. Except for an increase in the GI between T2 and T3, the control group showed no significant changes in BOP or GI over time. The only other significant changes that occurred pertained to the treatment group, which showed significant increases in PD (0.08 mm) and PI (0.18) between T2 and T3. Example 4 - Treatment of Wounds with AO Oral Gel

[0206] Oral wounds may occur as a result of accidental trauma or may result from dental and orthodontic procedures such as grafting, implants, gingival recontouring, or other surgical procedures. In addition, oral wounds may result from infection, autoimmune conditions, or exposure to irritants such as bleaches or nicotine. A series of patients suffering from wounds of various origins were treated with an antioxidant prepared according to the present disclosure.

[0207] Patient 1 exhibited gingival recession and lack of adequate attached gingiva facial to teeth #24-26. There was loss of interdental tissue fill and vestibular scarring from a previous oral surgery procedure. Soft tissue grafting was indicated for partial root coverage and increase in tissue thickness. A tunnel preparation was performed with intrasulcular incisions facial to teeth 24, 25 and 26. A papillary incision was made at 26 / 27 to aid site prep and graft insertion. An AlloDerm graft was inserted in the tunnel and secured with single 6-0 continuous sling suture. Some localized cyanosis is noted. The patient used AO oral gel 5x per day for the first two weeks post-op and 2x per day for the following two weeks. At 24 hours post-op there was good color and little swelling in the surgical site. At two weeks post-op there is advanced healing with little evidence of the papillary incision. At four weeks post-op, healing was essentially complete with the surgical objectives achieved with little evidence that a surgical procedure has been performed with the exception of the presence of the suture.

[0208] Patient 2 was a 26-year-old female with history of orthodontic therapy presented with severe generalized gingival recession. Treatment consisted of AlloDerm grafting along with the use of AO gel 5 times a day for three days, and thereafter 3-4 times a day for 3 months. See Figures 1A (pre-op), IB (baseline sutured), 1C (after 3 weeks), and ID (after 3 months).

[0209] Patient 3 was 35 years old and exhibited Class III gingival recession with thin, mobile marginal tissue facial to the mandibular central incisors and left first premolar and thin marginal tissue facial to left canine, and lateral incisor. The patient had experienced failure of a previous grafting procedure in this area. An AlloDerm graft, utilizing a tunnel technique, was placed facial to the left premolar, canine, lateral incisor, and both central incisors and secured coronally with a single 6-0 continuous sling suture. Platelet Rich Plasma was used at surgery and AO oral gel was thereafter applied by the patient twice daily after a chlorhexidine oral rinse. At one week postsurgery, there was minimal swelling and inflammation, and an appearance typical of two weeks or more of healing. The patient reported a post-operative period characterized by minimal discomfort and a far better experience than the previous grafting attempt.

[0210] Patient 4 was 43 years old and AlloDerm grafting was performed to treat the recession involving the maxillary anterior teeth. The patient was instructed to rinse with chlorhexidine. 48 hours after surgery, healing was not acceptable and the patient exhibited cyanosis at the grafting site. The patient was instructed to use AO oral gel five times per day in lieu of the chlorhexidine mouthrinse. The tissue responded with rapid resolution of the cyanosis and uneventful healing.

[0211] Patient 5 was 24 years old and exhibited AlloDerm exposure at left and right premolars 2 weeks after grafting surgery. See Figure 2A. The patient applied AO oral gel to the exposed sites five times a day. A dramatic recovery was seen one week later. See Figure 2B

[0212] Patient 6 suffered two major fractured maxillary centrals following a bicycle accident. AO oral gel was used daily for lip trauma and following extraction and placement of immediate implants. Excellent wound healing followed as shown by the ideal preservation of papillae and gingival contours by controlling inflammation during entire process. See Figures 3 A (immediately following extraction) and 3B (6 months following procedure).

[0213] Patient 7 was 50 years old and exhibited reactive lesion at the gingival margin adjacent to a composite restoration. The lesion was excised and the composite restoration was replaced. At 18 months after surgical excision, the reactive lesion recurred. AO oral gel was applied twice daily. At 6 weeks patient exhibited significant resolution of reactive lesion.

[0214] Patient 8 was 68 years old Patient and exhibited significant bums to the maxillary anterior papillae that were ulcerated and painful following bleaching of teeth with 15% hydrogen peroxide gel 2 hours each night for two consecutive nights. The patient used AO oral gel twice a day. Patient reported an immediate soothing effect and the tissue improved to near-complete resolution by 7 days.

[0215] Patient 9 was a 65-year-old female with Xerostomia and Erosive Lichen Planus involving the right buccal mucosa. Patient started application of AO oral gel three times daily. After 8 weeks, the patient exhibited a resolution of the ulcerated areas, significant reduction of inflammation, and relief of the dryness. The patient continued applying AO oral gel twice daily and maintained the resolution of the Lichen Planus and relief of the dryness for one year.

[0216] Patient 10 was a 39-y ear-old female with a 1 -year-old crown on her endodontically treated right central incisor. She reported gingival swelling and bleeding above the crown for several weeks. Under local anesthesia, the crown was removed and scaling and root planing was performed. A transitional crown was placed. AO oral rinse was used regularly. AO oral gel was applied topically 5x day for 3 days followed by 3x day for 5 days. After 8 days, the gingiva was healthy around the transitional crown.

[0217] Patient 11 was a 66-year-old female with xerostomia due to multiple medications and a history of tobacco use had endodontic and restorative treatment in the mandibular right quadrant. At a follow-up visit 5 days later to complete the endodontic therapy, the marginal gingiva was edematous and had herpetic-like pinpoint ulcerations. See Figure 4A. The patient was instructed to apply AO oral gel twice daily to the affected site. After a few days, the patient reported a dramatic improvement in appearance and comfort, and at 9 days the lesions were completely resolved and the gingiva had a normal color and form. See Figure 4B.

[0218] Patient 12 was a 27-year-old female had short term ortho, and upon completion, had aesthetic gingival re-contouring of teeth #’s 8, 9 & 10 with Diode Laser and porcelain veneers for teeth 7-10. Post operatively from the contouring, she applied AO oral gel twice daily. She experienced no post op pain, and her tissue healed rapidly and in the predicted locations. See Figures 5A (post-op) and 5B (day 5).

[0219] Patient 13 was 61 years old and presented with soft tissue fenestration over mandibular torus. See Figure 6A. Patient was given amoxicillin 500 #21, Vitamin E, and AO oral gel applied daily. Healing progress is pictured in Figures 6B (2 weeks), 6C (4 weeks) and 6D (6 weeks).

[0220] Patient 14 was a 9-year-old female who was treated with a rapid palatal expansion device. She presented ulceration, pain and debit impaction. The device was removed and the patient was given a cleqar essix retainer as retention and to cover the area. AO oral gel was given to be placed on the ulceration. After eight days, the ulceration, swelling, and pain were gone and patient could proceed with orthodontic treatment. Figure 7A shows the palate as baseline and Figure 7B shows the palate after 8 days of treatment with AO oral gel.

[0221] Example 5 - Treatment Following Periodontal Surgery

[0222] Patient was a 44-year-old male who suffered from severe periodontitis. His chief complaint was very loose teeth, especially his upper right central incisor and all of his lower incisors. Clinical evaluation displayed 4-9 mm probing depths, generalized 2-4 mm of gingival recession, and generalized 1-3 grade mobility. Radiographic evaluation displayed generalized horizontal bone loss with severe vertical bone loss on Teeth #8, 23, 24, 25, & 26.

[0223] Treatment began with periodontal surgery, bone grafting, and the removal of teeth #23-26 and replacement with a transitional fixed bridge. Tooth #8 had a very questionable prognosis but the patient wanted to keep it if at all possible.

[0224] Full mouth osseous surgery was performed. Full thickness flap elevation was used around all teeth except for the buccal of teeth #6-11 to preserve soft tissue architecture for esthetics. After thorough debridement and root planning, minimal osseous recontouring was performed to eliminate 1 walled defects in order to reduce pocket depth. Freeze dried bone allograft was packed into the vertical component of 2-3 wall osseous defects and covered with collagen membranes for regenerative purposes. Flaps were repositioned and closed with 4-0 and 5-0 coated vicryl continuous vertical mattress sling sutures. An external acid etch splint was placed on the palatal surface of teeth #7-10 to stabilize these teeth. Teeth #23-26 were extracted and a provisional fixed partial denture was placed on teeth #22-27. Post operative regimen consisted of Amoxicillin 500 mg 3x / day for one week, ibuprofen 800 mg every 6 hrs for 5 days, hydrocodone prn, medrol dose pack, and AO oral rinse and gel. No brushing was allowed prior to suture removal. Sutures were removed at 2 weeks post op. The patient presented reporting minimal post op pain. Tissues appeared firm, pink, and healthy, especially for a 2 week post operative period. No staining or altered taste sensation was reported as is typical with chlorhexidine rinse.

[0225] Following 8 weeks, #8 was no longer mobile. Final restorations consisted of fixed bridge #22-27, Porcelain veneers #7-10, and lingual composite splint #7-9.

[0226] Example 6 - Treatment in Conjunction with Veneer Restoration

[0227] The patient presented at the initial visit desiring veneer restorations of the maxillary anterior teeth.

[0228] After the initial preparations, the patient utilizes a tray fabricated from the model and placed AO oral gel in the tray on a nightly basis. After 3 weeks the provisionals removed gingivae appeared excellent with no bleeding or gingival inflammation.

[0229] Following delivery of the final veneer restorations patient continued to exhibit optimal gingival health. The tray delivery of the AO oral gel assured an ideal relationship between the gingival and restorative margins.

[0230] Example 7 - Treatment of Inflammation

[0231] A variety of other patients with various causes of inflammation were treated with antioxidants of the present disclosure as described below.

[0232] A 68-year-old female reported gum swelling and persistent discomfort that intensified upon brushing and eating. Clinical and radiographic examination revealed an ill-fitting bridge with open margins resulting in severe gingival inflammation. The decision was made to remake the bridge at a subsequent appointment. The patient was given AO oral gel and instructed to use morning and evening each day until returning to the office. When the patient presented one week later for her bridge appointment, the reduction in gingival inflammation was significant. The patient reported that her gums felt much better and didn’t ache like before.

[0233] A 48-year-old patient completed 6 sessions of scaling and root planing over 180 days. Following the procedures patient was given AO oral gel to be administered twice daily. After 3 weeks, patient exhibited enhanced reduction of gingival swelling and inflammation.

[0234] A 51 -year-old patient exhibited gingival swelling and marginal inflammation around the central incisor with a cervical composite restoration and the lateral incisor with a crown. After 6 weeks of using AO oral gel twice daily, patient exhibited a reduction of the marginal swelling and inflammation.

[0235] A 45-year-old patient complained of gingival tenderness associated with marginal inflammation at margins of properly designed and well-fitting crowns placed four months prior. Following twice daily AO oral gel administration, the marginal inflammation had resolved and the tissue was no longer tender.

[0236] 62-year-old female patient exhibited inflamed marginal tissue facial to a mandibular canine implant. There was no attached gingiva, and the mucosa was thin and mobile. The patient had been performing daily oral hygiene to the best of her ability. The patient was instructed to apply AO oral gel to the site twice daily prior. After 4 weeks of AO oral gel use, inflammation in the mucosa facial to the implant was dramatically reduced in spite of no improvement in oral hygiene.

[0237] A 27-year-old patient had a well-fitting full porcelain crown on tooth #24 and experienced tenderness, bleeding when flossing / toothbrushing, and consistent inflammation since the crown was placed two years prior. After six days of applying AO oral gel twice daily, patient reports a decrease in tenderness, inflammation, and bleeding.

[0238] 41 -year-old female patient complained of gingival tenderness and swelling on the lower left side. Radiographs were negative, and 4-5 mm "pseudo- pocketing" was noted between teeth #19 and 20. Following twice daily AO oral gel application for 8 days, the marginal swelling and inflammation resolved, the tissue was no longer tender, and the probing depth decreased to 3mm.

[0239] A 59-year-old patient exhibited inflammation despite probing depths within normal limits and demonstrated good oral hygiene. After four weeks of AO oral gel administration, the inflammation, although still present, is greatly reduced.

[0240] A 62-year-old male patient had probing depths within normal limits and demonstrated great oral hygiene around his veneers but exhibited inflammation. After using AO oral gel for two weeks the inflammation was almost negligible.

[0241] An 18-year-old female was referred for treatment of a localized gingival recession defect. The site exhibited severe erythema, heavy bleeding on probing, and suppuration. The patient was placed on AO oral gel to control the inflammation prior to grafting the tissue defect. After 2 weeks, with no treatment other than the AO gel, the gingival had significantly improved tone, reduced inflammation, and no suppuration or bleeding on probing.

[0242] Example 8 - Other Case Studies

[0243] A 35-y ear-old patient presented with a geographic tongue. Patient began regimen of applying AO oral gel twice daily and experienced fewer episodes, reduced area of involvement and more rapid resolution of recurrences. Figure 8 shows photos of the patient’s tongue at the start of treatment and following two weeks, six weeks, and six months of treatment.

[0244] A 47-year-old male reported suffering from black hairy tongue for the past several years. See Figure 9A. The condition was compounded by consumption of coffee, red wine, and colas. Regular tongue brushing and scraping did little to remove the discoloration. Patient began using AO oral gel regularly administered with a toothbrush or a tongue scraper. Within two days the stain was gone (see Figure 9B) and have not reappeared with daily use of AO oral gel.

[0245] Although only exemplary embodiments of the invention are specifically described above, it will be appreciated that modifications and variations of these examples are possible without departing from the spirit and intended scope of the invention. For example, throughout the specification particular measurements are given. It would be understood by one of ordinary skill in the art that in many instances particularly outside of the examples other values similar to, but not exactly the same as the given measurements may be equivalent and may also be encompassed by the present invention.

Claims

CLAIMS:

1. A method of facilitating oral wound healing in a patient’s mouth comprising applying to a soft oral tissue having an oral wound in the patient an oral wound healing antioxidant composition comprising: between 0.3% w / w and 0.05% w / w dihydrochalcone; between 0.2% w / w and 0.4% w / w phenylpropanoid; and between 65% w / w and 70% w / w water, wherein the oral antioxidant composition does not comprise chlorhexidine, and wherein the oral antioxidant composition prevents, reduces or eliminates at least one negative effect of inflammation in the patient’s mouth.

2. The method of claim 1, wherein the oral wound healing antioxidant composition further comprises between 0.02% and 0.1% w / w essential oil.

3. The method of claim 2, wherein the oral wound healing antioxidant composition further comprises between 0.02% w / w and 0.04% w / w menthol.

4. The method of any one of claim 2 or claim 3, wherein the oral wound healing antioxidant composition further comprises between 0.04% w / w and 0.06% w / w thymol5. The method of any one of Claims 1-4, wherein the oral wound healing antioxidant composition further comprises between 10% w / w and 14% w / w xylitol.

6. The method of any one of Claims 1-5, wherein the oral wound healing antioxidant composition further comprises between 0.0001% and 5.0% w / w of at least one additional antioxidant.

7. The method of any one of Claims 1-6, wherein the oral wound healing antioxidant composition does not comprise additional antioxidants other a dihydrochalcone, and a phenylpropanoid.

8. The method of any one of Claims 1-6, wherein the oral wound healing antioxidant composition further comprises citric acid and wherein the oral wound healing antioxidant composition does not comprise additional antioxidants other a dihydrochalcone, and a phenylpropanoid, and citric acid.

9. The method of any one of Claims 1-8, wherein the dihydrochalcone is phloretin.

10. The method of any one of Claims 1-9, wherein the phenylpropanoid is ferulic acid.

11. The method of any one of Claims 1-10, wherein the oral wound resulted from an accident.

12. The method of any one of Claims 1-10, wherein the oral wound resulted from an oral procedure.

13. The method of Claim 12, wherein the oral procedure included at least one of gingival tissue grafting, tooth extractions, gum flap surgery, crown lengthening, crown prep, laser surgery in the oral cavity, dental implants, bone grafting in the oral regions of the face, root canals, fillings, treatment of oral irritation, such as that from filling and adjustment of orthodontic appliances, treatment of oral ulcers, mouth bums, laser recontouring, and laser treatment of gum and other soft tissue.

14. The method of any one of Claim 12 or Claim 13, wherein the oral wound healing antioxidant composition is applied within 60 minutes of completion of the oral procedure.

15. The method of any one of Claims 12-14, wherein the oral wound healing antioxidant composition is applied for at least one day subsequent to the oral procedure.

16. The method of any one of Claims 12-15, further comprising applying the oral wound healing antioxidant composition every 2 hours.

17. The method of any one of Claim 12-16, further comprising applying the oral wound healing antioxidant composition at least one day prior to the oral procedure.

18. The method of Claim 17, further comprising applying the oral wound healing antioxidant composition every 2 hours until the commencement of the oral procedure.

19. The method of Claim 17, further comprising applying the oral wound healing antioxidant composition twice a day until the commencement of the oral procedure.

20. The method of any one of Claims 1-19, wherein the oral wound healing antioxidant composition is a topical oral gel.

21. The method of any one of Claims 1-20, wherein the oral wound healing antioxidant composition is an oral rinse.

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