MXPA00002772A - Smoking products containing antioxidants - Google Patents

Abstract

A composition for inclusion within a cigarette, cigar or pipe. The composition can be included within the tobacco itself, a filter for filtering tobacco smoke once burned or even within the paper or wrapper surrounding the tobacco product. The composition is capable of reducing free radical damage to the oro-pharyngeal cavity, respiratory tract and lungs resulting from tobacco smoke. The composition includes L-glutathione and a source of selenium such as selenomethionine.

Description

TECHNICAL FIELD The present invention deals with the combination of various synergistic antioxidants, enzymatic co-factors and amino acids in appropriate delivery vehicles used in cigar filters and in external filters as in "holders" of cigars and cigars, in "filters". pipe "and in tobacco, wrappings and papers as means of prevention or amelioration of the signs and symptoms and complications to the oro-pharyngeal cavity, respiratory tract and lungs from the damage by free radical species induced by tobacco smoke from filter cigarettes or tobacco smoke from cigars without filters, cigars or pipes.

BACKGROUND OF THE INVENTION The degenerative effects of tobacco abuse are well known and the regulatory agencies as well as the public constantly react to these scientific and epidemiological evidences. Tobacco is in fact a global public health risk accounting for significant morbidity and mortality. Although in places to smoke an abundant oxidant insults the oral cavity, respiratory tract and lungs, the evidence supports the notion that the oxidant load is in the smoker's entire organism. Smoking promotes the development or increase of atherosclerosis, causing cardiovascular disease, chronic obstructive pulmonary disease, recently marked as "smoker's lung", skin damage, especially to the face, called "smoker's face", and various forms of cancer, including carcinomas of the mouth, pharynx, esophagus and lung.

Tobacco is a substance consisting of dried leaves and stems of the Nicotiana tabacum plant. Tobacco contains the drug nicotine, which is very addictive. The plant is native to North America and is now grown worldwide. Tobacco abuse has been identified as the single most avoidable cause of disease, morbidity and mortality, since tobacco smoke contains many toxic chemicals, in the smoke in its tar and gas phase.

There are three main ways to consume tobacco: 1) smoking, 2) chewing and wetting, and 3) inhaling. Fifty million Americans smoke, and countless others are affected by tobacco smoke, so-called environmental or secondary smokers. Children of smokers also breathe this secondhand smoke and have more respiratory problems than children of non-smokers. Smokeless tobacco is used by as many as 12 million individuals and has degenerative effects on the oral cavity plus systemic effects derived from the oral absorption of nicotine and other chemicals.

Cigarette smoke is divided into two phases, gas phase smoke and tar. Cigar tar contains high concentrations of free radicals. Common oxidants include the semiquinone which is in equilibrium with hydroquinones and quinones, particularly in the viscous matrix of tar. Many tar extracts and oxidants, including those mentioned above, are soluble in water and reduce oxygen to its superoxide radical which can dismute to form H202. Importantly, fiberglass-type cigarette filters retain almost all tar particles that are greater than 0.1 micron. In this way, the filter acts as a tar trap in the smoke of the cigar. There is an extraordinarily large number of free radicals, greater than 1015, on each exhalation in the gas phase of cigarette smoke. While oxidants in tar are stable, those organic radicals in the gas phase smoke are reactive carbon and oxygen radicals with extremely short half-lives. Other free radical species, such as aldehyde species, have longer half-lives and can be more degenerative, resulting from lipid peroxidation. Interestingly, free radical concentrations of tobacco are kept at high levels for more than 10 minutes and tend to increase while tobacco smoke ages. Thus it is considered that these smoke oxidants in gas phase are in a stable state while they are being continuously formed and destroyed. The latter reactions are similar to those noted in smog, signaling extra-noxious stimulation to primary and secondary smokers in polluted atmospheres.

In other in vitro studies, cigarette smoke in the gas phase was evaluated in its filter and whole states (without filter) for oxidative effects in human plasma. Researchers noted the prevalence of lipid peroxidation in plasma after exposure to gas phase smoke, but not to whole cigarette smoke. The reaction of lipid peroxidation did not begin until the endogenous ascorbic acid had been consumed, that is, vitamin C was completely oxidized. They also noted that exposure to cigarette smoke caused oxidation of plasma protein thiols (methionine and cysteine amino acid junctions) and low density lipoproteins. They concluded that lipid peroxidation induced by gas phase smoke oxidants leads to changes in lipoproteins associated with atherogenesis. As noted here, the synergistic effect of ascorbic acid and reduced glutathione or ascorbic acid derivatives as their esters, are beneficial in combating tobacco oxidants both in the amelioration and in the retardation of the adverse effects of tobacco smoke in the oral epithelium. , pharyngeal and respiratory, on bronchoalveolar fluids and in the pulmonary parenchyma.

Cells subject to oxidative stress can severely affect cell function and cause damage to membrane lipids, proteins, cytoskeletal structures and DNA. The damage of free radicals to DNA has been measured as single-strand rupture formation, double-strand breaks and chromosomal aberrations. Cells exposed to ionizing radiation and cigarette smoke have also been shown to have increased intracellular DNA damage, hence the frequency of oro-pharyngeal, esophageal, and pulmonary carcinomas in tobacco users.

The macrophage and neutrophil cells have their phagocytic activity associated with the so-called "respiratory acceleration" reaction, which is dependent on the plasma membrane NADPH oxidase. The oxygen radical can then be transformed to H202 by the superoxide dismutase. Clausen (full quote) showed that smokers have a higher respiratory acceleration reaction of alveolar macrophages and peripheral neutrophils than nonsmokers and those who left also have a higher incidence of respiratory and oral signs and symptoms than nonsmokers, due to its exposure to inspired particles. The "respiratory acceleration" reaction can also destroy the elastic fibers due to the secretion of elastase neutrophils and can also damage alpha-1 anti-trypsin. It was shown that a decrease in the condition of the reaction of "respiratory acceleration" in smokers supplemented with mega oral doses of antioxidants occurred. The affections of the latter were evaluated with vitamins E and C, and beta-carotene in 10 smokers and 10 controls.

Other research studies have shown that tobacco smoke impairs the phagocytic function of alveolar macrophages. The gas phase of unfiltered cigar tobacco is a potent inhibitor of its G-3P-dehydrogenase enzyme, accounting for phagocytic dysfunction, probably through the blocking of the enzyme-sulfhydryl groups since protection is generally achieved by sulfur of the amino acid cysteine. Evans et al. (Arch environ hlth: 103-106, 1979) [citation complete] studied the affections of four types of cigarette filters in the inhibition of this enzyme by means of aqueous solutions of tobacco smoke in the free gas phase. They concluded that hydrogen sulfide was the main inhibitor in this smoke and the inhibition was dependent on age and the amount of solution in free gas phase, as well as the exposure time. Commercial acetate-carbon cellulose filters were effective in removing this inhibitor. Green [complete citation] has also shown the protective role in the alveolar macrophages of cigarette smoke by both reduced glutathione and L-cysteine. Both anti-oxidants are sources of protective sulfhydryl groups.

The lungs have adapted enzymatic biochemical and non-enzymatic antioxidant systems as prevention, limitation or reversal of oxidative damage to the lungs. This is a protective feature to maintain normal lung function, while the respiratory tissues operate in a high oxygen partial pressure environment and are continuously exposed to airborne contaminants. Because of their access to the environment, such as skin to oxygen and ultraviolet radiation, the lungs can be damaged by particular matter and inhaled gas, particularly in active and passive smokers. The lung lesion can produce alterations in the tone of both the tracheobronchial and pulmonary circulation resulting in plasma exudate. Locally, airway edema may decrease the lumen of the airways or the fluid may accumulate in alveolar spaces, as in the case of adult respiratory distress syndrome (ARDS).

Bronchial hyperactivity, as in asthma, can also result from these cytological lesions, ending the latter in the reduction of lung function, as evidenced by the oxygen desaturation in the blood and local accumulation of carbon dioxide. This is the so-called "smoker's lung".

Reactive oxidant species, as induced by inhalation of tobacco, smoke, ozone, smog and others are important factors in bronchial hyperresponsiveness and inflammatory lung injury. As in other tissues, antioxidant enzymes in the lung include superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide and catalase which reduces hydrogen peroxide to water. This reaction can also be catalyzed by the enzyme glutathione peroxidase cofactor selenium using reduced glutathione (GSH) as a substrate. Glutathione peroxidase can also reduce the lipid peroxide to the corresponding alcohols also using reduced glutathione.

The tripeptide ubiquitous nonenzymatic thiol, glutathione (GSH), plays a vital role in maintaining the integrity of reactive sensitive cellular components to oxygen free radical species.

This is achieved through its direct role as an antioxidant, in its reduced form (GSH), as well as a cofactor, as mentioned above. GSH has been detected in the bronchoalveolar lavage fluid. In cells, GSH is oxidized in this process to GSSG, but its cellular concentrations for antioxidant activity are maintained in equilibrium by the enzyme glutathione reductase, consuming NADPH as equivalent to the reduction of equivalents. Under states of GSH depletion, including poor nutrition and severe oxidative stress, as in smoking, cells can be injured and die.

Other non-enzymatic molecules playing an antioxidant role in the lung include ascorbates (vitamin C); particularly in the extracellular defenses of the lung, as teleologically, it is present in high concentrations in the fluid that lines the pulmonary route. Ascorbates as free radical scavengers also react with oxidized glutathione (GSSG) to reduce it to GSH. Also, in the lipid membrane of cells, the alpha-hydrophobic tocopherols (vitamin E), act synergistically with vitamin C to inhibit lipid peroxidation, as can be induced by cigarette smoke, by actively removing the peroxides lipids and other free radicals.

Several studies have correlated the importance of oxidative stress to various organs resulting from tobacco smoke and other harmful environmental factors and thus continue to exercise a tax on public health in all countries. Significant mortality and morbidity result from smoking tobacco from cigars, cigars and pipes and the local oral pathology of both smoking and chewing tobacco. Epidemiological studies have strongly implicated tobacco and the pathogenesis of atherosclerosis and coronary artery disease, emphysema and several malignancies, including oropharyngeal and pulmonary neoplasms. Cigarette smoking is chronically associated with the appearance of free radicals that induce oxidative damage. The measurement in the blood, urine and tissues of various antioxidants or products of the metabolic processes of free radicals is support for tissue oxidative damage in the pathogenesis of several diseases associated with tobacco smoking and environmental contaminants. An example to be cited is one of the F2 isoprostanes, 8-EPI-prostaglandin 2a, a stable product of lipid peroxidation, which can be assayed by chromatography in plasma or urine. Chronic smokers, particularly "heavy" smokers, have higher urine levels of 8-EPI-PGF 2a than their peers, non-smoking control subjects. The cessation of smoking with or without exchanging the nicotine patches, reduced urinary levels but not normal ranges. Subsequent studies, while the subjects continued smoking, revealed that the oral administration of ascorbic acid-A (vitamin C) which is known for its antioxidant properties reduced the urinary levels of 8-EPI-PGF 2a, suggesting the in vivo suppression of the damage oxidant in the body.

Studies have estimated that tobacco smoke has about 3,000 different constituents, of which a number are toxic, some are carcinogenic and can generate free radical species. Most of these compounds have been identified in the so-called main stream and side stream of tobacco smoke. The above is that the volume of the smoke that passes through the mouth piece of the tobacco product during the exhalation while the sidestream of the smoke is that the smoke emitted from the burning part of the cigar between exhalations. Although tar and nicotine are retained in the filter of the cigars, this applies mainly to the main stream of the smoke, when comparing cigarettes with filter and without filter. The emission of smoke from the mainstream is also markedly reduced in both low and ultra low producing cigars. However, the emissions of toxic and carcinogenic components in sidestream smoke are not significantly reduced in filter cigarettes when compared to their unfiltered counterparts. Thus, smoke from the sidestream is a major contributor to environmental smoke affecting both smokers and their non-smoking counterparts, so-called secondary smokers. The lower rates of consumption of cigarettes with high smoke production has not reduced the internal pollutants of carcinogenic substances and free radicals, generating the potential of tobacco smoke produced in the smoke from the side stream, although it has decreased its levels in the smoke of the mainstream through the smoking of low producing cigars and filter cigars.

Tobacco, whether smoked in the form of cigars, cigars or pipes, causes common adverse effects in the oral cavity. Tobacco smoke has two possibilities of exerting its degenerative effects in the mouth: when it is inhaled by the smoker and in its exit during the exhalation.

Leukoplakia, a white spot induced by tobacco in the buccal mucosa, as found in smokers, is a localized irritation due to the direct contact of smoked tobacco and is directly related to the frequency and years of tobacco abuse. Although leukoplakia is a benign oral lesion, these have a malignant potential, requiring a biopsy of the lesion to rule out cancer. Leukoplakia can be regressive or completely resolved when the use of tobacco products is discontinuous.

About 30,000 new cases of cancer of the oral cavity are diagnosed annually, accounting for two to four percent of all new cancers. Oral cancer kills 8,000 patients each year and only half of the cases diagnosed annually have a five-year survival. The vast majority of these patients use tobacco products. Other risk factors include alcohol abuse, nutritional deficiencies and poor oral hygiene.

Tobacco contributes to other symptoms or oral pathologies of the mouth and teeth. Tobacco can cause halitosis, can numb the taste buds, interfere with the smell and taste of food and can stain teeth and contribute to tooth decay. For example, smokers have more dental tartar (calculations) than non-smokers. Tobacco is also associated with destructive periodontal (gum) disease and tooth loss. Acute necrotizing ulcerative gingivitis ("oral ditch") is a destructive, painful inflammatory condition that occurs mainly in cigar smokers. Inflammation of the nasal and sinus membranes has also been associated, with importance, in individuals who are "allergic" to tobacco smoke.

Like cigars, the evidence shows that cigars are also toxic and addictive. Smokers of cigars and cigars have a similar increased risk for oral and laryngeal cancers but smokers of the latter are more likely to contract lung cancer, emphysema and cardiovascular disease. While cigar tobacco is usually cured by the duct with a slightly acidic resulting product, the slower cure methods for cigars render this alkalinity light. At this pH, nicotine is absorbed more quickly. Unlike cigars, cigars are less homogeneous and vary in size and nicotine content. Pure smokers can spend an hour smoking a single "Havana" large even though some actively inhale very little of this smoke; however, in non-inhalers, their nicotine levels may be elevated without any toxic co-absorption, as occurs in cigarette smokers. Pure smokers also commonly hold a cigar without igniting it in the mouth, exposing the oral cavity to more nicotine by local absorption. Thus, the consumption of cigars can produce a charge of smoke equal to or greater than exposure and the free radicals generated locally in the oral cavity which create degenerative effects and a risk of oropharyngeal cancer.

Lung carcinoma and chronic lung disease have been known to be the complications of the final stage of cigarette abuse. The tars of nicotine contain carcinogens and smoking also induces a reaction of free radicals in the respiratory tract, both putative to lung and oropharyngeal diseases and the neoplasias induced by tobacco abuse. Cigarette filters "trap" tars of nicotine but not compounds in gas phase. Epidemiological studies have been conducted in several countries to show the differential effects of tar content, the amount of cigarettes smoked, the type of tobacco smoked, and the use of filters in the risk of lung and oropharyngeal cancer in cigarette smokers. The effect of cessation of smoking on these respiratory diseases has also been investigated.

Under the epithelial alignment along the respiratory tract is a network rich in capillaries which carry systemic blood from the nasal and tracheobronchial arteries. These vessels provide nutrition to the mucosa to allow it to maintain protective functions. The vascular leakage of proteinaceous plasma is a cardinal sign of pulmonary inflammation, whatever the source of the stimulus, including tobacco smoke. Because of the differential in hydrostatic pressures, this plasma exudation is a unidirectional outward movement, which becomes a specific defense and an inflammatory response. This exudate thus results from a variety of inhaled provocations including noxious chemicals, gases, particular matter, and bacteria, to the mucosa of the airways. This first line of defense initially does not injure and is reversible, but persistent and overwhelming or chronic stimuli, such as tobacco smoke and other environmental pollutants, can cause lung damage from the oxidative damage of leukocytes, other free radicals and harmful agents.

As already noted, smoking cigarettes can result in the complex signs-symptoms known as chronic obstructive lung disease culminating in emphysema. Some clinical observations on the adverse effects of smoking are derived from an inherited multiple organ disease called alpha-1 antitrypsin deficiency. This deficiency of inherited homozygous alpha-1 protease inhibitor results in emphysema, but occurs in those patients who smoke at a young age, rather than in the tobacco-smoking population without this inherited defect. Smoking results in local damage by protease inhibitors whose function is to protect the pulmonary elastin tissue.

In patients with acute onset or crisis of pulmonary or bronchial diseases, inflamed respiratory epithelium and pleural exudates occur consequently to the local accumulation of leukocytes in response to the specific etiological agent or pathogens responsible in infectious disease (tracheobronchial or pulmonary). The function of white blood cells is to fight degenerative agents or putative microorganisms, which cause the release of hydrogen peroxide and several enzymes, including myeloperoxidases, into extra cellular fluids. These myeloperoxidases are able to catalyze hydrogen peroxide in the presence of the chlorine ion forming the highly reactive hypochlorous acid species. H0C1 then oxidizes tissue components and plasma protease inhibitors.

The lungs are very susceptible to the damage caused by the inhalation of harmful agents giving a response to this injury through respiratory epithelial cells and pulmonary vascular endothelium. Bacteria, fungi and viruses can also induce pulmonary infections. All the aforementioned evoke reactions of free radicals in the respiratory tissue and antioxidant-inflammatory responses. Teleologically, as a mechanism of frontal line of defense to inhaled particles and gases, the respiratory tract and lungs have enzymatically active defense mechanisms and non-enzymatic antioxidants to prevent, minimize, reverse and even repair this oxidative damage to the lungs and respiratory tract. This includes superoxide dismutase, which converts the degenerative superoxide radical to hydrogen peroxide and catalase which reduces H202 to water. This latter reaction can also be catalyzed by selenium containing glutathione peroxidase which can also reduce lipid hydroperoxides, products of induced oxidant lipid peroxidation, to alcohols, also using glutathione as the source of radical reduction. Thus, the tripeptide thiol, glutathione, (GSH) acts as a direct antioxidant and as a cofactor in the defense mechanisms of reactive oxygen species. In this process, glutathione becomes oxidized but its cellular concentration as a reduced compound is maintained by the related glutathione reductase enzyme.

It is also noted that some cells have sodium-dependent capture systems for GSH, allowing the cells to use both exogenous GSH and endogenously synthesized GSH, thereby increasing the cell's ability to survive free radical and oxidative species damaged in this way, extracellular GSH also protects the survival of the cells. Research studies have shown that cell viability correlates better with the content of GSH in the mitochondria. In the absence of GSH, lipid peroxidation is uncontrolled and leads to cell injury and death. Conversely, GSH protects cells from the ravages of free radicals, working synergistically with the antioxidant enzymes and antioxidants of dietary vitamins.

Non-enzymatic antioxidants also protect the lungs from damage resulting from a favorable oxidative environment. Ascorbates (Vitamin C) collect free radicals in extracellular lung tissue and superficial fluids and interact synergistically with oxidized glutathione to return glutathione to its metabolically active form as a reduced molecule.

Vitamin C, ascorbic acid, plays an important role in human metabolism. As an antioxidant, it protects the skin from free radical damage induced by radiation, tobacco smoke, and other inhaled or swallowed environmental pollutants. Vitamin C promotes the synthesis of collagen, tissue repair and wound healing. Vitamin also provides important protection against chemical damage associated with cigarette smoking, including nicotine, carbon monoxide, n-nitrous compounds, nitrogen oxides, nitric acid gas and others. Although ascorbic acid can be reduced in its role as a collector, the ascorbate radical can then be removed by the NADPH enzyme systems as a source of molecule reduction. Thus, Vitamin C can be recycled to reduce or reduce the process of lipid peroxidation through its synergistic function with tocopherols. The Markham patent (U.S. Pat. No. 4,822,8916) refers to the oral administration of Vitamin C to demonstrate its free radical attributes.

Cigar smokers often have lower plasma levels of ascorbic acid than their non-smoking controls. Clinical and investigative evidence suggests that smokers may have higher ascorbic acid requirements and that supplementing vitamin C in the diet may be protective for the smoker.

Vitamin A is an essential nutrient for humans, the relative deficiency of vitamin A can adversely affect the skin and mucous membranes, including the mucous membrane of the oral cavity and respiratory tract. These alterations are reversible in oral repletion with vitamin A or one of its many derivatives, all commercially available. Retinol is the transport form of vitamin A in the plasma, while the retinol ester is its storage form in the liver and mucous membranes. Mucosal deficiency of vitamin A has been reported in patients with bronchitis, after inhalation of nicotine, and with premalignant mucosal lesions. Biesalski, in the U.S. Pat. No. 5,112,598, dated May 12, 1992, described the use of vitamin A compounds in such a way that they could be transported by means of the specific protein molecule that binds to retinol, and therefore correct the deficiency of vitamin A without creating toxic levels. The patent x598, which is incorporated herein by reference, proposed the pharmaceutical preparations of retinoid acid or its retinol esters or esters as the active substance. For the respiratory tract in particular, aerosol preparations for topical use were proposed and described.

Waterbury in the U.S. Pat. No. 3, 667,478, dated June 6, 1972, which is incorporated herein by rence, disclosed a filter cigar incorporating a stabilized form of an aqueous emulsion of an active vitamin A preparation. This patent teaches that the method provides stability over the length of time before the cigar is smoked. As in the U.S. Pat. No. 3,339,558, the filter of the cigarette contains in front of the filter a breakable capsule with a specific amount of Vitamin A and a method of introducing it into the mouth and respiratory tract of the smoker. Prior to its ignition, pressure is applied to the putative capsule, So that the released active materials are dispersed with the filter, there Vitamin A is accessible to the smoke of the cigar that goes through. Patent 78 subsequently teaches that stabilized Vitamin A can also be dispersed, impregnated in the tobacco or provided through droplets or drip through the use of gelatin or other colloidal materials, such that stabilized Vitamin A can be easily placed by the smoke passing through the filtering elements. Thus, the dispersed and random distribution of the small liquid droplets of small particulate matter from the Vitamin A preparation is localized through appropriate tobacco or through the filtering medium of a filter cigar. Vitamin A is surrounded and protected in a method similar to micro encapsulation.

Irimi and collaborators taught in the U.S. Pat. No. 5,060,672, dated October 29, 1991, which is incorporated herein by reference, a highly efficient tobacco smoke filter. They revealed a composition with mechanical and / or absorptive filtering materials and one containing a compound having high nucleophilic ad- vival to formaldehyde in such a way that these are chemically reactive with the aldehydes that are not filtered. One component contains an enediol structure. The patent notes that the synergistic compositions remove the formaldehyde radical excited from tobacco smoke.

It has been noted that tar in the smoke can be reduced by the use of low tar tobaccos and cigar filters. Other efforts have been directed to the reduction of toxic and harmful substances in the same tobacco or by adding these filter modifications or adding chemicals to the filters. Caseley taught a method to further reduce the aldehydes in tobacco by using non-toxic salts of -mercapto-alkylene-sulfonates, as well as cysteine and acetylcysteine in the U.S. Pat. No. 4,532,947, dated August 6, 1985, which is incorporated herein by reference. These compositions were to be added to the filters of cigars or cigar holders comprising a filter for the purposes of reducing the toxic substances of the tobacco in situ, while smoking cigars. In the U.S. Pat. No. 3,972,335, dated August 3, 1976, which is incorporated herein by reference. Tiggelbeck and Mannes revealed a cigarette filter comprising menthol or other smoke flavoring agents. They taught the use of impregnation of an activated granular carbon with a pore modifying agent, such as sucrose, and thus improve the static life and delivery of the smoke flavoring agent. Part of the activated carbon is available for the absorption of menthol or another flavor.

In the U.S. Pat. No. 5,472,002, dated December 5, 1995, which is incorporated herein by reference, discloses a cigar filter for the administration of taurine by inhalation. The patent disclosed three methods or apparatuses for administering amino acids to smokers. The disclosure involves a cigarette filter which comprises a filtering material for the filtration of burning tobacco smoke and various means of taurine incorporation into the site in such a way that it is introduced into the smoke as it passes through the filter while the cigar is being smoked. Inhalation taurine has been shown to have preventive and beneficial effects on afflictions of the respiratory tract, including an important mucolytic property. The latter is similar to the action of cysteine, as taught by Puracelli, in the U.S. Pat. No. 4,910,222, dated March 20, 1990, also incorporated herein by reference.

A number of researchers have taught cigarette filtering systems to aid in the retention of tars from tobacco smoke, nicotine and other toxic chemicals. Choen and Luzio in the U.S. Pat. No. 5,009,239, dated April 23, 1991, which is incorporated herein by reference, demonstrated a process to improve the selective retention of the filter and pass through properties of cigarette filter elements. They used a polyethylene imine buffered with organic acids such as formic, propionic, lactic, etc. At a pH range of about 8 to 9.5 In this way there was retention of aldehyde and nicotine and nicotine products through the cigarette smoke filter.

Brown and collaborators in the U.S. Pat. No. 5,249,588, dated October 5, 1993, which is incorporated herein by reference, developed an article for smoking which comprises tobacco treated with a high wetting level of 4% to 15% by weight. This smoking article comprises a tobacco rod where the rod comprises cut expanded tobacco and a paper wrap, with said tobacco being loaded with the humectant. Von Borstel and Craig also teach a cigar filter with a humectant in the U.S. Pat. No. 5,501,238, dated March 26, 1996, which is also incorporated herein by reference. They revealed sodium pyroglutamate as a humectant plus a surfactant such as ethoxylates to absorb moisture from tobacco smoke for the wet filtration of tobacco smoke. They also revealed that other agents such as antioxidants and anti-carcinogenic agents that serve to filter or inactivate the toxic component of smoke can be added. The '238 patent revealed three types of filters to effectively remove tar from smoke: a) conventional cellulose acetate filter, b) cellulose acetate with sodium pyroglutate and c) commercial wet filtration system.

Lee and Harris revealed in the U.S. Pat. No. 4,964,426, dated October 23, 1993, which is incorporated herein by reference, both the tobacco smoke filters and the process for their production. The filter element such as cellulose acetate contains at least 1% by weight of microalicate crystals of compounds such as sodium carbonate on the surface of the filter element to promote filtration.

Cigarette smoke induces oxidative damage to lipids, DNA and proteins, particularly the SH protein groups for this smoke contains high levels of both free radicals and aldehydes, including acetaldehyde, propanol and acrolein as well as other degenerative molecules. In the oropharynx and in the lung, cigarette smoke also accelerates the production of reactive oxygen species through local recruitment and activation of phagocytic cells in response to harmful agents. The inhaled smoke first comes into contact with the lining fluids of the respiratory tract which are the first line of defense with its antioxidants, particularly the reduced glutathione, (GSH) and ascorbic acid. The attack by cigarette smoke and free radicals on plasma proteins can be measured by a carbonyl assay and by the loss of enzymatic activity and SH groups. Reznick et al. [full quote] showed that all cigarette smoke and gas phase causes the formation of carbonyl groups in human plasma, which is particularly inhibited by GSH. In contrast, the exposure of human plasma to the gas phase but not to all cigarette smoke produces oxidative damage to lipids. As such it is contemplated that the compositions of this invention will contain GSH, ascorbic acid and other synergistic antioxidants, to be in the internal filters of the cigars or in these external filters of smoking articles or in tobacco itself or in cigarette papers.

BRIEF DESCRIPTION OF THE INVENTION The present invention involves the inclusion of an antioxidant defense system incorporated within a filter to be used with tobacco products or within tobacco or in a wrapper for such tobacco products. The present application utilizes synergistic antioxidants delivered, for example, in tobacco filters such as those for cigarettes or external filters to prevent and ameliorate the free-radical damage induced by smoke to the pharynx-gold, respiratory tract and lungs. The composition is supplied by inhalation through various filters of the state of the art. The invention in these terms generally comprises glutathione in its reduced form and a co-ingredient for regeneration of the reduced form of glutathione, the ingredient then comprising selenium or aminoselic acids such as seleno methionine or selenocysteine. As optional ingredients afterwards, it is contemplated that the composition includes ascorbic acid and / or one of its derivatives, a sulfur containing amino acids such as L-cysteine, L-taurine and / or L-methionine alpha-tocopherol, vitamins A and E and salts of zinc.

In a more preferred aspect of the present invention, the aforementioned pharmaceutically active antioxidant system included within a filter comprising L-ascorbic acid, about 1.0 mg., L-reduced glutathione, 2.0 mcgm of selenium as selenium-methionine and about 0.5 mg. of L-cysteine. The composition can also have around 2.0 U.I. of acetate D, L-alpha-tocopherol and around 2.0 U.I. of Vitamin A. These are preferred amounts in the filter of each cigar or in the capsules after the filter with these ingredients encapsulated in liposomes.

DETAILED DESCRIPTION OF THE INVENTION Without being bound to a particular theory, it is noted that reduced glutathione is used to protect cells against oxidative stress by being oxidized themselves. Thus, L-glutathione must act in combination with another enzyme system in order to be reduced so that it can resume its role as a scavenger of free radicals. The GSH functions in coordination also with the enzyme glutathione peroxidase which requires selenium as a cofactor to exert this antioxidant biological function. Selenium compounds have been shown as scavengers of oxygen-focused radicals in vivo, with reduced glutathione through glutathione peroxidase. It is believed that selenium-GSH peroxidase catalyzes free hydrogen peroxidase in the presence of reduced glutathione. This reaction reduces glutathione to oxidized glutathione GSSG. In contrast, the GSSG is reduced again to GSH by the enzyme glutathione reductase, thereby maintaining abundant cellular GSH to collect free radicals again.

In addition, glutathione and selenium act synergistically in vivo as constituents of both the same enzyme system. GSH serves as a specific donor substrate while selenium, provided from dietary sources or locally topically applied selenium preparations, or selenoamino acids, provided by the prosthetic group of the GSH peroxidase. The antioxidant functions of glutathione and selenium are intrinsically related since they maintain a peroxidase in action, the GSH and selenium, contribute to the removal of the dismutation product of oxygen free radicals, that is, hydrogen peroxide. In a general sense, GSH and selenium modulate free radical chains initiated or sustained by hydroperoxides. Selenium is used in the present invention for this purpose as an antioxidant as well as for those anticarcinogenic and antimutagenic properties.

The aforementioned compositions can be particularly useful in the prevention and treatment of exposure to tobacco smoke or other gases or particles of matter. They represent a delicate balance of ingredients which serve not only to reduce the number of free radicals but also to inhibit enzymatic oxidation in tissues. More preferred formulations in accordance with the present invention also increase the formation of the composition by recycling certain antioxidant ingredients in the formulation after they are absorbed.

In a preferred embodiment of this invention, the antioxidant synergist complex is a dispersion of active materials through the filter medium of a tobacco filter, furthermore, as noted previously, the complex can also be incorporated in the same tobacco or in the wrapping paper. The antioxidant complex would be dispersed in the filter as a powder, as a stable solution, or as an aqueous emulsion, which may include micro-encapsulation of these active agents such as in liposomes. The assets may also be in thin droplets so that when the smoke produced by the burnt tobacco passes through the filter, the smoke would recover or transport the powdery complex or the thin droplets containing the putative antioxidant ingredients. Thus the smoke with the assets is inhaled by the smoker so that the smoke enters the oral cavity and is then inhaled into the respiratory tract and lungs of the individual: The antioxidant will then be available to neutralize and collect the free radicals both in the smoke of tobacco themselves and those generated by the harmful smoke of tobacco in the oral cavity and respiratory tract, and with that the complex will exert its beneficial effects locally on the mucosa and tissues of the smoker.

As previously noted as an alternative in both filter and non-filter cigarettes, it is contemplated that the present antioxidant complex be dispersed through the tobacco load of the product. In addition these can be located near the distal end of the end of the filter or the proximal opening of the unfiltered tobacco product, the antioxidant complex can also be uniformly and equally distributed throughout the entire product. Thus, particularly by employing microencapsulation techniques such as oral liposomes, these active ingredients can be administered in the filtration medium of a filtered cigar and within the filler of these tobacco, or of unfiltered and pure cigars.

In order to protect the active ingredient of this invention, various encapsulations or chemically protective techniques are available such as are known in the state of the art. The active ingredients can be encapsulated in micro-encapsulation vehicles such as liposomes, glycospheres and nonoespheres. Such vehicles for oral use as are well known in the state of the art for the cosmetic industry. Liposomes are lecithin spheres that form an oily protective membrane around the active ingredient of the composition of this invention. The active ingredients trapped in the liposome travel from the tobacco product and are released into the oral cavity where they locally perform both preventive and therapeutic functions to neutralize the various free radical species. further, the antioxidant can also be absorbed as usual by the oral mucosa for systemic use. It was noted that Unger et al. Have taught therapeutic drug delivery systems comprising gas-filled liposomes which encapsulate the active preparation in U.S. Pat. No. 5,580,573 dated December 3, 1996 which is incorporated herein by reference. Earlier, Chakrabarti and Associates disclosed preparations comprising a lipid and a modified peptide using liposomes as delivery vehicles. See U.S. Pat. No. 5,380,531 dated January 10, 1995 which is also incorporated herein by reference. Knight and collaborators in U.S. Pat. No. 5,049,388 dated September 17, 1991 which is also incorporated herein by reference, discloses small aqueous particles in aerosol droplets containing liposomes. The patents teach the inclusion of a medication drug interacting within the membrane of the liposome so that when the latter is broken, the active ingredient is not lost from the liposome. The inventors taught various methods of preparing the aerosol particles containing the liposome. The liposome-drug interactive particle combinations are used in treatments of small aerosol particles.

The liposome particles as contemplated herein have a diameter of less than five microns and can easily be prepared in uniform sizes with the active for dispersion and filter material of the cigarette filter or in the rupturable aqueous capsule which contains the liposomes encapsulating the antioxidants In each case, the active mixture in the liposomes would be inhaled by the smoker with each puff, thereby neutralizing the free radicals generated by tobacco smoke in the oropharynx and respiratory tract and lungs.

Alternatives for depositing the antioxidants of this invention in the filter, tobacco or encapsulations in front of the filter is to fix these in a treated cigarette paper. This would particularly reduce the free radicals in the parallel streams of smoke which are particularly harmful to those exposed to secondary smoke as well as to the primary smoker in both main streams and parallel streams of smoke.

Chad and collaborators revealed in U.S. Pat. No. 5,540,242, dated July 30, 1996, which is incorporated herein by reference, a method for reducing parallel streams of smoke by incorporating additives into cigarette smoke. Their papers include an alginate as a film forming agent in combination with a burnable additive such as alkali metal salts such as potassium succinate, citrate or acetate to form a coating that reduces the parallel stream of smoke. The antioxidant synergist group of this invention can be incorporated into the cigarette paper not only to reduce the parallel flow of smoke, but also to neutralize free radicals in the inhaled tobacco smoke. The paper then treated will not produce less flavor, modify the appearance of the ashes, or reduce the number of cigar smokes. The filter may also contain anti-oxidant complexes polished to be inhaled by the smoker and may or may not contain a menthol flavor, as is known in the state of the art.

The treatment of tobacco to reduce or inhibit toxic chemicals in tobacco smoke has been reported. For example, Wadell and Colleagues revealed in U.S. Pat. No. 4,967,772, dated November 6, 1990, a smoking article according to which tobacco and alcohol are stored in a container. This patent is incorporated herein by reference as it teaches that alcohol is similar to a cyclohexanol, whose vapor is inhaled in the tobacco smoke stream. That is, to inhibit the selective localization of nitrosamines of toxic tobacco and its derivatives or metabolites in the smoker's tissues without incalculable alcohol effects of this vapor in the smoke. Wadell in U.S. Pa. No. 4,966,169 dated October 30, 1990, also incorporated herein by reference, teaches fragments of re-dehydrated cut tobacco which is directly sprayed with an alcohol. The patent notes that this process reduces the risks to tobacco health as concomitantly smoked alcohol is removed hot and in bronchial tissue is available to block the location of putative nitrosamines.

In a preferred embodiment of this invention, the active ingredients comprising a group of synergistic antioxidants are to be employed in the following doses in the filter of each cigarette. It should be recognized that to express the quantity per package of cigarettes, each value will be multiplied by 20, the usual number of cigarettes sold in a package, with 10 packages in a carton. The ranges of each ingredient are expressed if each is dispersed in the filter material of each cigarette, such as a powder or gel or encapsulated in pellets or mixed with a super absorbent such as any acrylamide co-polymer or as polyvinyl alcohol incorporated with maleic anhydride. In the latter case, the assets are first solubilized in glycerin and then mixed with the super absorbent in proportions in the range of at least 1 to 1000 parts of active for at least 1 to 1000 parts of the super absorbent depending on its ability to retain a complex active based on aqueous glycerin.

In another preferred embodiment of this invention, the active synergistic antioxidants are first microencapsulated in such protective phospholipid vehicles as oral liposomes or by other micro-encapsulation techniques of the state of the art, as we already noted and which are well known in this art. industry for the protection of oral drugs, vitamins, amino acids, peptides, etc. The active ingredients are as follows: 1. L-Glutathione in an amount between at least 0.01 mg. to 20 mg, preferably 0.10 to 10 mg, more preferably 1.0 mg to 5.0 mg per cigar. 2. L-selenomethionine or L-selenocysteine at a concentration to give at least 0.01 mcgm to 10 mcgm of selenium, preferably 1.0 to 2.5 mcg of selenium per cigar.

Optional ingredients 3. L-cysteine and / or its ester, n-acetyl-L-cysteine in a range of 0.1 mg to 10.0 mgs., Preferably 0.5 mg to 5.0 mgm and more preferably 1.0 mgs to 2.5 mgm, per cigar. 4. Vitamin C as ascorbic acid or as an ascorbic palmitate or other ascorbic acid esters alone or microencapsulated such as in liposomes from 1.0 mg to 60.0 mg, preferably from 0.5 mg to 30.0 mgm, more preferably from 1.0 mgm to 3.0 mgm per cigar.

. Vitamin E as a powder for dispersion as tocopherol acetate or tocopherol succinate or other esters of 0.01 U.I. to 10.0 U.I., preferably of 1.0 U.I. at 5.0 per cigar. Vitamin E can also be used in liposomes at approximately the same doses. 6. Vitamin A actively as beta-carotene or retinyl palmitate or other vitamin A ester stabilized in an amount between approximately 1.0 U.I. to 500 U.I., preferably of 10.0 U.I. to 250 U.I., more preferably from 25.0 to 125 U.I. per cigar. The vitamin A compositions can also be administered by being micro-encapsulated, such as in liposomes. 7. As an optional ingredient, the compositions of the present invention can include a zinc salt, preferably a zin acetate or zinc gluconate in an amount of about 0.1 to 15 mg, preferably 90.5 to 7.5 mg, more preferably 0.75. mg. at 1.5 mg per cigarette. 8. As optional ingredients below the amino acids methionine and / or taurine, as we have already noted, can each be included in concentrations of at least about 0.5 mg. to 20 mg., preferably 1.0 mg. to 10 mg. per cigar.

In each example, the aforementioned and then noted levels of ingredients are based on a cigar filter only if the content within the filter as being absorbed into the filter material or as a breakable capsule or as a filter remaining only separated for use with cigars, pipes and cigars without a filter. When they are used in cigars or as additives for pipe tobacco, the large quantities of the ingredients noted above can be adjusted in proportion to the amount of tobacco as compared to the amount of tobacco contained in the typical cigar.

In the most preferred embodiment of this invention the same ingredients can be provided in an aqueous solution as a breakable capsule with the following composition: 1. L-glutathione, at least 0.01% at 2.0 & more preferably from 0.05 to 1.0% by weight. 2. L-selenomethionine of at least 0.01 to 1.0%, more preferably 0.05 to 0.1% by weight. 3. L-cysteine and / or its N-acetyl-L-cysteine ester of at least 0.01% to 2%, more preferably 0.05% to 0.5% by weight for each amino acid. 4. Ascorbic acid or its esters from 0.1% to 2.0%, more preferably from 0.5% to 1.0% by weight.

. Vitamin E or one of its esters at 0.05 to 1.0%, more preferably 0.1% to 0.25% by weight. 6. Vitamin a or one of its esters at 0.1% to 10%, more preferably 0.5% to 1% by weight. 7. 7? Amino acids, taurine and / or methionine from 0.05% to 1.0%, more preferably from 0.1% to 0.5%, by weight for each amino acid.

In one embodiment of this invention, optional ingredients, particularly exogenous antioxidants, can be added to the synergist complex both in the filter and in a receptacle capsule. These free radical scavengers used as antioxidants can be used in each cigar or filter: Japanese green tea (catechis) approximately 1.0 mcg Picnogenol approximately 0.05 mg.

Superoxide Dismutase approximately 0.01 mg.

Co-enzyme Q approximately 0.25 mcgm.

N-acetyl-L-Carnitine approximately 0.01 mgm.

Other optional ingredients may be used in the tobacco or in the filter which may include those ingredients which are known to bind, or chemically alter harmful molecules, such as aldehydes found in tobacco smoke. The putative antioxidants of this invention are used to neutralize the free radicals found in tobacco as well as those generated by tobacco smoke in the oral cavity, as they are inhaled from the filter in the smoke with each puff.

Having described the invention as above, the contents of the following are declared as property:

Claims (47)

1. A composition for inclusion with a cigar, cigar or pipe tobacco for reduction of damage by free radicals for the oro-pharyngeal cavity, respiratory tract and lungs of tobacco smoke, said composition characterized because it comprises L-glutathione and a selected source of selenium from a group consisting of L-selenomethionine and L-selenocysteine.

2. The composition of claim 1 further characterized in that it comprises vitamin C as a member selected from the group consisting of ascorbyl palmitate and ascorbic acid esters.

3. The composition of claim 1 further characterized in that it comprises a member selected from the group consisting of L-cysteine and N-acetyl-L-cysteine.

4. The composition of claim 1 further characterized in that it comprises vitamin E as a member selected from the group consisting of tocopherol acetate and tocopherol succinate.

5. The composition of claim 1 further characterized in that it comprises vitamin A.

6. The composition of claim 1 further characterized in that it comprises a zinc salt.

7. The composition of claim 1 further characterized in that it comprises methionine and taurine.

8. The composition of claim 1 characterized in that said composition is included within a cigar characterized in that said L-glutathione is contained in an amount between at least 0.01 to 20 mgs and the source of selenium is contained in an amount between at least about 0.01 a 10 mcgm.

9. The composition of claim 2 for inclusion within a cigar characterized in that said vitamin C is contained in an amount between about 0.1 mgs to 60 mgs.

10. The composition of claim 3 for inclusion within a cigarette characterized in that said L-cysteine or its N-acetyl-L-cysteine ester is contained in an amount between about 0.1 mgs to 10 mgs.

11. The composition of claim 4 for inclusion within a cigar characterized in that said vitamin E is contained in an amount between 0.01 u.I. to 10.0 U.I.

12. The composition of claim 5 for inclusion within a cigar characterized in that said vitamin A is contained in an amount between 1.0 U.I. to 500 U.I.

13. The composition of claim 6 for inclusion within a cigar characterized in that said zic salt is comprised as a member selected from a group consisting of zinc acetate and zinc glutonate in an amount of about 0.1 to 15 mgs.

14. The composition of claim 7 for inclusion within a cigar characterized in that said methionine and taurine are included in amounts between about 0.5 mgs to 20 mgs.

15. A cigar comprising a wrapping paper surrounding a load of tobacco, said cigar also characterized in that it comprises a composition for reducing the damage of free radicals to the oro-pharyngeal cavity, respiratory tract and lungs of tobacco smoke generated by said cigar, said composition characterized in that it comprises L-glutathione and a source of selenium selected from the group consisting of L-selenomethin and L-selenocysteine.

16. The cigar of claim 15 further characterized in that it comprises vitamin C as a member selected from the group consisting of ascorbyl palmitate and ascorbic acid esters.

17. The cigar of claim 15 further characterized in that it comprises a member selected from the group consisting of L-cysteine and N-acetyl-L-cysteine.

18. The cigar of claim 15 further characterized in that it comprises a member selected from the group consisting of tocopherol acetate and tocopherol succinate.

19. The cigar of claim 15 further characterized in that it comprises vitamin A.

20. The cigar of claim 15 further characterized in that it comprises a zinc salt.

21. The cigar of claim 15 further characterized in that it comprises methionine and taurine.

22. The cigar of claim 15 characterized in that said composition of L-glutathione is contained with an amount between at least 0.01 to 20 mgs and the source of selenium is contained in an amount between approximately 0.01 to 10 mcgm.

23. The cigar of claim 16 characterized in that said vitamin C is contained in an amount between approximately 0.1 mgs to 60 mgs.

24. The cigar of claim 17 for inclusion within a cigarette characterized in that said L-cysteine or its N-acetyl-L-cysteine ester is contained in an amount between about 0.1 mgs to 10 mgs.

25. The cigar of claim 18 for inclusion within a cigar characterized in that said vitamin E is contained in an amount between approximately 0.01 U.I. to 10.0 U.I.

26. The cigar of claim 19 for inclusion within a cigar characterized in that said vitamin A is contained in an amount between approximately 0.01 U.I. to 500 U.I.

27. The cigar of claim 18 for inclusion within a cigar characterized in that said zinc salt is comprised as a member selected from a group consisting of zinc acetate and zinc glutonate in an amount of about 0.1 to 15 mgs.

28. The cigar of claim 21 for inclusion within a cigar characterized in that said methionine and taurine is included in amounts between about 0.5 mgs to 20 mgs.

29. A filter for smoke filtration generated by a tobacco product, said filter characterized in that it comprises a filtering material and an antioxidant composition which is disposed within said smoke as it passes through said filtration material, said composition characterized in that it comprises L-10 glutathione and a source of selenium selected from the group consisting of L-selenomethionine and L-selenocysteine.

30. The filter of claim 29 further characterized in that it comprises vitamin C as a member selected from a group consisting of ascorbyl palmitate and ascorbic acid esters.

31. The filter of claim 29 further characterized by comprising a member selected from A \ a group consisting of L-cysteine and N-acetyl-L-cysteine.

32. The filter of claim 29 further characterized in that it comprises vitamin E as a member 25 selected from a group consisting of tocopherol acetate and tocopherol succinate.

33. The filter of claim 29 further characterized in that it comprises vitamin A.

34. The filter of claim 29 further characterized in that it comprises a zinc salt.

35. The filter of claim 29 further characterized in that it comprises methionine and taurine.

36. The filter of claim 29 characterized in that said composition of L-glutathione is contained in an amount between at least 0.01 to 20 mgs and the source of selenium is contained in an amount between about 0.0. mgs to 10 m gs. 6

37. The filter of claim 30 characterized in that said vitamin C is contained in an amount between about 0.1 mgs to 60 mgs.

38. The filter of claim 31 by inclusion within a cigarette characterized in that said L-cysteine or its N-acetyl-L-cysteine ester is contained in an amount between about 0.1 mgs to 10 mgs.

39. The filter of claim 32 For inclusion within a cigar characterized in that said vitamin E is contained in an amount between approximately 0.01 U.I. to 10.0 U.I.

40. The filter of claim 33 for inclusion within a cigar characterized in that said vitamin A is contained in an amount between 1.0 U.I. to 500 U.I.

41. The filter of claim 33 for inclusion within a cigar characterized in that said zinc salt is comprised as a member selected from the group consisting of zinc acetate and zinc glutonate in an amount of about 0.1 to 15 mgs.

42. The filter of claim 35 is included within a cigarette characterized in that said methionine and taurine are included in amounts between about 0.5 mgs to 20 mgs.

43. The filter of claim 29 characterized in that said antioxidant composition is encapsulated as a member selected from a group consisting of liposomes, glycospheres and nonospheres.

44. The filter of claim 29 characterized in that said composition for reducing free radical damage is incorporated within said filter as a powder.

45. The filter of claim 29 characterized in that said composition for reducing free radical damage is incorporated within said filter as a gel.

46. The filter of claim 29 characterized in that said composition is mixed with a superabsorbent selected from the group consisting of copolymers of acrylamide and polyvinyl alcohol and grafted with maleic anhydride.

47. The filter of claim 29 characterized in that said composition for reducing free radical damage is contained within an aqueous solution in the form of a breakable capsule.