EP1309253B1 - Methods and devices for removing nucleophilic toxins from tobacco and tobacco smoke - Google Patents
Methods and devices for removing nucleophilic toxins from tobacco and tobacco smoke Download PDFInfo
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- EP1309253B1 EP1309253B1 EP00941705A EP00941705A EP1309253B1 EP 1309253 B1 EP1309253 B1 EP 1309253B1 EP 00941705 A EP00941705 A EP 00941705A EP 00941705 A EP00941705 A EP 00941705A EP 1309253 B1 EP1309253 B1 EP 1309253B1
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- tobacco
- filter
- smoke
- air
- agents
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- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
- A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
- A24D3/06—Use of materials for tobacco smoke filters
- A24D3/08—Use of materials for tobacco smoke filters of organic materials as carrier or major constituent
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- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
- A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
- A24D3/06—Use of materials for tobacco smoke filters
- A24D3/14—Use of materials for tobacco smoke filters of organic materials as additive
Definitions
- This invention relates generally to methods, devices and agents for the removal of nucleophilic toxins present in tobacco and tobacco smoke.
- Nucleophilic toxins are removed by the passage of tobacco smoke or air containing tobacco smoke through a nucleophilic toxin-removing filter device.
- Agents may also be incorporated into smoking and smokeless tobacco to prevent volatilization and absorption, respectively, of nucleophilic toxins. Dosimetry of nucleophilic tobacco combustion products is used to monitor toxin exposure.
- Tobacco smoke is a complex mixture which includes numerous chemical compounds and particulates which to a major extent are responsible for both the enjoyment of smoking and the dangers to health in so doing.
- Use of tobacco products, especially smoking, is associated with increased incidence of lung and other types of cancer, emphysema, and cardiovascular disease. Less lethal adverse effects such as tooth discoloration and facial wrinkling also occur.
- the purported addictive component nicotine, compounds responsible for flavor, and those either proven harmful or believed to be harmful to human health are the purported addictive component nicotine, compounds responsible for flavor, and those either proven harmful or believed to be harmful to human health.
- Tobacco smoke contains chemical toxins such as carbon monoxide and hydrogen cyanide, and known carcinogens such as formaldehyde and hydrazine. Specific compounds in tobacco smoke may fall into more than one of these categories, such as those responsible for flavor. Methods for reducing the exposure of smokers to these toxic compounds without affecting the flavor of smoke have been sought for many decades.
- a porous filter is provided as a first line trap for harmful components, interposed between the smoke stream and the mouth.
- This type of filter often composed of cellulose acetate, both mechanically and by adsorption, traps a certain fraction of the tar present in smoke.
- This type of filter is present on most cigarettes available, yet it allows a significant amount of harmful compounds to pass into the mouth.
- Epidemiological data connects use of filtered cigarettes with adverse health effects.
- U.S. Patent 5,076,294 provides a filter element containing an organic acid, such as citric acid, which reduces the harshness of the smoke.
- a significant body of art focuses on removing formaldehyde, a prevalent component of tobacco smoke with an established and adverse toxicological profile.
- U.S. Patent 4,300,577 describes a filter comprising an absorptive material plus an amine-containing component which removes aldehydes and hydrogen cyanide from tobacco smoke.
- Patent 5,009,239 describes a filter element treated with polyethyleneimine modified with an organic acid, to remove aldehydes from tobacco smoke.
- U.S. Patent 5,850,840 describes the stabilizing of early glycosylation products in tobacco and tobacco smoke by reaction with compounds such as acetaldehyde.
- U.S. Patent 4,246,910 describes a filter impregnated with alkali ferrate compounds, or activated carbon or alumina impregnated with potassium permanganate, for removing hydrogen cyanide from tobacco smoke.
- Patent 5,060,672 also describes a filter for specifically removing aldehydes, such as formaldehyde, from tobacco smoke by providing a combination of an enediol compound, such as dihydroxyfumaric acid or L-ascorbic acid, together with a radical scavenger of aldehydes, such as oxidized glutathione or urea, or a compound of high nucleophilic activity, such as lysine, cysteine, 5,5-dimethyl-1,3-cyclohexanedione, or thioglycolic acid.
- U.S. Patent 5,706,833 describes a wet-disintegrable filter rod comprising certain water-soluble polymers which serve as disintegrable adhesives.
- US Patent 5 850 840 describes a filter for removing advanced glycolisation end-products from tobacco smoke.
- nucleophile and nucleophilic refer to a negative ion or neutral molecule, such as an amino group or primary or secondary amine, that brings an electron pair into a chemical reaction with another molecule or positive ion, called an electrophile, which is capable of accepting the electron pair, such as an active carbonyl group.
- Nucleophilic compounds will chemically react with compounds bearing active carbonyl groups, such as aldehydes, anhydrides, activated ketones, and active esters.
- Smokeless tobacco includes tobacco products which are used by methods other than smoking, for instance, as snuff and chewing tobacco. Toxic products present in tobacco also enter the body by these methods of using tobacco which do not involve combustion, and these products are also associated with numerous adverse sequelae of tobacco use.
- nucleophilic compounds incorporated in a filter were used to trap aldehyde-type toxins in tobacco smoke
- the nucleophilic toxins present in tobacco and tobacco smoke may be removed from tobacco and tobacco smoke by agents, or filters derivatized with chemical moieties comprising these agents, which chemically trap nucleophilic compounds.
- Tar, mutagens, and known carcinogens present in tobacco and tobacco smoke may be effectively removed by these agents or filters comprising these agents which chemically traps nucleophilic toxins.
- agents which trap nucleophilic toxins may be incorporated into air filters to remove tobacco-derived toxins from room air, to reduce exposure to second-hand (sidestream) smoke.
- the invention described herein provides a method for reducing the level of nucleophilic toxins present in tobacco or in mainstream and/or sidestream tobacco smoke by incorporating agents into the tobacco or passing the tobacco smoke through a filter element comprising agents which chemically react with and trap nucleophilic compounds present in tobacco combustion products.
- the agents may be admixed with smoking or smokeless tobacco.
- the filter element may comprise a porous filter matrix wherein the filter matrix bears chemical substituents which trap nucleophiles, or the filter may comprise a porous matrix and one or more agents that chemically trap nucleophiles.
- Agents with low vapor pressures and high melting points, such as insoluble, polymeric agents, are preferred for use in a smoking device filter.
- nucleophile-trapping agents of the present invention may comprise or be incorporated into air filters for removing tobacco combustion product toxins from room air.
- Non-limiting examples of the types of agents that may be added to tobacco, or that comprise or may be incorporated into the filter of the present invention which traps nucleophiles include compounds belonging to the classe of aldehydes.
- the methods, agents and devices of the present invention while removing toxic nucleophilic compounds from tobacco and tobacco smoke, preferably do not detract from the flavor of the tobacco product.
- the agents and devices of the present invention may be used with cigarettes, cigars, pipes, as well as in the form of separate filters placed between the tobacco source and the mouth. Removal of toxic nucleophilic compounds from mainstream and sidestream smoke are aspects of the invention.
- suitable agents will trap nucleophiles present in the tobacco or formed during burning, and not release them when the agent itself burns, during, for example, the smoking of a cigarette.
- Agents incorporated into smokeless tobacco must be of acceptable low toxicity and stability to achieve the trapping of nucleophilic toxins while present within the oral cavity or other routes of exposure.
- Filters for use in tobacco smoking devices such as cigarettes or separate cigarette filters are contemplated, as well as filters for use in air treatment or filtration systems through which room or ambient air is actively or passively exposed, to remove nucleophilic toxins therefrom.
- filters may range in size from the filter of a cigarette to replaceable filters for commercial or industrial air handling systems.
- Suitable filter matrices bearing substituents that may trap nucleophiles may include periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose; or other polymers, resins or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties.
- a porous filter element such as a cigarette filter may be prepared which comprises an agent capable of trapping nucleophilic toxins present in tobacco smoke.
- Non-limiting example of aldehyde compounds that may be used as the agent in the porous filter or tobacco additive of the present invention include dialdehyde starch, dialdehyde cellulose, adenosine dialdehyde, inosine dialdehyde, O-phthaldialdehyde, aldehyde agarose, and ethylenedioxybis(3-benzaldehyde). Dialdehyde starch is preferred.
- the device may comprise a porous filter matrix wherein the filter matrix bears chemical substituents which trap nucleophiles, or the filter may comprise a porous matrix and one or more agents that chemically trap nucleophiles.
- Agents with low vapor pressures and high melting points, such as insoluble, polymeric agents, are preferred for use in a smoking device.
- the types of agents that is used in the filter of the present invention include compounds belonging to the classe of aldehydes. Non-limiting examples of agents capable of chemically reacting with and trapping nucleophilic compounds present in tobacco smoke are recited above. Passage of tobacco smoke through the device mechanically and adsorptively removes compounds and particulates, and the agent or moieties chemically react with and trap nucleophilic compounds present in the tobacco smoke.
- Suitable filter matrices bearing substituents or moieties that may trap nucleophiles include periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose; or other polymers or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties.
- Agents with low vapor pressures and high melting points, such as insoluble, polymeric agents, are preferred.
- Non-limiting examples of the types of agents that may be used in the filter of the present invention include compounds belonging to the classe of aldehydes. Non-limiting examples of suitable compounds are recited above.
- Human carcinogens include benzene, 2-naphthylamine, 4-aminobiphenyl, and the radioactive element polonium-210.
- Probable human carcinogens include such compounds as formaldehyde, hydrazine, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyzrolidine, benzo[a]pyrene, N-nitrosodiethanolamine, and cadmium.
- Reduction in exposure of individuals to toxic compounds present in tobacco and tobacco smoke may be achieved by the agents and device of the present invention at several points along the route from the tobacco itself to the point of exposure by the individual.
- Agents may be added to or blended into the tobacco itself, either smoking or smokeless tobacco, which bind and sequester toxins, not permitting them to be leached or absorbed from the smokeless tobacco or not permitting them to be volatilized into the smoke as the tobacco burns.
- a second stage of intervention is in removing toxic products from the smoke stream. This may be achieved to some extent by toxin-sequestering agents added to the tobacco itself, which before burning act as a filter.
- a filter placed between the column of combusting tobacco and the mouth, or in a separate device, through which the smoke passes before entering the body.
- present filters remove particulates, tar, and other components from the smoke.
- exhaled tobacco smoke or sidestream smoke produced from the burning smoking device and present in the environment may be filtered of toxins by passing ambient room air through or in contact with a material or filter which removes toxins.
- porous, fibrous smoke filters remove a portion of these toxic compounds by mechanical trapping and adsorption to the fibrous surface. Nevertheless, toxic compounds remain in the inhaled smoke and contribute to enormous morbidity and mortality, mainly lung and other cancers, other lung diseases such as emphysema, and cardiovascular disease including heart attack and stroke. Numerous theories exist relating various pathophysiological disease processes with specific tobacco smoke components. It is apparent from this body of work that tobacco smoke contains toxins which are incompatible with health, and that reduction of the exposure to the body of these toxins is prudent.
- a significant reduction in the level of mutagens and tar present in tobacco smoke may be achieved without reduction in enjoyment of the product by the use of a filter which in addition to providing a mechanical porous barrier, also traps nucleophilic compounds present in tobacco smoke.
- Nucleophilic compounds present in tar and tobacco smoke include hydrazine and the aromatic amines 4-aminobiphenyl, 2-naphthylamine, and aniline, among other compounds.
- the aforementioned smoke components are known mutagens and known or suspected carcinogens.
- Filter materials capable of trapping nucleophilic toxins from tobacco smoke include a filter in which the filter matrix material bears nucleophile-trapping groups, such as aldehydic groups; alternately, one or more agents capable of trapping nucleophiles may be incorporated into the filter matrix.
- These toxins may also be removed by incorporating suitable nucleophile-trapping agents directly into the tobacco, and furthermore, these toxins may be removed from smokeless tobacco products by incorporating suitable nucleophile-trapping agents in the smokeless tobacco product.
- nucleophilic-trapping methods, agents and devices of the present invention which for example comprise aldehydic groups on a filter material, from the significant body of prior art in which electrophilic substances, such as aldehydes, were desirably removed from tobacco smoke by filters comprising nucleophiles.
- the present invention is essentially the reverse of the prior art.
- aldehydes in smoke were trapped by amino groups in or on filters; in the present invention, amines in the tobacco smoke are trapped by aldehydes in or on the filters.
- Suitable filter matrices bearing substituents that may trap nucleophiles may include periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose; or other polymers, resins or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties.
- periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose or other polymers, resins or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties.
- Suitable compounds for incorporation directly into smoking and smokeless tobacco products comprise those suitable for the intended purpose.
- suitable agents must have a toxicological profile compatible with the extent of exposure to the individual, and furthermore not interfere with the taste, flavor, or enjoyment of the product.
- Compounds should be of low toxicity and preferably not absorbed.
- the agents For incorporation into smoking tobacco to sequester nucleophilic toxins in the tobacco and that formed upon burning, the agents must not interfere with the flavor or enjoyment of the product, the rate of combustion of the smoking product either during or between inhalation, and not release the sequestered toxin when the agent within the tobacco is burned.
- Nucleophile-binding agents present in the tobacco act in part like a porous filter material for smoke passing through the as-yet unburned portion of the tobacco column.
- the presence of the toxin-removing material should not interfere with the draw, or resistance to passage of air and smoke, through the tobacco column or filter.
- Non-limiting examples of aldehyde compounds that may be used in the present invention include dialdehyde starch, dialdehyde cellulose, adenosine dialdehyde, inosine dialdehyde, O-phthaldialdehyde, aldehyde agarose, and ethylenedioxybis(3-benzaldehyde).
- Polymeric aldehyde compounds are preferred; of these, dialdehyde starch is preferred.
- the foregoing agents may be prepared in various forms for incorporation into the filter element of the devices of the invention and for use in the methods of the invention. Such forms do not detract from the ability of the agents to bind nucleophilic toxins from tobacco smoke, but permit more facile manufacture of a suitable filter. Numerous methods known to one of skill in the art may be used to prepare the agent in a form suitable for incorporation into a filter, one non-limiting example being a granularized material prepared by comminution of a dried, extruded paste prepared from the agent, such as dialdehyde starch, and a binder, such as cornstarch. Alternate binding agents may include dialdehyde starch itself.
- aldehydes Prior uses of aldehydes in tobacco smoking articles has been limited to the inclusion of aldehyde compounds as aroma or flavor modifiers.
- the compounds n-hexenal, n-octanal, n-nonenal, n-decanal, n-tetradecanal, n-heptanal, n-undecanal, and n-dodecanal were incorporated into the tobacco or filter material in accordance with U.S. Patent 4,627,449, in order to improve the aroma and taste of the tobacco smoke and particularly the aroma of sidestream smoke, i.e., the smoke which passes from the burning tobacco directly to the environment.
- These compounds are volatilized from the tobacco into the smoke to mask the adverse odors of burning cigarettes. Their vapor pressures make them unsuitable for use in the present invention as they would be volatilized and lost from the filter and unable to trap nucleophiles from tobacco smoke.
- dialdehyde starch Also known as oxidized starch or polymeric dialdehyde, it is prepared by the periodate oxidation of starch, which produces free aldehyde groups that may react with nucleophiles such as alcohols, amines, hydrazines, hydrazides, and other reagents that condense with aldehydes.
- Dialdehyde starch may be obtained from any of a number of chemical suppliers, such as Sigma Chemical Company (Catalog No. P9265) or a manufacturer, Monomer-Polymer & Dajac Laboratories, Inc.
- Dialdehyde starch has been used previously for other applications, such as for increasing the wet strength of paper, such as tissue paper; for hardening gelatin; for making water-resistant adhesives; and for tanning leather.
- dialdehyde starch has been used to aid in the attachment of proteins to polymer surfaces, by chemically reacting with hydroxyl groups of a polymer film. It was further used directly as a polymer surface-modifying agent in U.S. Patents 5,281,660 and 5,563,215 to enable biologically active molecules and subsequently cells to bind to the modified surface without altering the biological properties of the molecules.
- Moderate heat treatment 50°C to 150°C was necessary in order for the dialdehyde starch to bind to the polymer surface.
- agents suitable for the practice of the present invention may be selected from polymers such as agarose (e.g. SEPHAROSE(R)), cellulose, chitosan, dextran (e.g., SEPHADEX(R)), polyvinylpyrrolidone, and the like, which may be chemically derivatized to provide free nucleophile-trapping groups.
- agarose may be derivatized to contain N-hydroxysuccinimidyl groups, such as Sigma Chemical Co. Catalog No. H8635, N-hydroxysuccinimidyl-activated SEPHAROSE(R) or Catalog No. A9019, 6-aminohexanoic acid N-hydroxysuccinimide ester coupled to SEPHAROSE(R).
- Aldehyde-agarose (Sigma Chemical Co. Catalog No. A9951) may also be used; one method of preparation involves derivatization of agarose with 4-aminobutyraldehyde diethyl acetal, and subsequent mild acid hydrolysis of the acetal to generate the aldehyde (Korpela and Hinkkanen, 1976, Analytical Biochem. 71:322-323).
- insoluble polymers recited above may also be used directly as the filter material of the present invention.
- the device of the present invention may be prepared by any one of several methods known to the skilled artisan wherein the toxin-removing agent or agents are incorporated into an air filter or tobacco smoke filter at any of a number of stages in the manufacturing process.
- an agent or agent so the present invention may be mixed with the raw material comprising the mechanical filter and then co-extruded or spun to form fibers comprising filter material and the toxin-removing agent, which may then be made into filters.
- extruded or spun fibers comprising the filter material may be coated with a molten agent or agents of the present invention, or a solution of the agent or agents in a suitable solvent, prior to the manufacture of the filters.
- the agent may be dissolved or suspended in a plasticizer and they sprayed onto the filter fibers.
- the filter devices of the present invention may be prepared from existing mechanical filters by preparing a solution or suspension of the agent or agents in a solvent, absorbing the solvent into the porous filter material, and then removing the solvent by evaporation, drying, freeze-drying, lyophilization, critical point drying, or another suitable method.
- the filter material would retain its mechanical properties as a barrier to particulate materials and an extensive surface to which tar may be adsorbed.
- an agent of the invention may be prepared in a granular form for incorporation into the filter of a smoking device. Binding agents such as cornstarch or gum arabic may be used to aid in the preparation of granules.
- dialdehyde starch is used as the nucleophilic-toxin-trapping agent
- dialdehyde starch itself may be used as the binder to granulate dialdehyde starch in an active nucleophilic-toxin-trapping form.
- the filter material itself for example, cellulose acetate
- the filter material itself, for example, cellulose acetate
- cellulose acetate may be prepared and chemically derivatized to contain aldehyde groups, following standard methods.
- cellulose may be partially acetylated or a certain percentage of the acetate groups on cellulose acetate may be hydrolyzed by treatment at high pH. The resulting partially-acetylated cellulose then may be subjected to periodate oxidation.
- the cellulose acetate may retain its fibrous and porous filter characteristics while also bearing aldehyde substituents capable of trapping nucleophilic toxins in tobacco smoke.
- Other polysaccharides with filter-like properties such as cellulose, agarose, and the like may also be periodate treated to produce free aldehyde groups.
- the filter material will retain its mechanical filtration properties, by providing a mechanical barrier and extensive surface area to which tar may be adsorbed, in addition to its nucleophile-binding activity.
- air filters available for these systems to filter particulates and other air contaminants may be prepared which also contain an agent or agents of the present invention; alternatively the filter material itself may be derivatized or be prepared from an agent of the present invention, such that the air filter retains its mechanical filtration properties and in addition has the ability to remove nucleophilic toxins from the air.
- Similar filters or replaceable filter cartridges may be prepared for smaller units, such as those used to filter or purify the air in a single room or shared air space, automobile, bus, train, car, aircraft passenger compartments, racetracks, gambling and off-track betting parlors, bars, saloons, and similar areas in which tobacco products, especially smoking tobacco products, are used, and in some instances in which exposure to sidestream smoke is of particular concern to nonsmokers present therein.
- a personal air filtration system similar in construction to a gas mask or face mask, may also be prepared using a filter device of the present invention, for individuals in proximity to such areas but seeking personal protection from the harmful effects of sidestream smoke.
- the filter agent of the present invention would not be expected to remove aldehydes from tobacco smoke, such as formaldehyde, unless the compounds also possess a group which may be trapped by an aldehyde.
- trapping of amines by the filter agent of the present invention may produce new functional groups which may then be capable of absorbing, trapping, and chemically inactivating aldehydes and nitrosamines.
- Cigarette smoke was filtered through 250 mg portions of each of the compounds listed in Table I. In order to achieve adequate draw with filters made from dialdehyde starch and oxidized starch, these compounds were deposited onto cellulose acetate fibers which had been spread out into swatches 0.64-7.6 cm (0.25 by 3 inches). The treated fibers were then dried overnight at 37 C. The smoke from one cigarette was drawn through the filter material and then through 3 mls of distilled water using a water-pipe smoking device which was constructed from a 25 ml glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min.
- cellulose acetate filter fibers were spread out into a swatch 0.64 cm by 7.6 cm (0.25 inches by 3 inches) and then coated with the following amounts of dialdehyde starch suspended in distilled water: 250 mg, 125 mg, 25 mg and 0 mg. The treated fibers were dried at 37 C overnight and then made into a tobacco cigarette using a tube cigarette maker.
- the smoke from 1 of each type of filter cigarette was then drawn through 3 mls of distilled water using a water-pipe smoking device which was constructed from a small (25 ml) glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min. Three 100 microliter aliquots were removed from each flask, placed into ELISA plated wells and read in an ELISA plate reader at 405 nm.
- Cellulose acetate filter fibers were spread out into a swatch 0.25 inches by 3 inches and then coated with the following amounts of dialdehyde starch suspended in distilled water: 250 mg, 125 mg, 100 mg, 50 mg, 25 mg and 0 mg.
- the treated fibers were dried in a 37 C oven overnight and then made into a tobacco cigarette using a tube cigarette maker.
- the smoke from five of each type of filter cigarette was then drawn through 5 mls of acetone using a water-pipe smoking device which was constructed from a small (25 ml) glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min.
- Figure 2 indicates that filters containing an agent of the present invention can remove over 90% of the tar from both "light” and “regular” tobaccos. If over 250 mg/filter is used, tar is still removed, but the "drag" may be judged too difficult by the typical smoker.
- Dialdehyde starch was prepared in granular form using various binders, examples of which are described below.
- Cellulose acetate filters were spread out into swatches of 0.25 inches by 3 inches and then coated with 250 mg or 0 mg of dialdehyde starch suspended in distilled water. The treated fibers were then dried in a 37°C oven overnight and then made into a tobacco cigarette. The smoke from 2 of each type of cigarette was drawn into 1 ml of Phosphate Buffered Saline and the placed immediately on ice. Each sample was then applied to ELISA plate wells coated with 5% non-fat milk (100 microliters/well). Plates were incubated for 3 days @ 37°C and then washed four times with 0.05% Tween/PBS. Pigments which remained bound to the wells were then solubilized in 100 microliters DMSO. Absorbance was then read at 405 nm. Results in Figure 4 show the average of three wells ⁇ standard deviation.
- a bacterial mutagenicity assay was performed as described by Ames et al. (Maron DM and Ames BN. 1983. Revised methods for the Salmonella mutagenicity assay. Mutation Research 113:173-215). Briefly, Salmonella strain TA98 was cultured overnight at 37 C in Oxoid nutrient broth #2, incubated with serial dilutions of cigarette smoke condensate from the following filter cigarettes: 250 mg dialdehyde starch/filter, 125 mg dialdehyde starch/filter, and 0 mg/filter diluted in 0.1 M sodium phosphate, pH 7.4 containing 33 mM KC1, 8 mM MgC1 2 , 5 mM glucose-6-phosphate, 500 micromolar NADP and rat liver S9 microsomal nucleases, in triplicate for 30 minutes at 37 C.
- Tester strain TA 98 detects frameshift mutations, such as those generated by aromatic primary amines. Mutagens in the sample are detected as the number of bacteria induced to revert to their wild-type phenotype.
- Figure 5 shows that increasing amounts of dialdehyde starch present in the cigarette filter result in a decrease in the mutagenicity of the smoke extract. Using the 250 mg filter, the number of revertants was no different than the negative control.
- Cellulose acetate filter fibers were spread out into a swatch 0.25 inches by 3 inches and then coated with 250 mg of dialdehyde starch suspended in distilled water. The treated fibers were dried at 37 C overnight and then made into a tobacco cigarette using a tube cigarette maker. The smoke from one of each type of filter cigarette was then drawn through 3 mls of distilled water using a water-pipe smoking device which was constructed from a small (25 ml) glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min.
- Figure 6 shows that 250 mg of the agent of the present invention diminished the level of nitrosamines in the tobacco smoke extract by several fold.
- a double-blind taste test was performed on 12 individuals in an office environment in a large city. The subjects were asked to fill out a brief questionnaire inquiring about their age, years of smoking, daily usage and preferred brand. After answering these questions, the subjects then lit two cigarettes, one with the filter of the present invention comprising dialdehyde starch, and one with a regular filter. As they smoked the cigarettes side by side, they were asked to record which cigarette was preferred and to describe any differences perceived between the two.
- the average age of the participants was 41 years, average duration of smoking 18.4 years, and each smoked on average 25.7 cigarettes per day. Eight of the twelve participants preferred the test cigarette with the dialdehyde starch filter over the control cigarette, and four individuals did not prefer one cigarette over the other.
- Cigarettes with cellulose acetate filters or with filters comprising an agent of the present invention were evaluated an independent laboratory for total particulate matter, nicotine, tar, water and carbon monoxide, according to the standardized FTC method.
- the cigarettes tested were made by treating cellulose acetate filters with 250 mg dialdehyde starch (DAS) in distilled water ("DAS Filter Cigarettes”). The treated fibers were dried overnight and incorporated into cigarettes using a tube cigarette maker.
- DAS Filter Cigarettes 250 mg dialdehyde starch
- the treated fibers were dried overnight and incorporated into cigarettes using a tube cigarette maker.
- two types of control cigarettes were run: the standard "Kentucky Reference” cigarettes (provided by Lab Stat, Kitchener, Ontario, Canada) and "Ordinary Cigarettes" which were constructed in the laboratory of the inventors.
- Cigarettes were constructed the same way as the filter cigarettes of the invention and they contain the same amount of tobacco and cellulose acetate fibers, but do not contain the filter additive.
- Results shown indicate that 58% of this group of smokers thought the DAS filtered cigarette was a regular cigarette, 33% thought it was a light cigarette and 8% thought it was an ultralight cigarette. Taken together the taste test results demonstrate that the DAS filtered cigarettes not only taste like ordinary cigarettes (unlike other "safer” cigarettes), but are also preferred by smokers.
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Abstract
Description
- This invention relates generally to methods, devices and agents for the removal of nucleophilic toxins present in tobacco and tobacco smoke. Nucleophilic toxins are removed by the passage of tobacco smoke or air containing tobacco smoke through a nucleophilic toxin-removing filter device. Agents may also be incorporated into smoking and smokeless tobacco to prevent volatilization and absorption, respectively, of nucleophilic toxins. Dosimetry of nucleophilic tobacco combustion products is used to monitor toxin exposure.
- Tobacco smoke is a complex mixture which includes numerous chemical compounds and particulates which to a major extent are responsible for both the enjoyment of smoking and the dangers to health in so doing. Use of tobacco products, especially smoking, is associated with increased incidence of lung and other types of cancer, emphysema, and cardiovascular disease. Less lethal adverse effects such as tooth discoloration and facial wrinkling also occur. Among the many compounds present in tobacco smoke are the purported addictive component nicotine, compounds responsible for flavor, and those either proven harmful or believed to be harmful to human health. Tobacco smoke contains chemical toxins such as carbon monoxide and hydrogen cyanide, and known carcinogens such as formaldehyde and hydrazine. Specific compounds in tobacco smoke may fall into more than one of these categories, such as those responsible for flavor. Methods for reducing the exposure of smokers to these toxic compounds without affecting the flavor of smoke have been sought for many decades.
- The harmful effects of tobacco use, and principally cigarette smoking, derive from the delivery to the body of toxic compounds present in tobacco and volatilized during its combustion, as well as those formed as a result of combustion. These include gaseous compounds, such as carbon monoxide, hydrogen cyanide, ammonia, and formaldehyde, and others that are volatilized in tobacco smoke, such as benzene, acrolein, hydrazine, and aniline. Collectively, the material which may be condensed from tobacco smoke is known as tar. Several compounds in smoke and tar are classified as carcinogens: benzene, 2-naphthylamine, 4-aminobiphenyl, and the radioactive element polonium-210. Others are considered probable human carcinogens, such as formaldehyde, hydrazine, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, benzo[a]pyrene, N-nitrosodiethanolamine, and cadmium. Further compounds in tobacco smoke have been proven to be animal carcinogens. While the carcinogenic potential of these tobacco smoke components has never been tested directly in humans, a cause-and-effect relationship between smoking and the aforementioned adverse effects has been strongly established through epidemiologic studies.
- Numerous methods and devices to reduce or remove toxic components from tobacco and tobacco have been proposed and constructed. In general, a porous filter is provided as a first line trap for harmful components, interposed between the smoke stream and the mouth. This type of filter, often composed of cellulose acetate, both mechanically and by adsorption, traps a certain fraction of the tar present in smoke. This type of filter is present on most cigarettes available, yet it allows a significant amount of harmful compounds to pass into the mouth. Epidemiological data connects use of filtered cigarettes with adverse health effects.
- An improvement in the effectiveness afforded by a mechanical-type filter such as those described above may be provided by including means for chemically trapping disagreeable and harmful components present in smoke. For example, U.S. Patent 5,076,294 provides a filter element containing an organic acid, such as citric acid, which reduces the harshness of the smoke. A significant body of art focuses on removing formaldehyde, a prevalent component of tobacco smoke with an established and adverse toxicological profile. U.S. Patent 4,300,577 describes a filter comprising an absorptive material plus an amine-containing component which removes aldehydes and hydrogen cyanide from tobacco smoke. U.S. Patent 5,009,239 describes a filter element treated with polyethyleneimine modified with an organic acid, to remove aldehydes from tobacco smoke. U.S. Patent 5,850,840 describes the stabilizing of early glycosylation products in tobacco and tobacco smoke by reaction with compounds such as acetaldehyde. U.S. Patent 4,246,910 describes a filter impregnated with alkali ferrate compounds, or activated carbon or alumina impregnated with potassium permanganate, for removing hydrogen cyanide from tobacco smoke. Control of the delivery of tar, nicotine, formaldehyde and total particulate matter was afforded by a filter element containing zinc thiocyanate, sarcosine hydrochloride, zinc chloride, ferrous bromide, lithium bromide, or manganese sulfate, as describe in U.S. Patent 4,811,745. Inclusion of L-ascorbic acid in a filter material to remove aldehydes is disclosed in U.S. Patent 4,753,250. U.S. Patent 5,060,672 also describes a filter for specifically removing aldehydes, such as formaldehyde, from tobacco smoke by providing a combination of an enediol compound, such as dihydroxyfumaric acid or L-ascorbic acid, together with a radical scavenger of aldehydes, such as oxidized glutathione or urea, or a compound of high nucleophilic activity, such as lysine, cysteine, 5,5-dimethyl-1,3-cyclohexanedione, or thioglycolic acid. U.S. Patent 5,706,833 describes a wet-disintegrable filter rod comprising certain water-soluble polymers which serve as disintegrable adhesives.
- US
Patent 5 850 840 describes a filter for removing advanced glycolisation end-products from tobacco smoke. - As used throughout this application, the terms nucleophile and nucleophilic refer to a negative ion or neutral molecule, such as an amino group or primary or secondary amine, that brings an electron pair into a chemical reaction with another molecule or positive ion, called an electrophile, which is capable of accepting the electron pair, such as an active carbonyl group. Nucleophilic compounds will chemically react with compounds bearing active carbonyl groups, such as aldehydes, anhydrides, activated ketones, and active esters.
- Smokeless tobacco includes tobacco products which are used by methods other than smoking, for instance, as snuff and chewing tobacco. Toxic products present in tobacco also enter the body by these methods of using tobacco which do not involve combustion, and these products are also associated with numerous adverse sequelae of tobacco use.
- Contrary to the above-cited prior art in which nucleophilic compounds incorporated in a filter were used to trap aldehyde-type toxins in tobacco smoke, it has been discovered that the nucleophilic toxins present in tobacco and tobacco smoke may be removed from tobacco and tobacco smoke by agents, or filters derivatized with chemical moieties comprising these agents, which chemically trap nucleophilic compounds. Tar, mutagens, and known carcinogens present in tobacco and tobacco smoke may be effectively removed by these agents or filters comprising these agents which chemically traps nucleophilic toxins.
- Furthermore, agents which trap nucleophilic toxins may be incorporated into air filters to remove tobacco-derived toxins from room air, to reduce exposure to second-hand (sidestream) smoke.
- The invention described herein provides a method for reducing the level of nucleophilic toxins present in tobacco or in mainstream and/or sidestream tobacco smoke by incorporating agents into the tobacco or passing the tobacco smoke through a filter element comprising agents which chemically react with and trap nucleophilic compounds present in tobacco combustion products. The agents may be admixed with smoking or smokeless tobacco. The filter element may comprise a porous filter matrix wherein the filter matrix bears chemical substituents which trap nucleophiles, or the filter may comprise a porous matrix and one or more agents that chemically trap nucleophiles. Agents with low vapor pressures and high melting points, such as insoluble, polymeric agents, are preferred for use in a smoking device filter. Furthermore, the nucleophile-trapping agents of the present invention may comprise or be incorporated into air filters for removing tobacco combustion product toxins from room air. Non-limiting examples of the types of agents that may be added to tobacco, or that comprise or may be incorporated into the filter of the present invention which traps nucleophiles include compounds belonging to the classe of aldehydes.
- The methods, agents and devices of the present invention, while removing toxic nucleophilic compounds from tobacco and tobacco smoke, preferably do not detract from the flavor of the tobacco product. The agents and devices of the present invention may be used with cigarettes, cigars, pipes, as well as in the form of separate filters placed between the tobacco source and the mouth. Removal of toxic nucleophilic compounds from mainstream and sidestream smoke are aspects of the invention.
- For incorporation into smoking tobacco, suitable agents will trap nucleophiles present in the tobacco or formed during burning, and not release them when the agent itself burns, during, for example, the smoking of a cigarette. Agents incorporated into smokeless tobacco must be of acceptable low toxicity and stability to achieve the trapping of nucleophilic toxins while present within the oral cavity or other routes of exposure.
- Filters for use in tobacco smoking devices such as cigarettes or separate cigarette filters are contemplated, as well as filters for use in air treatment or filtration systems through which room or ambient air is actively or passively exposed, to remove nucleophilic toxins therefrom. Such filters may range in size from the filter of a cigarette to replaceable filters for commercial or industrial air handling systems.
- Suitable filter matrices bearing substituents that may trap nucleophiles may include periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose; or other polymers, resins or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties. Alternatively, a porous filter element such as a cigarette filter may be prepared which comprises an agent capable of trapping nucleophilic toxins present in tobacco smoke.
- Non-limiting example of aldehyde compounds that may be used as the agent in the porous filter or tobacco additive of the present invention include dialdehyde starch, dialdehyde cellulose, adenosine dialdehyde, inosine dialdehyde, O-phthaldialdehyde, aldehyde agarose, and ethylenedioxybis(3-benzaldehyde). Dialdehyde starch is preferred.
- It is another object of the present invention to provide a device for reducing the levels of nucleophilic toxins present in tobacco smoke. The device may comprise a porous filter matrix wherein the filter matrix bears chemical substituents which trap nucleophiles, or the filter may comprise a porous matrix and one or more agents that chemically trap nucleophiles. Agents with low vapor pressures and high melting points, such as insoluble, polymeric agents, are preferred for use in a smoking device. The types of agents that is used in the filter of the present invention include compounds belonging to the classe of aldehydes. Non-limiting examples of agents capable of chemically reacting with and trapping nucleophilic compounds present in tobacco smoke are recited above. Passage of tobacco smoke through the device mechanically and adsorptively removes compounds and particulates, and the agent or moieties chemically react with and trap nucleophilic compounds present in the tobacco smoke.
- It is a further object of the present invention to provide a filter material which is capable of reducing the level of nucleophilic toxins present in tobacco smoke passing through the filter, the filter matrix bearing chemical substituents which trap nucleophiles. Suitable filter matrices bearing substituents or moieties that may trap nucleophiles include periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose; or other polymers or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties.
- It is yet another object of the present invention to provide an agent that can chemically trap nucleophilic toxins present in tobacco smoke and may be included in a porous filter matrix. Agents with low vapor pressures and high melting points, such as insoluble, polymeric agents, are preferred. Non-limiting examples of the types of agents that may be used in the filter of the present invention include compounds belonging to the classe of aldehydes. Non-limiting examples of suitable compounds are recited above.
- It is yet a further object of the invention to provide reduction in exposure of individuals to the toxic components in tobacco and tobacco smoke without reducing the enjoyment of using the tobacco products.
- These and other aspects of the present invention will be better appreciated by reference to the following drawings and Detailed Description.
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- FIGURE 1 is a graph depicting a dose response of the removal of tar, measured colorimetrically, from cigarette smoke by an agent and device of the present invention.
- FIGURE 2 is a graph depicting a dose response of the removal of tar, measured gravimetrically, from smoke from two different types of cigarettes by an agent and device of the present invention.
- FIGURE 3 depicts the removal of tar by a formulation of an agent of the present invention in the form of granules.
- FIGURE 4 depicts the removal of staining pigments from tobacco smoke by an agent and device of the present invention.
- FIGURE 5 depicts a dose response of the removal of mutagens from tobacco smoke by an agent and device of the present invention.
- FIGURE 6 depicts the removal of nitrosamines from tobacco smoke by an agent and device of the present invention.
- Of the numerous components heretofore identified in tobacco believed to contribute to the adverse consequences of smoking, direct toxins, human carcinogens, mutagens, probable human carcinogens and proven animal carcinogens are present. Human carcinogens include benzene, 2-naphthylamine, 4-aminobiphenyl, and the radioactive element polonium-210. Probable human carcinogens include such compounds as formaldehyde, hydrazine, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyzrolidine, benzo[a]pyrene, N-nitrosodiethanolamine, and cadmium. Further compounds in tobacco smoke have been proven to be animal carcinogens, including benz[a]anthracene, butyrolactone and N-nitrosonornicotine. Many of the aforementioned compounds are also directly toxic to cells in the body. While the toxicologic, mutagenic and carcinogenic potential of these tobacco smoke components has never been tested by direct experimentation in humans, a strong cause-and-effect relationship between smoking and adverse effects has been established epidemiologically.
- Although smoking of tobacco, principally cigarette smoking, but also including cigar and pipe smoking, is strongly linked epidemiologically to the aforementioned adverse sequelae, exposure to smokeless tobacco products, including chewing tobacco and snuff, also carries a risk of developing adverse health effects. Furthermore, smokers are principally exposed to what is termed "mainstream" smoke, i.e, that which is inhaled from the smoking device. However, recent studies have implicated exposure of nonsmoking individuals to what is termed "sidestream" smoke, that which arises from the smoking device itself, with adverse effects. The latter exposure has led to significant concern that individuals breathing "second-hand" smoke are at risk for developing the same adverse health consequences that typify smokers. Methods of removing toxic components from tobacco and especially tobacco smoke, from mainstream and sidestream smoke, are desirable in reducing the excessive health care costs associated with the consequences of tobacco and tobacco smoke exposure.
- Reduction in exposure of individuals to the toxic components in tobacco and tobacco smoke is desirable, without reducing the enjoyment of using the tobacco products. While the removal or retention of nicotine is not a feature of the instantly-claimed methods or devices, in one embodiment of the invention, retention of some or all of the nicotine content of the smoke is desired.
- Reduction in exposure of individuals to toxic compounds present in tobacco and tobacco smoke may be achieved by the agents and device of the present invention at several points along the route from the tobacco itself to the point of exposure by the individual. Agents may be added to or blended into the tobacco itself, either smoking or smokeless tobacco, which bind and sequester toxins, not permitting them to be leached or absorbed from the smokeless tobacco or not permitting them to be volatilized into the smoke as the tobacco burns. For smoking tobacco, a second stage of intervention is in removing toxic products from the smoke stream. This may be achieved to some extent by toxin-sequestering agents added to the tobacco itself, which before burning act as a filter. More useful is a filter placed between the column of combusting tobacco and the mouth, or in a separate device, through which the smoke passes before entering the body. By mechanical and adsorptive properties, present filters remove particulates, tar, and other components from the smoke. At a further stage, exhaled tobacco smoke or sidestream smoke produced from the burning smoking device and present in the environment may be filtered of toxins by passing ambient room air through or in contact with a material or filter which removes toxins.
- As described above, porous, fibrous smoke filters remove a portion of these toxic compounds by mechanical trapping and adsorption to the fibrous surface. Nevertheless, toxic compounds remain in the inhaled smoke and contribute to enormous morbidity and mortality, mainly lung and other cancers, other lung diseases such as emphysema, and cardiovascular disease including heart attack and stroke. Numerous theories exist relating various pathophysiological disease processes with specific tobacco smoke components. It is apparent from this body of work that tobacco smoke contains toxins which are incompatible with health, and that reduction of the exposure to the body of these toxins is prudent. Except for abstaining from smoking and perhaps altering genetically the components in the tobacco leaf, reduction in exposure of the smoker to tobacco smoke toxins may be achieved only by adding toxin-sequestering agents to the tobacco or selectively removing toxins from the smoke before inhalation.
- On the other hand, it is desirable to not reduce the enjoyment of using tobacco products in accordance with the objects of the present invention.
- With the identification of significant amounts of the suspected carcinogen formaldehyde in cigarette smoke, considerable effort has been expended by others on developing chemical trapping methods for removing formaldehyde from smoke, mainly by including an aldehyde-trapping chemical in the filter. This may be achieved by the inclusion of nucleophilic compounds in the filter, such as those containing amino groups, as cited in the Background section above. Examples described above of filters incorporating nucleophilic compounds such as lysine apparently have not achieved their desired effect as they have not been commercially introduced.
- It was found surprisingly and unexpectedly by the inventors herein that a significant reduction in the level of mutagens and tar present in tobacco smoke may be achieved without reduction in enjoyment of the product by the use of a filter which in addition to providing a mechanical porous barrier, also traps nucleophilic compounds present in tobacco smoke. Nucleophilic compounds present in tar and tobacco smoke include hydrazine and the aromatic amines 4-aminobiphenyl, 2-naphthylamine, and aniline, among other compounds. The aforementioned smoke components are known mutagens and known or suspected carcinogens. Filter materials capable of trapping nucleophilic toxins from tobacco smoke include a filter in which the filter matrix material bears nucleophile-trapping groups, such as aldehydic groups; alternately, one or more agents capable of trapping nucleophiles may be incorporated into the filter matrix. These toxins may also be removed by incorporating suitable nucleophile-trapping agents directly into the tobacco, and furthermore, these toxins may be removed from smokeless tobacco products by incorporating suitable nucleophile-trapping agents in the smokeless tobacco product.
- It is important to distinguish the intent of the nucleophilic-trapping methods, agents and devices of the present invention, which for example comprise aldehydic groups on a filter material, from the significant body of prior art in which electrophilic substances, such as aldehydes, were desirably removed from tobacco smoke by filters comprising nucleophiles. The present invention is essentially the reverse of the prior art. As an example encompassing the prior art, aldehydes in smoke were trapped by amino groups in or on filters; in the present invention, amines in the tobacco smoke are trapped by aldehydes in or on the filters.
- Suitable filter matrices bearing substituents that may trap nucleophiles may include periodate-oxidized (dialdehyde) derivatives of the polysaccharides cellulose, starch, agarose, and partially-acetylated cellulose; or other polymers, resins or plastics of suitable porosity for use as a tobacco smoke filter and derivatizable with aldehydic moieties.
- Suitable compounds for incorporation directly into smoking and smokeless tobacco products comprise those suitable for the intended purpose. For smokeless tobacco products, suitable agents must have a toxicological profile compatible with the extent of exposure to the individual, and furthermore not interfere with the taste, flavor, or enjoyment of the product. Compounds should be of low toxicity and preferably not absorbed. For incorporation into smoking tobacco to sequester nucleophilic toxins in the tobacco and that formed upon burning, the agents must not interfere with the flavor or enjoyment of the product, the rate of combustion of the smoking product either during or between inhalation, and not release the sequestered toxin when the agent within the tobacco is burned. Nucleophile-binding agents present in the tobacco act in part like a porous filter material for smoke passing through the as-yet unburned portion of the tobacco column. The presence of the toxin-removing material should not interfere with the draw, or resistance to passage of air and smoke, through the tobacco column or filter.
- Non-limiting examples of aldehyde compounds that may be used in the present invention include dialdehyde starch, dialdehyde cellulose, adenosine dialdehyde, inosine dialdehyde, O-phthaldialdehyde, aldehyde agarose, and ethylenedioxybis(3-benzaldehyde). Polymeric aldehyde compounds are preferred; of these, dialdehyde starch is preferred.
- The foregoing agents may be prepared in various forms for incorporation into the filter element of the devices of the invention and for use in the methods of the invention. Such forms do not detract from the ability of the agents to bind nucleophilic toxins from tobacco smoke, but permit more facile manufacture of a suitable filter. Numerous methods known to one of skill in the art may be used to prepare the agent in a form suitable for incorporation into a filter, one non-limiting example being a granularized material prepared by comminution of a dried, extruded paste prepared from the agent, such as dialdehyde starch, and a binder, such as cornstarch. Alternate binding agents may include dialdehyde starch itself.
- Prior uses of aldehydes in tobacco smoking articles has been limited to the inclusion of aldehyde compounds as aroma or flavor modifiers. The compounds n-hexenal, n-octanal, n-nonenal, n-decanal, n-tetradecanal, n-heptanal, n-undecanal, and n-dodecanal were incorporated into the tobacco or filter material in accordance with U.S. Patent 4,627,449, in order to improve the aroma and taste of the tobacco smoke and particularly the aroma of sidestream smoke, i.e., the smoke which passes from the burning tobacco directly to the environment. These compounds are volatilized from the tobacco into the smoke to mask the adverse odors of burning cigarettes. Their vapor pressures make them unsuitable for use in the present invention as they would be volatilized and lost from the filter and unable to trap nucleophiles from tobacco smoke.
- The preferred agent of the present invention is dialdehyde starch. Also known as oxidized starch or polymeric dialdehyde, it is prepared by the periodate oxidation of starch, which produces free aldehyde groups that may react with nucleophiles such as alcohols, amines, hydrazines, hydrazides, and other reagents that condense with aldehydes. Dialdehyde starch may be obtained from any of a number of chemical suppliers, such as Sigma Chemical Company (Catalog No. P9265) or a manufacturer, Monomer-Polymer & Dajac Laboratories, Inc.
- Dialdehyde starch has been used previously for other applications, such as for increasing the wet strength of paper, such as tissue paper; for hardening gelatin; for making water-resistant adhesives; and for tanning leather. In enzyme studies, dialdehyde starch has been used to aid in the attachment of proteins to polymer surfaces, by chemically reacting with hydroxyl groups of a polymer film. It was further used directly as a polymer surface-modifying agent in U.S. Patents 5,281,660 and 5,563,215 to enable biologically active molecules and subsequently cells to bind to the modified surface without altering the biological properties of the molecules. Moderate heat treatment (50°C to 150°C) was necessary in order for the dialdehyde starch to bind to the polymer surface.
- Other agents suitable for the practice of the present invention may be selected from polymers such as agarose (e.g. SEPHAROSE(R)), cellulose, chitosan, dextran (e.g., SEPHADEX(R)), polyvinylpyrrolidone, and the like, which may be chemically derivatized to provide free nucleophile-trapping groups. For example, agarose may be derivatized to contain N-hydroxysuccinimidyl groups, such as Sigma Chemical Co. Catalog No. H8635, N-hydroxysuccinimidyl-activated SEPHAROSE(R) or Catalog No. A9019, 6-aminohexanoic acid N-hydroxysuccinimide ester coupled to SEPHAROSE(R). Aldehyde-agarose (Sigma Chemical Co. Catalog No. A9951) may also be used; one method of preparation involves derivatization of agarose with 4-aminobutyraldehyde diethyl acetal, and subsequent mild acid hydrolysis of the acetal to generate the aldehyde (Korpela and Hinkkanen, 1976, Analytical Biochem. 71:322-323).
- The insoluble polymers recited above may also be used directly as the filter material of the present invention.
- The device of the present invention may be prepared by any one of several methods known to the skilled artisan wherein the toxin-removing agent or agents are incorporated into an air filter or tobacco smoke filter at any of a number of stages in the manufacturing process. For example, an agent or agent so the present invention may be mixed with the raw material comprising the mechanical filter and then co-extruded or spun to form fibers comprising filter material and the toxin-removing agent, which may then be made into filters. Alternatively, extruded or spun fibers comprising the filter material may be coated with a molten agent or agents of the present invention, or a solution of the agent or agents in a suitable solvent, prior to the manufacture of the filters. In another process, the agent may be dissolved or suspended in a plasticizer and they sprayed onto the filter fibers. In another example, the filter devices of the present invention may be prepared from existing mechanical filters by preparing a solution or suspension of the agent or agents in a solvent, absorbing the solvent into the porous filter material, and then removing the solvent by evaporation, drying, freeze-drying, lyophilization, critical point drying, or another suitable method. The filter material would retain its mechanical properties as a barrier to particulate materials and an extensive surface to which tar may be adsorbed.
- In another embodiment, an agent of the invention may be prepared in a granular form for incorporation into the filter of a smoking device. Binding agents such as cornstarch or gum arabic may be used to aid in the preparation of granules. In another embodiment in which dialdehyde starch is used as the nucleophilic-toxin-trapping agent, dialdehyde starch itself may be used as the binder to granulate dialdehyde starch in an active nucleophilic-toxin-trapping form. These and other means for preparing filter materials comprising an agent of the invention are embraced herein.
- In another embodiment, the filter material itself, for example, cellulose acetate, may be prepared and chemically derivatized to contain aldehyde groups, following standard methods. For example, cellulose may be partially acetylated or a certain percentage of the acetate groups on cellulose acetate may be hydrolyzed by treatment at high pH. The resulting partially-acetylated cellulose then may be subjected to periodate oxidation. Thus, the cellulose acetate may retain its fibrous and porous filter characteristics while also bearing aldehyde substituents capable of trapping nucleophilic toxins in tobacco smoke. Other polysaccharides with filter-like properties, such as cellulose, agarose, and the like may also be periodate treated to produce free aldehyde groups. Other polymers including plastics may also be chemically derivatized to produce aldehydic substituents. Preferably, the filter material will retain its mechanical filtration properties, by providing a mechanical barrier and extensive surface area to which tar may be adsorbed, in addition to its nucleophile-binding activity.
- For use in industrial or commercial air handing systems, air filters available for these systems to filter particulates and other air contaminants may be prepared which also contain an agent or agents of the present invention; alternatively the filter material itself may be derivatized or be prepared from an agent of the present invention, such that the air filter retains its mechanical filtration properties and in addition has the ability to remove nucleophilic toxins from the air. Similar filters or replaceable filter cartridges may be prepared for smaller units, such as those used to filter or purify the air in a single room or shared air space, automobile, bus, train, car, aircraft passenger compartments, racetracks, gambling and off-track betting parlors, bars, saloons, and similar areas in which tobacco products, especially smoking tobacco products, are used, and in some instances in which exposure to sidestream smoke is of particular concern to nonsmokers present therein. A personal air filtration system, similar in construction to a gas mask or face mask, may also be prepared using a filter device of the present invention, for individuals in proximity to such areas but seeking personal protection from the harmful effects of sidestream smoke.
- While the inventors do not wish to be bound by theory, the observation that aldehydes and other agents which chemically react with nucleophiles remove tar from tobacco smoke as will be seen in the following examples suggests that a significant portion of the toxic, mutagenic, and carcinogenic compounds present in tobacco smoke are nucleophiles. Of the established carcinogens known to be present in tobacco smoke, 4-aminobiphenyl, 2-naphthylamine, aniline, and hydrazine have primary amino groups. The data empirically show that the materials of the present invention also remove N-nitrosamines, but the mechanism of removal is not presently known. One would also reasonably expect that filter agent of the present invention would also remove hydrogen cyanide, which would react with the aldehyde groups to form cyanohydrins.
- The filter agent of the present invention would not be expected to remove aldehydes from tobacco smoke, such as formaldehyde, unless the compounds also possess a group which may be trapped by an aldehyde. However, trapping of amines by the filter agent of the present invention may produce new functional groups which may then be capable of absorbing, trapping, and chemically inactivating aldehydes and nitrosamines.
- The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
- Cigarette smoke was filtered through 250 mg portions of each of the compounds listed in Table I. In order to achieve adequate draw with filters made from dialdehyde starch and oxidized starch, these compounds were deposited onto cellulose acetate fibers which had been spread out into swatches 0.64-7.6 cm (0.25 by 3 inches). The treated fibers were then dried overnight at 37 C. The smoke from one cigarette was drawn through the filter material and then through 3 mls of distilled water using a water-pipe smoking device which was constructed from a 25 ml glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min. Three 100 microliter aliquots were removed from each flask, placed into ELISA plate wells and read in an ELISA plate reader at 405 nm. The percentage or tar removed is based on a comparison between the cigarette comprising the filter containing the test agent and an appropriate control cigarette. The results are presented in the table below:
COMPOUND % TAR REMOVAL Dialdehyde starch 92.3 Oxidized starch 93 Camphorquinone 53.9 Ninhydrin 83 Phenylglyoxal 53 Hematein (6a,7-dihydro-3,4,6a,10 tetrahydroxyben[b]indeno[1,2-d]pyran-9(6H)-one) 48.7 O-phthaldialdehyde 84 (5,5-dimethyl-1,3-cyclohexanedione 26 Hydrindantin 95 Alloxan 96.9 N-α-t-BOC-L-alanine-N- hydroxysuccinimide ester 25 Fumarophenone 87.5 Ethylenedioxybis(3-benzaldehyde) 19.3 N-α-t-BOC-L-glutamic-α-benzyl ester-γ-N-hydroxysuccinimide ester 96.7 BOC-ε-aminocaproic acid-N-hydroxysuccinimide ester 74 Curcumin 97.9 Dicinnamalacetone 98.1 2-Dodecen-1-ylsuccinic anhydride 98.2 Bicyclo(2,2,2)oct-7-ene-2,3,5,6-tetracarboxylic dianhydride 98.2 Ethylenediaminetetraacetic dianhydride 98.2 (+)-Diacetyl-1-tartaric anhydride 32.1 - To demonstrate the dose-response effect of increasing amount of an agent of the present invention in removing tar from tobacco smoke, cellulose acetate filter fibers were spread out into a swatch 0.64 cm by 7.6 cm (0.25 inches by 3 inches) and then coated with the following amounts of dialdehyde starch suspended in distilled water: 250 mg, 125 mg, 25 mg and 0 mg. The treated fibers were dried at 37 C overnight and then made into a tobacco cigarette using a tube cigarette maker. The smoke from 1 of each type of filter cigarette was then drawn through 3 mls of distilled water using a water-pipe smoking device which was constructed from a small (25 ml) glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min. Three 100 microliter aliquots were removed from each flask, placed into ELISA plated wells and read in an ELISA plate reader at 405 nm.
- As shown in Figure 1, increasing amounts of dialdehyde starch resulted in an increased effectiveness of removal of tar from the tobacco smoke.
- Cellulose acetate filter fibers were spread out into a swatch 0.25 inches by 3 inches and then coated with the following amounts of dialdehyde starch suspended in distilled water: 250 mg, 125 mg, 100 mg, 50 mg, 25 mg and 0 mg. The treated fibers were dried in a 37 C oven overnight and then made into a tobacco cigarette using a tube cigarette maker. The smoke from five of each type of filter cigarette was then drawn through 5 mls of acetone using a water-pipe smoking device which was constructed from a small (25 ml) glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min. After the cigarettes were burned the 5 mls of tar containing acetone was removed from each of the flasks and absorbed onto a pre-weighed disc of filter paper. Each flask was then rinsed with 1 ml of additional acetone two times. Acetone from the rinses was also absorbed onto the appropriate filter paper discs. Filter discs were dried overnight and then weighed. The original pre-weight of the individual filter discs was subtracted from the final weight of the individual filter discs to obtain the number of milligrams of tar obtained from each of the filter cigarettes, and the results are expressed as percent of tar removed.
- Figure 2 indicates that filters containing an agent of the present invention can remove over 90% of the tar from both "light" and "regular" tobaccos. If over 250 mg/filter is used, tar is still removed, but the "drag" may be judged too difficult by the typical smoker.
- Dialdehyde starch was prepared in granular form using various binders, examples of which are described below.
- 1) Using cornstarch as a binder. Cornstarch (0.15 g) was suspended in 10 mls of distilled water, heated to boiling for several minutes and then the mixture was allowed to cool to room temperature. Dialdehyde starch (15 g) was mixed in and the resulting paste was extruded through a #16 wire mesh. Two batches of extruded material were combined and dried overnight at 70 C overnight and then lightly crushed to form granules. These were sized through a #16 mesh, to give a material retained on a #30 mesh. These granules were then dried at 70 C to a constant weight of 18 g. These granules had moderate resistance to crushing.
- 2) Using gum arabic as a binder. The procedure described above in (1) was modified by using gum arabic (0.15 g) in place of cornstarch; also, the gum arabic was dissolved in the 10 ml of water at room temperature and was not heated prior to adding 15 g dialdehyde starch. Three batches of the resulting paste were combined and converted to granules as above, weighing 17.5 g after drying to constant weight. These granules had poor resistance to crushing.
- 3) Using dialdehyde starch as a binder. Dialdehyde starch (10g) was suspended in 50 mls of distilled water. This solution was boiled for 2 hours until it became a clear yellowish paste. The paste was cooled to room temperature and divided into four 10 ml aliquots. The following amounts of dry dialdehyde starch was then blended into one of each of aliquots: 2 g, 5 g 10 g and 25 g. The materials were then dried at 37 C for 38 hours, and then crushed into granules. All of the different types of granules were sized through a #16 mesh to give a material retained on a #30 mesh. All granules were then dried at 37 C to a constant weight. All granules had moderate-good resistance to crushing.
- The ability of the granules prepared according to
method 3 above to remove tar from cigarette smoke was evaluated as described in Example 2 above. "Regular" cigarette tobacco was used. As shown in Figure 3, increasing amounts of the granules showed a proportional increase in the removal of tar. - Cellulose acetate filters were spread out into swatches of 0.25 inches by 3 inches and then coated with 250 mg or 0 mg of dialdehyde starch suspended in distilled water. The treated fibers were then dried in a 37°C oven overnight and then made into a tobacco cigarette. The smoke from 2 of each type of cigarette was drawn into 1 ml of Phosphate Buffered Saline and the placed immediately on ice. Each sample was then applied to ELISA plate wells coated with 5% non-fat milk (100 microliters/well). Plates were incubated for 3 days @ 37°C and then washed four times with 0.05% Tween/PBS. Pigments which remained bound to the wells were then solubilized in 100 microliters DMSO. Absorbance was then read at 405 nm. Results in Figure 4 show the average of three wells ± standard deviation.
- A bacterial mutagenicity assay was performed as described by Ames et al. (Maron DM and Ames BN. 1983. Revised methods for the Salmonella mutagenicity assay. Mutation Research 113:173-215). Briefly, Salmonella strain TA98 was cultured overnight at 37 C in Oxoid
nutrient broth # 2, incubated with serial dilutions of cigarette smoke condensate from the following filter cigarettes: 250 mg dialdehyde starch/filter, 125 mg dialdehyde starch/filter, and 0 mg/filter diluted in 0.1 M sodium phosphate, pH 7.4 containing 33 mM KC1, 8 mM MgC12, 5 mM glucose-6-phosphate, 500 micromolar NADP and rat liver S9 microsomal nucleases, in triplicate for 30 minutes at 37 C. The bacteria were then plated on minimal glucose plates. After a 48 hour incubation period at 37 C, the number of revertant mutants on each plate was counted. Each bar in the graph represents the average number of colonies on three plates ± standard deviation. Tester strain TA 98 detects frameshift mutations, such as those generated by aromatic primary amines. Mutagens in the sample are detected as the number of bacteria induced to revert to their wild-type phenotype. - Figure 5 shows that increasing amounts of dialdehyde starch present in the cigarette filter result in a decrease in the mutagenicity of the smoke extract. Using the 250 mg filter, the number of revertants was no different than the negative control.
- Cellulose acetate filter fibers were spread out into a swatch 0.25 inches by 3 inches and then coated with 250 mg of dialdehyde starch suspended in distilled water. The treated fibers were dried at 37 C overnight and then made into a tobacco cigarette using a tube cigarette maker. The smoke from one of each type of filter cigarette was then drawn through 3 mls of distilled water using a water-pipe smoking device which was constructed from a small (25 ml) glass Erlenmeyer flask attached to a vacuum source with an air flow rate of approximately 35 ml/min. Five hundred microliters of each sample was added to 500 microliters of each of the following solutions (1) 1% sulphanilic acid in 30% acetic acid (2) 0.1% naphthylamine in 30% acetic acid. The mixture was then incubated at 56 C. Samples were removed at 0,10,20 and 30 minutes and read a 540 nm using 620 nm as a reference value. Formation of color indicates the presence of nitrosamine compounds.
- Figure 6 shows that 250 mg of the agent of the present invention diminished the level of nitrosamines in the tobacco smoke extract by several fold.
- A double-blind taste test was performed on 12 individuals in an office environment in a large city. The subjects were asked to fill out a brief questionnaire inquiring about their age, years of smoking, daily usage and preferred brand. After answering these questions, the subjects then lit two cigarettes, one with the filter of the present invention comprising dialdehyde starch, and one with a regular filter. As they smoked the cigarettes side by side, they were asked to record which cigarette was preferred and to describe any differences perceived between the two.
- The average age of the participants was 41 years, average duration of smoking 18.4 years, and each smoked on average 25.7 cigarettes per day. Eight of the twelve participants preferred the test cigarette with the dialdehyde starch filter over the control cigarette, and four individuals did not prefer one cigarette over the other.
- Cigarettes with cellulose acetate filters or with filters comprising an agent of the present invention were evaluated an independent laboratory for total particulate matter, nicotine, tar, water and carbon monoxide, according to the standardized FTC method. The cigarettes tested were made by treating cellulose acetate filters with 250 mg dialdehyde starch (DAS) in distilled water ("DAS Filter Cigarettes"). The treated fibers were dried overnight and incorporated into cigarettes using a tube cigarette maker. In this series of tests two types of control cigarettes were run: the standard "Kentucky Reference" cigarettes (provided by Lab Stat, Kitchener, Ontario, Canada) and "Ordinary Cigarettes" which were constructed in the laboratory of the inventors. Ordinary Cigarettes were constructed the same way as the filter cigarettes of the invention and they contain the same amount of tobacco and cellulose acetate fibers, but do not contain the filter additive.
"Brand" Weight mg/cig Puffs (per cig) TPM (mg/cig) CO (mg/cig) Water (mg/cig) Nicotine (mg/cig) Tar (mg/cig) Kentucky Reference 1069 8.6 11.3 13.2 0.892 0.831 9 Control Cigarette 986 8.7 17.99 15.8 3.245 1.056 13 DAS Filter Cigarette 1189 8.2 6.9 13.41 0.778 0.464 5 - The following results were obtained:
- The taste test was designed as follows: Subjects, n=20.
Cigarette # 1 = DAS filtered cigarette with a Marlboro ultralight tobacco column (detached from a store-bought Marlboro ultralight).Cigarette # 2 = Marlboro ultralight cigarette (store bought). Both types of cigarettes had the same tar and nicotine ratings. The subjects were asked to fill out a brief questionnaire inquiring their age, years of smoking, daily usage and preferred brand. After answering these questions, the subjects then lit the two cigarettes, one with the DAS filter and a Marlboro Ultralight. Subjects were not given any information on the putative properties of the DAS filter other than that it was a new type of cigarette filter. As they smoked the cigarettes side by side, they were asked to decide how they would rate the tar and nicotine level in the DAS filtered cigarette, i.e., regular, light or ultralight. - Results shown indicate that 58% of this group of smokers thought the DAS filtered cigarette was a regular cigarette, 33% thought it was a light cigarette and 8% thought it was an ultralight cigarette. Taken together the taste test results demonstrate that the DAS filtered cigarettes not only taste like ordinary cigarettes (unlike other "safer" cigarettes), but are also preferred by smokers.
- This invention may be embodied in other forms or carried out in other ways without departing from the essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.
- It is to be understood that the devices of the invention is not limited to the description herein, which are deemed to be merely illustrative of the best modes of carrying out the invention, and which are susceptible of modification of form, size, arrangement of parts and details of operation. The invention rather is intended to encompass all such modifications which are within its scope as defined by the claims.
Claims (8)
- A method for reducing the level of nucleophilic toxins present in air containing tobacco combustion products by passing said air through a filter element capable of removing nucleophilic toxins present in said air, wherein said filter element comprises a polymer derivatized with an aldehydic group.
- The method of claim 1, wherein said air comprises mainstream tobacco smoke and said smoke retains desirable flavor components after passage through said filter.
- The method of claim 1, wherein said polymer is periodate-oxidized cellulose, periodate-oxidized starch, periodate-oxidized agarose, periodate-oxidized partially-acetylated cellulose or a combination thereof.
- The method of claim 1, wherein said polymer derivatized with aldehydic groups is dialdehyde starch, dialdehyde cellulose or a combination thereof.
- The method of claim 4, wherein said toxin-removing agent is dialdehyde starch.
- The method of claim 1, wherein said aldehydic group is adenosine dialdehyde, inosine dialdehyde, o-phthaldialdehyde, ethylenedioxybis (3-benzaldehyde) or a combination thereof.
- A device for reducing the level of toxins present in air containing tobacco combustion products wherein said device comprises a filter element through which air passes, said filter comprising a polymer derivitized with an aldehydic group.
- The device of claim 7, used to filter air in a tobacco smoke-generating device or in a tobacco smoke-containing environment which is a cigarette, a free-standing cigarette filter, a pipe, a cigar, an air ventilation filter, a gas mask or a face mask.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/US2000/017452 WO2002000046A1 (en) | 2000-06-26 | 2000-06-26 | Methods, agents and devices for removing nucleophilic toxins from tobacco and tobacco smoke |
Publications (2)
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EP1309253A1 EP1309253A1 (en) | 2003-05-14 |
EP1309253B1 true EP1309253B1 (en) | 2007-05-23 |
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EP00941705A Expired - Lifetime EP1309253B1 (en) | 2000-06-26 | 2000-06-26 | Methods and devices for removing nucleophilic toxins from tobacco and tobacco smoke |
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EP (1) | EP1309253B1 (en) |
JP (1) | JP4447218B2 (en) |
CN (1) | CN1271960C (en) |
AT (1) | ATE362718T1 (en) |
AU (1) | AU2000256373A1 (en) |
BR (1) | BR0017258B1 (en) |
CA (1) | CA2414377A1 (en) |
DE (1) | DE60034968T2 (en) |
DK (1) | DK1309253T3 (en) |
ES (1) | ES2286026T3 (en) |
HK (1) | HK1052440A1 (en) |
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WO (1) | WO2002000046A1 (en) |
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AU2004206861B2 (en) * | 2003-01-15 | 2008-08-28 | Stryker Corporation A Corporation Of The State Of Michigan | Ambulance cot loading and unloading device |
EP1856991B1 (en) * | 2005-02-02 | 2014-12-31 | Daicel Chemical Industries, Ltd. | Cigarette filter material and cigarette filter |
JP4739875B2 (en) * | 2005-09-13 | 2011-08-03 | ダイセル化学工業株式会社 | Tobacco filter manufacturing method |
DE102008011671B4 (en) * | 2008-02-28 | 2012-04-26 | Gunther Krieg | Method for detecting cigarette butts and cigarette ash in hollow bodies, in particular beverage bottles |
US8952038B2 (en) * | 2010-03-26 | 2015-02-10 | Philip Morris Usa Inc. | Inhibition of undesired sensory effects by the compound camphor |
IT1404015B1 (en) * | 2011-02-04 | 2013-11-08 | Hsd Holding Smart Device S R L | USE OF A DESTRANO POLYMER RETICULATED AS A FILTER AGAINST INHALATION OF HEALTH HARMFUL SUBSTANCES |
JP5882775B2 (en) * | 2012-02-13 | 2016-03-09 | 株式会社Adeka | Cellulosic resin composition and film |
EP4176960A1 (en) * | 2013-09-06 | 2023-05-10 | Massachusetts Institute of Technology | Filter materials including functionalized cellulose |
US10383369B2 (en) * | 2017-06-07 | 2019-08-20 | Rai Strategic Holdings, Inc. | Fibrous filtration material for electronic smoking article |
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US3063892A (en) * | 1959-10-14 | 1962-11-13 | United Shoe Machinery Corp | Preparation of hide fiber |
US3346519A (en) * | 1964-11-12 | 1967-10-10 | Hawley Products Co | Process of adhering anionic and non-ionic substances to anionic substances |
DE2230118A1 (en) * | 1972-06-21 | 1974-01-24 | Heinrich Borgwaldt Fa | Reinforcing treatment of cellulose fibres - for use in tobacco filters |
DE3820089A1 (en) * | 1988-06-13 | 1989-12-14 | Bat Cigarettenfab Gmbh | METHOD FOR IMPREGNATING FIBERS OF A TOBACCO FUEL FILTER WITH DI- OR POLYCARBONIC ACIDS OR. ANHYDRIDES THERE |
CA2127817C (en) * | 1993-07-13 | 2007-07-03 | Hitoshi Tsugaya | Tobacco filters and method of producing the same |
DE4416101C2 (en) * | 1994-04-19 | 1997-06-12 | Reemtsma H F & Ph | Tobacco products or tobacco products similar goods with natural substances having an antioxidative effect and process for producing the same |
US5850840A (en) * | 1995-11-15 | 1998-12-22 | Alteon Inc. | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
US6119701A (en) * | 1998-02-13 | 2000-09-19 | Cerami Consulting Corp. | Methods, agents and devices for removing nucleophilic toxins from tobacco and tobacco smoke |
-
2000
- 2000-06-26 DE DE60034968T patent/DE60034968T2/en not_active Expired - Fee Related
- 2000-06-26 EP EP00941705A patent/EP1309253B1/en not_active Expired - Lifetime
- 2000-06-26 WO PCT/US2000/017452 patent/WO2002000046A1/en active IP Right Grant
- 2000-06-26 BR BRPI0017258-8A patent/BR0017258B1/en not_active IP Right Cessation
- 2000-06-26 AT AT00941705T patent/ATE362718T1/en not_active IP Right Cessation
- 2000-06-26 CA CA002414377A patent/CA2414377A1/en not_active Abandoned
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- 2000-06-26 AU AU2000256373A patent/AU2000256373A1/en not_active Abandoned
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- 2000-06-26 ES ES00941705T patent/ES2286026T3/en not_active Expired - Lifetime
- 2000-06-26 DK DK00941705T patent/DK1309253T3/en active
- 2000-06-26 CN CNB008197873A patent/CN1271960C/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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EP1309253A1 (en) | 2003-05-14 |
BR0017258A (en) | 2004-01-06 |
DE60034968D1 (en) | 2007-07-05 |
CN1271960C (en) | 2006-08-30 |
DE60034968T2 (en) | 2008-01-24 |
BR0017258B1 (en) | 2011-03-22 |
HK1052440A1 (en) | 2003-09-19 |
MXPA03000125A (en) | 2004-12-06 |
WO2002000046A1 (en) | 2002-01-03 |
CA2414377A1 (en) | 2002-01-03 |
CN1454063A (en) | 2003-11-05 |
ATE362718T1 (en) | 2007-06-15 |
ES2286026T3 (en) | 2007-12-01 |
DK1309253T3 (en) | 2007-09-17 |
JP4447218B2 (en) | 2010-04-07 |
AU2000256373A1 (en) | 2002-03-28 |
JP2004500901A (en) | 2004-01-15 |
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