Antioxidant gel for gingival conditions

A gel, paste, gum or lozenge composition for oral application to human gums to prevent and reduce symptoms of gum disease. The composition includes reduced glutathione and a source of selenium.

TECHNICAL FIELD OF THE INVENTION
 The present invention deals with the combination of several synergistic
 antioxidants, enzymatic co-factors and amino acids in appropriate delivery
 vehicles forming gels, pastes, gums or lozenges. The gels, pastes, gums or
 lozenges are intended to be applied or taken orally to prophylactically
 prevent gum disease and remedially to a patient to reduce reactive oxygen
 and other free radical species which are causative inflammatory factors in
 establishing and promoting such gingival diseases.
 BACKGROUND OF THE INVENTION
 Dentists and other professionals involved with the science of oral hygiene
 have dealt with a number of symptoms or pathologies of the mouth, gum and
 teeth. Some of these pathologies are initiated and exacerbated through
 tobacco consumption, whether smoked or chewed, as smokers often suffer
 from leukoplakia, a white patch on the buccal mucosa. Although leukoplakia
 is a benign oral lesion, it has a malignant potential requiring a biopsy
 of the lesion to rule out cancer. Smokers also have more dental tartar
 (calculus) than non-smokers and often suffer from halitosis.
 It is known that tooth loss can directly result from untreated destructive
 periodontal (gum) disease. Further, acute necrotizing ulcerative
 gingivitis is a destructive, painful inflammatory condition which is,
 again, more acutely observed in cigarette smokers and tobacco users.
 Besides leukoplakia, another type of generalized whitish hue on the buccal
 mucosa is associated with oral submucous fibrosis. This disease occurs
 mainly in India and Pakistan and their emigres to the western world and is
 a chronic, progressive, pre-malignant condition, related to tobacco and
 betel nut chewing.
 Periodontal disease, which includes inflammation of the gums, is one of the
 most prevalent health problems in the world and is the major cause of
 tooth loss in the adult population.
 Periodontal disease is composed of two entities:
 a) Gingivitis: Inflammation is confined to the gums (gingival tissue).
 b) Periodontitis: The inflammation and infection is present both in the
 gingiva and in the connective tissue which supports the teeth.
 There is initially an inflammation in the local blood vessel walls
 (vasculitis) which accounts for the most common symptom of bleeding gums.
 This is accompanied by migration of white blood cells (leucocytes) to help
 combat the tissue invasion by pathogenic mouth bacteria. In this
 inflammatory reaction, most cells liberate histamine. Inflammatory (white
 blood cells) also locally generate countless free radicals and anti-enzyme
 molecules, both of which contribute to tissue pathology. Collagen
 production may also then be interfered with due to local Vitamin C
 deficiency, which contributes to the swelling (edema) and redness
 (erythema) of gingival tissues.
 Chewing tobacco and the areca nut are associated with higher frequencies of
 periodontal disease, oral submucous fibrosis and oral malignancies. Betel
 Quid chewing is common in India, Southeast Asia and the South Pacific
 Islands. Free radical damage induced by these deleterious alkaloids
 initiate an inflammatory reaction in the oral cavity. Studies in Taiwan
 reveal that arecoline, the major alkaloid in areca nut interferes with the
 migration, attachment and growth of human gingival fibroblasts. Arecoline
 also inhibits these cells' ability to synthesize collagen and all these
 inhibitory effects have been shown to be associated with an intracellular
 depletion of L-glutathione (GSH). The repeated and long term exposure to
 Betel Quid's cytotoxic arecoline and tobacco chewing renders these abusers
 to periodontal and other oral disease, in part due to losses of the
 locally vital protective antioxidant and detoxificant, GSH.
 Prencipe et al. disclose an anti-bacterial, anti-plaque dentifrice in their
 U.S. Pat. No. 5,424,059. The '059 patent teaches that plaque can be
 inhibited and that gingivitis and cavities can be reduced or inhibited by
 applying a dentifrice in the form of a white water soluble alkaline earth
 metal polishing agent such as dicalcium phosphate or dimagnesium
 pyrophosphate used together with an anti-bacterial agent and the polyol,
 xylitol.
 Galiana Arano in WO96/38122 discloses a novel dentifrice composition in the
 form of a tablet for buccal hygiene which does not require a toothbrush,
 toothpaste or dental powder. The tablet comprises an abrasive and foaming
 agent, sugar, one or more lubricants, a fluoride source and sweeteners. It
 is taught that the cleansing effect of water is obtained from the saliva
 stimulated by sugars while the mechanical effect of "brushing" is obtained
 from the granules emanating from the destruction of the tablet.
 However, prior attempts to treat gum disease have failed for they have not
 recognized the role played by free radicals. For example, cigarette tar
 contains high concentrations of free radicals. The most common oxidants
 include semiquinone which is in equilibrium with hydroquinones and
 quinones, particularly in the viscous tar matrix. Many tar extracts are
 water soluble and reduce oxygen to the superoxide radical which can
 dismutate to form H.sub.2 O.sub.2. Importantly, glass-fiber type cigarette
 filters retain almost all of the tar particles that are larger than 0.1
 micron. Thus, the filter acts as a trap for tars and cigarette smoke.
 There are an inordinately large number of free radicals, greater than
 10.sup.15, in each puff of the gas phase of cigarette smoke. While the
 oxidants in tar are stable, those organic radicals in the gas phase smoke
 are reactive carbon and oxygen centered radicals with extremely short
 half-lives. Interestingly, concentrations of free radicals are maintained
 at high levels for more than ten minutes and tend to increase as tobacco
 smoke is aged. It is thus considered that these gas phase smoke oxidants
 are in a steady state as they are both continuously formed and destroyed.
 The latter reactions are similar to those noted to occur in smog, pointing
 to the extra noxious stimuli to primary and secondary smokers in polluted
 environments. In fact, environmental pollution in urban areas such as
 London, New York, Los Angeles and Mexico City promote gum disease and
 enhance the damage done to the oral cavity through the consumption of
 tobacco products. There is now also an established association between gum
 disease and coronary artery (heart) disease.
 It is thus an object of the present invention to provide a gel, paste, gum
 or lozenge intended to be applied to the gums and teeth of a patient or
 taken orally as a means of preventing and ameliorating signs and symptoms
 and complications to the oral-pharyngeal cavity and mouth including the
 buccal mucosa and gums from damage caused by free radical species
 generating inflammation in gingival tissues.
 These and further objects will be more readily apparent when considering
 the following disclosure and appended claims.
 SUMMARY OF THE INVENTION
 The present invention is directed to a gel, paste, gum or lozenge
 composition and a method of using it for preventing and reducing symptoms
 of periodontal disease in humans. The composition comprises a carrier and,
 as active ingredients, an effective amount of reduced glutathione and a
 source of selenium. Although the present composition is not considered a
 substitute for toothpaste, it can be applied to the gums in the case of a
 gel or paste by any well recognized means including the use of a tooth
 brush and other external applicators.

DETAILED DESCRIPTION OF THE INVENTION
 Human gums, are exposed to numerous environmental stimuli. Gums may be
 damaged by inhaled, ingested or chewed noxious substances, such as tobacco
 products, and may also be injured by systemic xenobiotics and by
 endogenous processes, such as inflammatory reactions. Innocent
 by-standers, the secondary smokers, may equally be adversely affected.
 Reactive oxidizing species, as induced by inhaled tobacco smoke, ozone and
 nitrous oxide, are important factors in generating free radicals and
 inducing inflammatory reactions resulting in the development of
 periodontal disease. The present invention has now recognized that such
 periodontal disease resulting from free radical generation can be in large
 prevented and its symptoms reduced by applying an effective amount of
 reduced glutathione and a source of selenium in a gel base or paste to the
 gum surface. The terms gel or paste include compositions wherein medicinal
 products may be included for specific oro-pharyngeal and odontologic
 conditions. Examples would include an anti-microbial agent such as those
 for treatment of oral candidiasis (thrush) or corticosteroid for
 management of oro-pharyngeal ulcers as both occur commonly in smokers and
 in patients with AIDS. In these oral condition, and particularly in
 patients with AIDS and their opportunistic infections, free radical
 species are indeed pathogenetic. Thus, gels or paste with the compositions
 of this invention provide significant adjuncts of therapy in the
 management of oral conditions including gum disease.
 It is now recognized that reducing the intracellular levels of GSH in cells
 increases their sensitivity to oxidant damage. Further, an L-cysteine
 delivery agent not only enhances endothelial cell GSH concentration, but
 also protects cells from damage from endogenous hydrogen peroxide. Without
 being bound to any particular theory, it is noted that reduced glutathione
 is employed in protecting cells against oxidative stress by itself being
 oxidized. Thus, L-glutathione must act in combination with other enzyme
 systems or cellular antioxidants in order to be reduced so that it may
 renew its role as a free radical scavenger. The enzyme glutathione
 reductase is vital to reduce the glutathione. GSH functions coordinately
 with the enzyme glutathione peroxidase which requires selenium as a
 cofactor to exert its biological antioxidant function. Selenium compounds,
 themselves, scavenge oxygen-centered radicals in vivo with reduced
 glutathione through glutathione peroxidase. By this physiologic method,
 selenium also functions as an anti-carcinogen. It is believed that
 selenium-GSH peroxidase catalyzes toxic hydrogen peroxidase in the
 presence of reduced glutathione. This reaction reduces glutathione to
 oxidized glutathione (GSSG). In turn, the GSSG is reduced back to GSH by
 the enzyme GSH reductase thereby maintaining abundant cellular GSH to
 scavenge free radicals anew.
 In summary, the major functions of reduced glutathione (GSH) in protection
 against lipid peroxidation involve three types of reactions, all
 inter-related and synergistic in combining non-enzymic scavengers and
 enzymic and dietary (vitamins C and E) provided antioxidants, to wit:
 1. GSH with selenium co-factor glutathione peroxidase eliminate toxic
 peroxides.
 2. GSH reduces oxidized forms of vitamin C which, in turn, maintains
 vitamin E in its reduced form promoting its metabolic functions. Thus, GSH
 supports free radical reductions and free radical chain-terminating
 functions of the two nutrient antioxidants, vitamins C and E.
 3. GSH functions through the glutathione S-transferases to detoxify
 reactive aldehydes created during the process of lipid peroxidation.
 Glutathione and selenium act synergistically in vivo as they are both
 constituents of the same enzymatic system. GSH serves as a specific donor
 substrate while selenium, provided from alimentary sources or locally from
 topically administered preparations of selenium, selenoamino acids or
 selenium yeast extract, provides the prosthetic group for GSH peroxidase.
 The glutathione and selenium antioxidant functions are intrinsically
 related since, by keeping a peroxidase in action, the GSH and selenium
 contribute to the removal of the dismutation product of free oxygen
 radicals, namely, hydrogen peroxide. In a broad sense, GSH and selenium
 modulate free radical chains initiated or sustained by hydroperoxides.
 Selenium is used in the present invention for its role as an antioxidant
 as well as its anticarcinogenic and antimutagenic properties. Thus,
 selenium-glutathione complex may lower the level of potentially damaging
 peroxide radicals that are generated from various carcinogenic promoting
 chemicals, including tar phase and gas phase tobacco smoke inhaled
 by-products, particularly side stream smoke, that smoke which flows while
 the cigarette is being held in between puffs.
 Glutathione peroxidase, a group of water soluble enzymes, also catalyze the
 destruction of both aqueous and membrane-bound hydroperoxides. In dietary
 selenium deficiency, these enzyme levels are markedly decreased resulting
 in severe free radical damage to the tissues so involved. The other
 related antioxidant systems cannot make up for depressed local activity of
 selenium and selenium dependent enzymes; thus, the importance of providing
 selenium in these intra-oral antioxidant preparations, as well as
 ascertaining adequate nutritional supplements.
 L-ascorbic acid (vitamin C) or its derivatives can be employed in these
 compositions primarily for their antioxidant activities. Stabilized
 vitamin C is employed so that it does not lose its physiological reducing
 activities because of its high susceptibility to oxidation.
 Other components were also investigated as being useful in practicing this
 invention, for example, the sulphur containing amino acid cysteine, which
 is one of the three amino acid constituents of the tripeptide antioxidant
 glutathione (GSH).
 Vitamin A is an essential nutrient. Relative vitamin A deficiency may
 adversely affect the skin and mucous membranes, including the mucosa of
 the oral cavity and the gingiva. These alterations are reversible on
 repletion with vitamin A or one of its derivatives.
 The present preparations may include flavorings. Flavors may be based on
 oils of spearmint and peppermint. Other flavoring materials may include
 menthol, clove, cinnamon, wintergreen, citrus fruits, eucalyptus, aniseed
 and others commercially available for these flavoring purposes.
 Flavors may range in concentrations depending on the product from about
 0.1% to about 6.0% by weight of the total composition.
 The gels or pastes of this invention may include bicarbonates with
 thickening agents in a concentration from 0.5% to 5.0% by weight. State of
 the art thickeners with bicarbonate and zinc salts include, but are not
 limited to chicle, xanthan, arabic, karaya or tragacanth gums. Alginates,
 carrageenans and cellulose derivatives such as sodium carboxymethyl,
 methyl, or hydroxy ethyl compounds are appropriate for the intended
 preparations; surfactants and abrasives may also be included. Alcohols
 will otherwise be avoided for their known risk factor for oral cancers. In
 order to decrease dental cavities and add flavor, without using
 metabolizable sugars, sweetening agents as saccharin, sodium cyclamate,
 sorbitol, aspartamane and others may be used in concentrations from 0.005%
 to 5.0% by weight of the total composition, albeit the polyol xylitol, is
 preferred. Xylitol has been shown to prevent dental caries and decrease
 gum disease, in part by reducing the putative oral bacteria, especially
 Streptococcus mutans.
 Gels and dentifrices may contain fluoride anticaries compounds. These
 fluoride compounds, such as salts of sodium, potassium, calcium,
 magnesium, stannous and others have been known to protect teeth from
 developing cavities. Hence, the various fluorinated water systems
 throughout the country. Fluorides may be present in various amounts in the
 gels, pastes, gums or lozenges ranging from 0.01% to 3.0% by weight,
 preferably from 0.05% to 2.0% by weight, most preferably from 0.1% to 1.2%
 by weight. These sources of stabilized fluoride are taught in U.S. Pat.
 No. 5,372,802 by Barrows et al., issued Dec. 13, 1994 and which is herein
 incorporated by reference. These compositions should release from 25 to
 2000 PPM of the fluoride ion. The aforementioned patent taught a peroxygen
 compound, a fluoride and a zinc compound to inhibit the decomposition of
 the former. Thus, fluorides, optionally may be incorporated in the gels or
 pastes of these antioxidant preparations to prevent and repair free
 radical induced gingival diseases.
 Other dental antiplaque oral compositions for gels and pastes have been
 patented with other compounds as optional ingredients. Gaffar in U.S. Pat.
 No. 5,472,685 issued Dec. 5, 1995, which is also incorporated herein by
 reference, teaches that the triclosan antimicrobial and antiplaque benefit
 is enhanced in the presence of a phenolic flavoring agent, such as
 menthol, eucalyptol or thymol. Antimicrobials may optionally be included
 in these gels and pastes to help decrease or eliminate the putative
 bacteria which contribute to the inflammatory reactions in gingivitis and
 periodontitis.
 Lactitol may also be used as a substitute for sucrose in sugar-free
 compositions. Lactitol is a disaccharide sugar alcohol derived from
 lactose, highly water soluble and of low hygroscopicity, making it a
 suitable non-caloric sweetener for use in solid dosage forms. A number of
 compounds may be added in order to enhance the aromas or tastes of these
 preparations. These substances may also impart fragrances to the
 aforementioned. Grapefruit and citrus aroma and flavors have been included
 in smoking tobacco articles. Methyl phenyl pentanol derivatives have been
 used to augment and enhance aromas, such as in perfumes and colognes.
 Schreck patented these derivatives for use in tobaccos and tobacco
 articles in U.S. Pat. No. 4,458,699, issued Jul. 10, 1994, which is herein
 incorporated by reference. Floral, green, weedy, fruity, minty, citrusy,
 oriental and green pepper-like aroma and taste nuances are well known to
 those skilled in the art of flavors and fragrances for such compositions
 as in oral sprays, mouthwashes, mouth rinses, gels, dentifrices and other
 medicinal, nutritional or breath freshener products.
 As an optional embodiment, the compositions herein described may also
 contain zinc or zinc compounds. The state of the art of oral care and
 hygiene has long recognized the value of zinc to neutralize oral malodor
 and the value of zinc ions for their anti-plaque and anti-calculus
 properties. Mouth rinses, mouthwashes, gels and dentifrices will thus
 complement the properties of the xylitol sweetener in oral and dental
 preventative care.
 Various patents have described different zinc compounds and other complexes
 in oral compositions. Domke and Bergman taught an aqueous zinc-polyamide
 complex as a solution for control of halitosis, dental care and to
 decrease the astringency and metallic taste of zinc in the mouth in U.S.
 Pat. No. 5,587,147, issued Dec. 24, 1996, which is herein incorporated by
 reference. This patent discloses previous documents dealing with zinc
 salts such as zinc chloride, zinc phenol, zinc sulfonate, zinc citrate and
 other zinc complexes, some of which purportedly also exhibit oral
 antimicrobial activities. The zinc ion concentrations in these
 compositions will be at least 0.1% to 3.0% by weight and these will
 preferably be in an alkaline pH to avoid demineralization of tooth enamel
 at acid levels. In any event, these aqueous compositions will not have a
 pH below 6, and preferably about 7.
 In order to reduce plaque formation, a number of optional ingredients may
 be added to the composition of the present invention. This is important
 for dental plaque is not only a source of dental cavities, but also a
 significant pathogenetic mechanism for gingivitis and periodontitis. The
 latter two clinical entities are the main targets of the dentifrice
 ingredients of the present invention. The oral bacteria and other
 pathogens associated with dental plaque not only create inflammation with
 an outpouring of white blood cells (leucocytes) which generate free
 radical species, but these micro-organisms also secrete enzymes and
 endotoxins which aggravate inflammation in the gums (gingivitis). This
 causes the gums to bleed and to lose their toughness that promotes its
 separation from the teeth, leading to infectious pockets (periodontitis).
 Thus, optional ingredients in these compositions include abrasives to help
 reduce plaque, as taught by Rice in U.S. Pat. No. 5,716,601 (Feb. 10,
 1998) which is herein incorporated by reference.
 The gels and pastes of this invention can also include one or more of the
 following abrasives at an inclusion range level of 5 to 95% by weight,
 based upon the weight of the entire composition such as hydrated silica,
 calcium carbonate, sodium bicarbonate, bicalcium phosphate, bentonite clay
 or kaolin clay. The preferred level of hydrated silica is 10-30%, the most
 preferred range is 15-22%.
 Another method of application of the gel, paste, gum or lozenge of the
 present invention is to incorporate the various antioxidants, minerals and
 amino acids in liposomes or other state of the art encapsulating vehicles,
 akin to nanospheres, glycospheres and others as used in topical
 compositions. Liposomes are lecithin spheres that form an oil protective
 membrane around the putative active ingredients of the composition. These
 carriers also deliver the active ingredients locally for their preventive
 and therapeutic functions as well as systemically through buccal mucosal
 absorption. Unger and co-workers, in U.S. Pat. No. 5,580,575, issued Dec.
 3, 1996, which is herein incorporated by reference, have taught
 therapeutic drug delivery systems comprising gas-filled liposomes which
 encapsulate the active preparation. Earlier, Chakrabarti and associates,
 in U.S. Pat. No. 5,380,531, issued Jan. 10, 1995, which is also herein
 incorporated by reference, disclosed preparations comprising a lipid and a
 modified peptide for incorporation into liposomes. In addition, Knight et
 al. (U.S. patent '388) has taught small particle aerosol liposomes and
 liposome combinations for medical delivery uses.
 As an example of the present invention, a paste can be formulated having
 the following ingredients.