SE529462C2 - Nicotine product used as tobacco product, comprises nicotine consisting of specific amount of nitrosamine, and carrier, diluent or excipient - Google Patents

Abstract

A nicotine product comprises (a) nicotine consisting of less than 0.1 mu g of nitrosamine with respect to 1 mg of nicotine, and (b) carrier, diluent or excipient. An independent claim is also included for production of nicotine product, which involves extracting nicotine and fibers from tobacco material using cationic exchange resin, and isolating nicotine to produce nicotine product.

Description

l5 20 25 30 529 462 2 studies that address the human risks of SLT use, which primarily consist of case-controlled studies performed over a 40-year period beginning in 1957. Then, when examining some of the substances that may enhance or inhibit cancer development in long-term SLT users. Potential cancer-causing agents in SLT have been studied intensively for the past 30 years. The risk from the monograph program from the International Agency for Research on Cancer (IARC), an official source of information for determining carcinogenic risks.

Potential cancer inhibitors in SLT have received very little attention. However, they do exist, and are found in quite impressive concentrations, primarily as antioxidants.

Therefore, there is a need to develop new methods which allow the possibility of producing nicotine with a reduced amount of carcinogenic components, and thereby be able to produce new nicotine as well as new tobacco products with smaller amounts of carcinogenic components.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to a new process as well as to new products which have a reduced level of at least nitrosamines. The invented process gives rise to new improved nicotine as well as nicotine and tobacco products including said nicotine. The nicotine as well as the nicotine and tobacco products include less than 0.5 pg of nitrosamines / nicotine as well as reduced amounts of other components such as Fe, Cr, Al, Pb, As, Ni, Hg and Cd, which are harmful to humans consuming said nicotine. or gives a bad taste, such as a bitter taste, to the nicotine product. Accordingly, the invention relates to a method of producing said nicotine in which said method comprises the steps of supplying tobacco material, extracting nicotine from said tobacco material and / or fibers from the tobacco material, removing at least the nitrosamines from said nicotine and / or or said fibers and obtaining nicotine wherein said nicotine comprises less than 0.5 pg nitrosamines / mg nicotine, where the nicotine can be extracted from said tobacco using cation exchange.

By providing such a new nicotine, it is possible for the first time to produce nicotine-containing products with reduced amounts of nitrosamines as well as Cr, Pb, As, Fe, Al, Ni, Hg and Cd, which are harmful to humans, as well as giving the nicotine product a bitter taste and reduce the coloration when using a tobacco product, such as Swedish snus.

DETAILED DESCRIPTION OF THE INVENTION Definitions In the context of the present application and the invention, the following definitions apply: The term "tobacco" refers to any part of a tobacco plant and mixtures of tobacco plants which arise from the same or different species as well as being genetically modified (GMO). The tobacco plant belongs to the family Solanaceae and the genus Nicotiana. Examples of tobacco plants are those from Nicotiana tabacum and Nicotiana rustica. Examples of parts are leaves, method such as being fresh, frozen, deep-frozen, freeze-dried stem, roots, etc. which can be obtained with any or prepared.

The term "nicotine product" refers to any product such as inhaler, tablet, capsule, lozenge, chewing gum, mucous membrane or transdermal patch, nasal drops, nasal and / or oral spray, transdermal gel / cream or any other local administration, rectal application, etc. used in any application where nicotine is to be delivered to the human body.

The term "tobacco product" refers to any product made from or containing tobacco such as nasal snuff, orally moist or dry snus, chewing tobacco, pipe tobacco, cigar or cigarette tobacco, tablet, capsule, lozenge, chewing gum, mucous or transdermal patch, etc. used in any application where nicotine is to be delivered to the human body. It also refers to any such nicotine-free product.

The term "tobacco-specific nitrosamines" (TSNA) on a number of nitrosamines, such as N '- nitrosonornicotine (NNN), (NAT), (NAB) and 4- (N-methylnitrosamino) -1-) 3-pyridyl) -1-butanone (NNK), N'-nitrosonornicotine.

The term "tobacco fibers" is intended to mean any part of the tobacco plant which includes cellulose, cellulose fibers and / or starch. The invention relates to nicotine which has improved properties over other nicotine, such as a low content of the nitrosamines, such as a content of nitrosamines of less than 0.5 pg nitrosamines / mg nicotine, such as less than 0 , 4, 0.3, 0.2, 0.1 pg / mg nicotine or 0.01 Ng / mg or empty less than 0.01 ug nitrosamines / mg nicotine. Examples are 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 pg nitrosamines / mg nicotine, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 pg nitrosamines / mg nicotine or even 10 15 20 25 30 35 529 462 5 even lower, i.e. the nicotine may be substantially free of nitrosamines. The nitrosamines may be N'- (NNN), (NAT>, N'- (NAB), and 4- (N-methylnitrosamino) -1- (3-pyridyl) -1-butanone (NNK), and 4- (methylnitrosamino ) -1- (3-pyridyl) -1-butanone, nitrosonornicotine N'-nitrosoanatabine nitrosoanabasine Furthermore, the nicotine may comprise Cd in an amount of less than 0.5 pg / g, such as less than 0.4, 0.3, 0, 2, 0.1, 0.05 or 0.01 pg / g, Pb in an amount less than 1.0 pg / g, such as less than 0.9, 0.8, 0.7, 0.6, 0 , 5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 pg / g, As in an amount less than 0.25 pg / g, such as less than 0.1, 0.05, or 0.01 pg / g, Ni in an amount less than 2.25 pg / g, such as less than 2.0, 1.5, 1.0, 0.5, 0.4, 0, 3, 0.2, 0.1, 0.05 or 0.01 pg / g, Cr in an amount less than 1.5 pg / g, such as less than 0.4, 0.3, 0.2, 0, 1, 0.05 or 0.01 pg / g.

A reduction in the above substances will give rise to a healthier nicotine product, as these products are carcinogenic or otherwise harmful to the body or give the nicotine a bitter taste. Consequently, the nitrates as well as the nitrites are reduced. The nicotine may be substantially free of tobacco fibers, i.e. the insoluble fibers. The nicotine may be stabilized by the formation of a salt such as with an organic acid. Examples of acids are sulfuric acid.

Nicotine can be used to make nicotine products as well as tobacco products.

The nicotine products include the above-defined nicotine as well as an accepted diluent, buffer, carrier or binder, such as a pharmaceutically acceptable one.

"Acceptable" means a diluent, buffer, vehicle, or binding agent so that the dose and concentration used do not cause any adverse effects in patients.

Acceptable buffers, carriers or binders are well known in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th edition, AR Gennaro, Ed., 10 15 20 25 30 35 529 462 6 Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000) Examples of carriers include carriers selected from the group consisting of polacrilex, cyclodextrin, starch, cellulose and cellulose derivatives, chewing gum bases, gelatin, sodium alginate, PVP and fibers such as tobacco fibers.

The nicotine in the nicotine product can be mixed with adjuvants such as lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, acacia gum, gelatin, polyvinylalkylvinyl and is formed into tablets or capsules for conventional administration.

Alternatively, nicotine can be dissolved in physiological saline, water, polyethylene glycol, propylene glycol, ethanol, oils, gum tragacanth and / or various buffers.

Other adjuvants and modes of administration are well known in the pharmaceutical art. The carriers or diluents may include controlled release materials, such as glycerol monostearate or glycerol distearate alone or in combination with a wax or other material well known in the art.

The nicotine product may be subject to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, buffering agents, fillers, etc., e.g. as published elsewhere herein.

The nicotine product of the invention may be administered topically or systemically, such as topically, intravenously, orally and t.o.m. Rectal use is possible.A Examples of nicotine products are tablets, capsules, lozenges, chewing gum, mucosal or transdermal patches, nasal drops, nasal or oral sprays. Other examples are smoking articles, such as cigarettes, cigars, finely chopped smoking articles and non-smoking articles such as nasal snuff, orally moist or dry snuff and chewing tobacco.

Furthermore, the nicotine can be used to produce a tobacco product, such as a tobacco product which comprises tobacco nicotine as defined above, which contains less than 0.5 pg nitrosamines / mg nicotine, such as less than 0.4, 0.3, 0.2, 0, 1 or 0.01 pg / mg or even less than 0.01 pg nitrosamines / g nicotine. Examples are 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 pg nitrosamines / mg nicotine, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 pg nitrosamines / mg nicotine or even lower, ie. the nicotine may be substantially free of nitrosamines.

The nicotine product or tobacco product may also include one or more additives selected from the group consisting of natural, nature-identical, synthetic and semi-synthetic additives such as menthol, bergamot, eucalyptus and coffee, citrus or other fruit flavors, licorice, etc. Furthermore, the nicotine product or tobacco monosaccharide may also contain , fructose, sorbitol, xylitol or sweeteners such as aspartame.

In addition, the nicotine or tobacco product may also include polysaccharides such as sucrose, starch, maltodextrin, etc.

The tobacco product may have tobacco fiber material as a core and the tobacco nicotine and / or salt adsorbed on the tobacco fiber material or absorbed in the tobacco fiber material, such as spraying the nicotine and / or the salt on the tobacco fiber material. Furthermore, the nicotine and / or fibers from tobacco may be encapsulated in nonwoven materials, well known to those skilled in the art.

The nicotine product or tobacco product may be formulated in one or more forms of preparation, such as sachets, pouches, stick-packs, cheek pads or patches or compressed into chewable tablets, lozenges, reconstitution tablets or lozenges. packed in airtight packages to prevent losses by oxidation and / or evaporation of the nicotine.

The nicotine product or tobacco product may have an in vitro release profile analyzed for 35 minutes during the following intervals; Nicotine released after 5 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Nicotine released after 10 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Nicotine released after 15 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Nicotine released after 20 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Nicotine released after 25 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Nicotine released after 30 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0, 9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Nicotine released after 35 minutes is 0.1, 0.2, 0.3, 0.4, 0.5, 0, 6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg The release profile can be designed with respect to the rate and amount of nicotine and unwanted substance release through the formulation. The release of nicotine from nicotine or tobacco products can be designed to be released in a sufficient amount and / or a sufficient rate to allow the desired effect and on the other hand designed to retain substances which are normally gives rise to side effects, such as e.g. nitrosamines, and / or to release such substances in a substantially lower amount and / or at a substantially lower rate.

In another embodiment of the invention, the release of the invented nicotine may be delayed compared to commercially available moist snus to mimic the effect of nicotine replacement products, such as e.g. band-Aid. The release profile can be 0.1-0.3 mg / h.

The tobacco product can be designed so that at least 50% w / w of the total nicotine content is released within a maximum of 60 minutes when subject to the release test described in the latest edition of European Pharmacopoeia.

The tobacco product of the invention may be designed so that at least 50% w / w of the total nicotine content is released within a maximum of 120 minutes when subjected to the release test.

Extracted release Normal release is tested in in vitro studies, extracted release is the amount released during the use of snuff, snus, nicotine product. Average extracted amount is calculated by subtracting individual or average value of product used from the average content of "unused product".

Whether the steady state or single plasma nicotine levels of a refined tobacco product based on natural tobacco and / or genetically modified and / or a tobacco substitute and / or nicotine according to the invention, the tobacco and / or tobacco substitute and / or pharmaceutical product may preferably have the calculated extracts. the amounts in humans that are typical: extraction (mg) 0.1, 0.2, 0.3, 10 15 20 25 30 35 529 462 10 0.4, 0.5, 0.6, 0.7, 0, 8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg Whether the steady state nicotine or simple plasma levels from a refined tobacco product based on natural tobacco and / or genetically modified and / or a tobacco substitute and / or nicotine according to the invention, the tobacco and / or the tobacco substitute and / or pharmaceutical product may have biological parameters in humans which are typical: Cmax (ng / ml) 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, ll, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33 , 34, 35, 36, 37, 38, 39, 40 or more u pp to 50 ng / ml). AUC (hours x ng / ml) 1.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more up to 50 hours x ng / ml.

Whether the nicotine pH levels from a nicotine or a tobacco product in accordance with the invention have the pH parameters that are typically; pH 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 7.8, 7.9, 8.0, 8.2, 8.3, 8, 4, 8.5, 8.6 8.8, 8.9, 9.0, 9.1 to 10 The nicotine can be prepared by any method such as one of those described in the examples. 8.1, A method for producing nicotine The invention also relates to a method for producing nicotine as described above. The nicotine is extracted from tobacco, such as from Tobacco tabacum. The tobacco plant may be a genetically modified plant, such as a genetically modified plant in which the amount of nitrosamines has been reduced. The tobacco plant material may be any part of the plant such as the roots, stem or leaves such as the lamellae from the leaves. The tobacco plants can be grown in fields or in greenhouses, with or without fertilizer or the addition of other growth-stimulating components. In a specific embodiment, the plant material is leaves which are harvested and directly transferred to a temperature which is below 0 ° C, such as being frozen by freezing in liquid nitrogen and / or dry ice and / or deep-freezing containers and / or any other technology which stops all ongoing processes within the plant and thereby reduces and / or eliminates the possibility that nitrosamines will be produced within the plant material. The harvested plant material can also be treated in other ways as long as the production of nitrosamines is inhibited. The harvested plant material can then be crushed, cut, ground or divided and mixed with an aqueous solution to which a base is added such as sodium hydroxide (NaOH) or calcium carbonate (CaCO 3, limestone) or calcium hydroxide (slaked lime) 10% by weight and 25% moisture. The plant material can then be packed in a percolator and water can pass through the percolator to allow the nicotine to be extracted from the plant material.

Alternatively, the plant extract can be added to a cation column, such as Amberlit, passed through this column whereby the nicotine will bind to the column.

The nicotine can then be released from the column by using an acid such as the use of acetic acid or phosphoric acid. After such a method, the nicotine will be released / extracted from the plant fibers.

The method gives rise to the possibility of separating the nicotine and the fibrous material from the tobacco plant material and removing and / or minimizing the amount of certain substances in the nicotine as well as in the fibrous material, such as carcinogenic as well as bitter taste components. The plant material may be exposed to a subset of washing steps such as both alkaline and acidic washing steps to remove undesirable components on or in the material. Examples of washing steps are washing with sodium hydroxide and water or purified water. 10 15 20 25 30 35 529 462 12 The washing steps can be performed one or more times depending on the starting material. Samples can be taken after each washing step to monitor the washing effect of unwanted components, which are reduced and / or eliminated in the washing steps.

Furthermore, the resulting nicotine product or tobacco product may comprise Cd in an amount less than 0.5 pg / g, such as less than 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 pg / g. , Pb in an amount less than 1.0 pg / g, such as less than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0 , 1, 0.05 or 0.01 pg / g, As in an amount less than 0.25 pg / g, such as less than 0.1, 0.05 or 0.01 pg / g, Ni in an amount less than 2.25 ng / g, such as less than 2.0, 1.5, 1.0, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 pg / g, Cr in an amount less than 1.5 pg / g, such as less than 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01 pg / g. A reduction in the above substances will give rise to a healthier nicotine product because these products are carcinogenic or otherwise harmful to the body or give the nicotine a bitter taste. Consequently, the nitrates as well as the nitrites are reduced. Finally, a nicotine product or tobacco product is obtained in which the nitrosamines are reduced as well as other components such as Fe, Al, Ni, Hg and especially nitrates and nitrites and the heavy metals Pb, Cd and As.

In order to obtain nicotine as well as fibers from tobacco plant materials with minor amounts of contaminants, the quality of the chemicals used during the processes is important.

The nicotine obtained by the invented method has the same characteristics as the nicotine defined above.

The following examples are intended to illustrate, but not limit, the invention in any way, manner or form, whether explicitly or implicitly.

EXAMPLE 10 15 20 25 30 529 462 13 EXAMPLE 1 PURIFICATION OF NICOTIN FROM TOBACCO DUST BY USING AN ORGANIC WATER-SOLUBLE, NON-POLAR SOLVENT Step 1 Mixture Tobacco dust, stalks and stalks, stalks and stalks ) or calcium hydroxide (slaked lime) 10% by weight mixed (rib type) of machine steel. Water is added to give the mixture a moisture content of 25%. in a mixer Step II Percolation The slightly moist raw tobacco mixture is packed in a machine steel percolator, i.e. a cylindrical extractor, water is percolated through the mixture to give a nicotinized soup.

Step III Extraction This nicotinized soup, i.e. the nicotine-containing aqueous mother liquor, is subjected to a liquid-liquid extraction with an organic water-insoluble, non-polar solvent, such as ethyl acetate, in high columns of machine steel or stainless steel for liquid-liquid extraction. Nicotine is thereby converted to an organic, water-insoluble, non-polar solvent. The lye leaving the column at the bottom is essentially free of nicotinic alkaloid. Liquid ~ Liquid extraction not only separates and isolates the alkaloid rapidly, but it also contributes to its purification because some impurities are insoluble in the organic solvent. Step 15 Separation The nicotine concentration in an organic water-insoluble non-polar solvent is estimated by titration. Ten (10) ml of the solvent is mixed with 10 ml of 10normal H 2 SO 4 in a beaker and titrated against 10normal NaOH solution using phenolphthalein as indicator. The amount will determine the quantity of nicotine in the solvent. The larger the amount, the greater the quantity of nicotine dissolved in the solvent and a calculated quantity of dilute sulfuric acid in water is added with shaking in a mechanical or stainless steel reaction vessel to form 40% nicotine sulfate. Nicotine sulfate 40%, insoluble and heavier than the organic water-insoluble non-polar solvent, collects from the bottom of the vessel. which is Step V Filtration and purification Nicotine sulphate 40% is filtered and purified by passing it through a stainless steel supercentrifuge (8000 rpm for at least 6 minutes) to separate suspended particles and remove traces of the organic water-insoluble non-polar solvent .

Step VI Packaging The purified nicotine sulphate is packed in epoxy-coated drums under an inert gas such as nitrogen and stored in a cool and dry place.

Step VII Alkalization Nicotine sulphate 40% steel and sodium hydroxide are added with gentle stirring.

When the alkalization is complete, nicotine separates 95% on top and is decanted. is added to a reactor in stainless steel 10 15 20 25 30 35 462 5 529 1 Step VIII Purification of nicotine alkaloid Nicotine alkaloid is washed again with strong alkaline (NaOH) aqueous solution and separated by supercentrifugation to give pure nicotine alkaloid 98%.

Step IX Distillation of nicotine alkaloid Nicotine alkaloid of 97% to 98% purity is taken up in a distillation equipment (preferably glass or glass coated). Under high vacuum (almost 760 mm) the impurity (water) begins to distill at about 70 ° C.

After the distillation slows down (after about 4% of the quantity charged), the receiving bottle is emptied (preferably replaced) to collect the nicotine alkaloid. With the vacuum maintained high, the nicotine begins to distill at about 140 ~ 160 ° C. The distilled alkaloid is then stored in either stainless steel glass or vessel under an inert atmosphere.

Step X Testing After distilling the nicotine alkaloid, it was then tested for nitrosamine content (TSNA, i.e. NNN, NNK, NAT and NAB). The total content, when tested, was at least less than 0.5 micrograms per milligram. Therefore, as indicated, the total amount of nitrosamines in the tobacco can be selectively reduced.

Step XI Packaging The purified nicotine is packaged in epoxy-coated drums under an inert gas such as nitrogen and stored in a cool and dry place.

EXAMPLE 2 PURIFICATION OF NICOTINE FROM FRESH LEAVES BY USING AN ORGANIC SOLVENT 10 15 20 25 30 35 529 462 16 Step 1 Mixture Fresh tobacco leaves from tobacco plants (= "green tobacco") and calcium carbonate (Ca 2+ carbonate carbonate) 10% by weight is mixed in a stainless steel (rib type) mixer. Water is added to give the mixture a moisture content of 25%.

Step II Percolation The slightly moist raw tobacco mixture is packed in a machine steel percolator, i.e. a cylindrical extractor.

Water is percolated through the mixture to give a nicotinized soup.

Step III Extraction This nicotinized soup, i.e. the nicotine-containing aqueous mother liquor is subjected to a liquid-liquid extraction with a water-insoluble, non-polar solvent, such as ethyl acetate, in high columns of machine steel or stainless steel for liquid-liquid extraction. Nicotine is thereby transferred to the organic solvent. The lye leaving the column at the bottom is essentially free of nicotinic alkaloid. Liquid-liquid extraction not only separates and isolates the alkaloid quickly, but it also contributes to its purification because some impurities are insoluble in the organic solvent.

Step IV Separation The concentration of nicotine in the organic solvent is determined by titration and a calculated quantity of dilute sulfuric acid in water is added with stirring in a reactor vessel made of mechanical steel or stainless steel to form 40% nicotine sulphate. Nicotine sulfate 40%, insoluble and heavier than the organic water-insoluble non-polar solvent, collects from the bottom of the vessel. which is 10 15 20 25 30 35 529 l 462 7 Step V Filtration and purification Nicotine sulphate 40% pass it through a stainless steel supercentrifuge to be filtered and purified by separating suspended particles and removing traces of the organic solvent.

Step VI Packaging The purified nicotine sulphate is packed in epoxy-coated drums and stored in a cool, dry place.

Step VII Alkalization Nicotine sulphate 40% is taken up in a stainless steel reactor and sodium hydroxide is added with gentle stirring.

When the alkalization is complete, nicotine separates 95% on top and is decanted.

Step VIII Purification of nicotine alkaloid Nicotine alkaloid is washed again with strong alkaline (NaOH) aqueous solution and separated by supercentrifugation to give 98% pure nicotine alkaloid.

Step IX Distillation of nicotine alkaloid Nicotine alkaloid with 97% to 98% of the distillation equipment (preferably glass or glass coated). Under high vacuum (almost 760 mm) the impurity (water) begins to distill at about 70 ° C.

After the distillation slows down (after about 4% of the quantity taken up), the receiving flask (preferably replaced) is emptied to collect the nicotine alkaloid. With the vacuum maintained high, the nicotine begins to distill at about 140-160 ° C. The distilled alkaloid is then stored in either glass or stainless steel vessels under an inert atmosphere. purity is taken up in Step X Testing After distilling the nicotine alkaloid, it was tested (TSNA, i.e. NNN, NNK, NAT The total content, when tested, was at least then for nitrosamine content and NAB). less than 0.5 micrograms per milligram. Therefore, as indicated, the total amount of nitrosamines in the tobacco can be selectively reduced.

Step XI Packaging The purified nicotine is packaged in epoxy-coated drums under an inert gas such as nitrogen and stored in a cool, dry place.

EXAMPLE 3 PURIFICATION OF NICOTINE FROM DEFROZEN LEAVES USING AN ORGANIC SOLVENT Step 1 Mixture Tobacco leaves from tobacco plants (= "green tobacco") are collected and deep-frozen (-20 ° C) collected in less than three hours.

Step II Mixing and percolation The frozen tobacco leaves and calcium carbonate (CaCO3, limestone) (slaked lime) 10% by weight are mixed in a machine steel mixer (rib type).

Water is added to bring the moisture in the mixture to 25% the tobacco mixture is packed in a machine steel percolator, or calcium hydroxide moisture content. The slightly moist raw i.e. a cylindrical extractor. Water is percolated through the mixture to give a nicotinized soup.

Step III Extraction This nicotinized soup, i.e. the nicotine-containing water mother liquor is subjected to liquid-liquid extraction with an organic, water-insoluble, non-polar solvent, in high columns of machine steel or stainless steel for liquid-liquid extraction. Nicotine is thereby transferred to the organic solvent. The lye leaving the column through the bottom is substantially free of nicotinic alkaloid. Liquid-liquid extraction not only separates and isolates the alkaloid rapidly, but it also contributes to its purification because some impurities are insoluble in the organic solvent.

Step IV Separation The nicotine concentration in the organic solvent is determined by titration and a calculated amount of dilute sulfuric acid in water is added with stirring in a mechanical or stainless steel reactor vessel to form 40% nicotine sulphate. Nicotine sulfate 40%, insoluble and heavier than the organic solvent, collects from the bottom of the vessel. which is Step V Filtration and Purification Nicotine sulfate 40% pass it through a stainless steel supercentrifuge to be filtered and purified by separating suspended particles and removing traces of organic solvent.

Step VI Packaging The purified nicotine sulphate is packed in epoxy-coated drums and stored in a cool, dry place.

Step VII Alkalization Nicotine sulphate 40% is taken up in a stainless steel reactor and sodium hydroxide is added with slow stirring.

When the alkalization is complete, nicotine separates 95% on top and is decanted. step VIII Purification of nicotine alkaloid Nicotine alkaloid is washed again with strong alkaline (NaOH) aqueous solution and separated by supercentrifugation to give pure nicotine alkaloid 98%.

Step IX Distillation of nicotine alkaloid Nicotine alkaloid of 97% to 98% purity is taken up in the distillation equipment (preferably glass or glass coated). Under high vacuum (almost 760 mm) the impurity (water) begins to distill at about 70 ° C.

After the distillation slows down (after about 4% of the quantity taken up), the receiving flask (preferably replaced) is emptied to collect the nicotine alkaloid. With the vacuum maintained high, the nicotine begins to distill at about 140-160 ° C. The distilled alkaloid is then stored in either glass or stainless steel vessels under an inert atmosphere.

Step X Testing After distilling the nicotine alkaloid, it was tested (TSNA, i.e. NNN, NNK, NAT and NAB). The total content, when tested, was at least less than 0.5 micrograms per milligram. Therefore, as indicated for nitrosamine content, the total amount of nitrosamines in the tobacco can be selectively reduced.

Step XI Packaging The purified nicotine is packaged in epoxy-coated drums under an inert gas such as nitrogen and stored in a cool and dry place.

EXAMPLE 4 PURIFICATION OF NICOTINE FROM DEEPLANTED LEAVES BY USING AN ION CHANGER COLUMN 10 15 20 25 30 529 462 21 Step 1 Harvest and deep freeze Fresh tobacco leaves from tobacco plants (= "green tobacco") are collected less than -20 ° C) three hours.

Step II Mixing and percolation The frozen tobacco leaves and calcium carbonate (CaCO3, limestone) or calcium hydroxide (slaked lime) 10% by weight are mixed in a machine steel mixer (rib type).

Water is added to bring the moisture in the mixture to 25% humidity. The slightly moist raw tobacco mixture is packed in a machine steel percolator, i.e. a cylindrical extractor. Purified water is percolated through the mixture to give a nicotinized soup.

Step III Extraction This nicotinized soup, i.e. the nicotine-containing water mother liquor, is transferred to a cation exchanger packed in high columns in machine steel or stainless steel. The nicotine cation exchange complex is washed with purified water to remove contaminants.

Step IV Separation The nicotine is eluted from the cation exchange column with 1M sulfuric acid. The nicotine salt precipitates and collects from the bottom of the vessel.

Step V Filtration and Purification The nicotine salt is filtered and purified by passing it through a stainless steel supercentrifuge (8000 rpm for at least 6 minutes) to remove traces of water. Step VI Testing After filtration and purification of the nicotine alkaloid, it was then tested for the nitrosamine content (TSNA, i.e.

NNN, NNK, NAT and NAB). The total content, when tested, was at least less than 0.5 micrograms per milligram.

Therefore, as indicated, the total amount of nitrosamines in the tobacco can be selectively reduced.

Step VII Packaging The purified nicotine is packaged in epoxy-coated drums under an inert gas such as nitrogen and stored in a cool and dry place.

EXAMPLE 5 REFINED TOBACCO CONTAINING PUREN Nicotine Step I Washing of the insoluble fraction After extraction of tobacco dust (stalks, top leaves, stem, debris and dust are tobacco waste), fresh or frozen tobacco leaves according to examples 1-4 above. the five times with pure water (acidic, alkaline and neutral) and finally with ethyl alcohol for 30 minutes each.

Step II Centrifugation and drying of the insoluble fraction The insoluble fraction is centrifuged for at least 6 minutes at 8000 rpm to remove most of the water.

Step III Centrifugation and drying of the insoluble fraction After centrifugation, the refined fibers are dried by fluidized bed drying until they have less than 1% moisture content. 10 15 20 25 529 462 23 Step IV Reconstitution of tobacco by impregnation After centrifugation and fluidized bed drying, the refined fibers (the net) are impregnated with the high purity nicotine solution to obtain purified clear tobacco, which has a nicotine content of 0.5-10% by weight.

Step V Testing the tobacco After purification and impregnation, the tobacco was then tested for the nitrosamine content (TSNA, i.e. NNN, NNK, NAT and NAB). The total content was at least less than 0.5 micrograms per gram. Therefore, as indicated, the total content of nitrosamines in the tobacco can be selectively reduced without substantially reducing other levels of components in the tobacco, such as carbohydrates, starch and cellulose. See table l.

Table 1. Total content of some pollutants in tobacco Batch No. TSNA As Pb Cd NO3 ~ N NO2-N 11/9 u / qu / g 4/9 u / qu / g 1 200kg 1,040 * 0.03 * 0.31 < 0.003 7 7 13 0.890 2 200kg <0.01 * 0.12 * 0.013 8.6 12 3 Nonnic 2 0.460 * 0.08 * 0.19 * 0.007 2.6 2.9 4 Nonnic 2 0.620 <0.01 * 0.13 * 0.004 3.3 4.4 Step VI Packaging The nicotine product or tobacco product may be formulated into one or more preparations, such as sachets, stick-packs, cheek pads or cheek pads or pressed into chewable tablets, lozenges, loosening tablets or lozenges. . The resulting product is packed in airtight packages to prevent losses by oxidation and / or evaporation of the nicotine. During storage which precedes the packaging in consumer packaging, the purified tobacco as well as the formulated products prepared from it are packaged in epoxy-tight drums under inert gas such as nitrogen and stored in cool and dry places.

EXAMPLE 6 Nicotine chewing gum product To obtain 1000 g of chewing gum, 22 g of nicotine obtained in Example 1-4 were mixed with chewing gum premix consisting of 600 g of Dreyco Gum Base, 205 g of sorbitol, 20 g of xylitol, 55 g of talc, 40 g of sodium bicarbonate, 20 g of sodium bicarbonate. , 3 g aspartame, 1 g acesulfame potassium, 5 g menthol and flavoring oils. Mixture of the nicotine, flavors, buffer and pre-melted gum base was made in a rubber kneader.

After the following manufacturing steps, nicotine chewing gum was obtained: extrusion, cooling, rolling, assessment, curing and packaging. The following values for strength and purity were achieved: Testing of the final rubber product Nicotine analysis method Nicotine analysis (initial) * 2.00-2.20 mg / unit Nicotine analysis (after 6 months 1.8-2.20 mg / unit storage) * 10 15 20 529 462 25 'Pollutants / degradation products Cotinine <0.5 2 ** 3 0.75% *** Nicotine trans ~ N - 3 0.5% ** 3 2.5% *** oxide Nicotine cis - N - 3 0.5% ** 3 1.75% *** oxide Total 3 1.0% ** 3 5% *** * = Determined in the finished product.

** = Values for nicotine carriers used in the kit 'and expressed as a percentage of its nicotine analysis value.

*** = Determined in the final product and expressed as a percentage nicotine analysis value.

Note: Carriers are polacrilex, cyclodextrin, starch, cellulose and cellulose derivatives, chewing gum bases, gelatin, sodium alginate, PVP and tobacco and other fibers.

The chewing gum was then tested for the nitrosamine content (TSNA, i.e. NNN, NNK, NAT and NAB). The total content was at least less than 0.1 micrograms per gram.

EXAMPLE 7 A SNAPPING PRODUCT The tobacco from Example 5 is made into portion snuff bags (portion bags) of woven or non-woven material. The tobacco product, such as portion bags, pouches, stick-packs, is packaged in airtight packages to prevent losses by oxidation and / or evaporation of the nicotine.

EXAMPLE 8 A TOBACCO GUM PRODUCT A tobacco chewing gum (1000 g) mixing a premix of 15 g glycerin and 15 g finely ground tobacco was prepared by (Example 5) with the chewing gum premix of Example 8 containing 600 g of Dreyco Gum. Base, 205 g sorbitol, 20 g xylitol, 55 g talc, 50 g sodium bicarbonate, 3 g aspartame, 1 g acesulfame potassium, 5 g menthol and flavoring oils.

Mixture of tobacco, flavors, buffer and pre-digested chewing gum base was made in a chewing gum kneader.

After the following manufacturing steps, a tobacco chewing gum was obtained: extrusion, cooling, rolling, assessment, curing and packaging.

Tobacco chewing gum: Nicotine analysis (initial) 2.00-2.20 mg / unit 1.8-2.20 mg / unit The tobacco chewing gum was then tested for (TSNA, i.e. NNN, NNK, NAT and NAB).

The nitrosamines were analyzed by a gas chromatography system, LC-MS-MS. (after 6 months storage) nitrosamine content The total content was at least less than 0.5 micrograms per gram.

EXAMPLE 9 ANALYSIS OF THE NITROSAMINES The nitrosamines were analyzed according to the method published in J Chromatogr A. 2003 Aug 8; l008 (2): l35-43, Jansson et al, “Analysis of tobacco-specific N-nitrosamines in snuff by ethyl acetate extraction and liquid chromatography -tandem mass spectrometry ”.

A fast, selective and sensitive method for routine analyzes of the four tobacco-specific N-nitrosamines, N'-nitrosonornicotine, N'-nitrosoanatabine, N'-nitrosoanabasine and 4- (methyl-nitrosamino) -1- (3-pyridyl) -1 - butanone in snus has been developed. The nitrosamines were isolated by ethyl acetate extraction and analyzed by LC-MS-MS.

Apart from evaporation and filtration, no further purification steps are needed in the proposed method.

The detection limits for standard solvents are between 0.0005 and 0.001 micrograms / ml (0.005 and 0.01 micrograms / g).

EXAMPLE 10 MEASUREMENT OF COLOR INDEX Color index was measured in the supernatant after dispersing and incubating the tobacco for 30 minutes followed by filtration. The measurements were made according to a modified "European Pharmacopea" method.

As a measure of the color of the nicotine product and / or tobacco product, the visible color index VCI was introduced.

The bags, which contain the refined tobacco product, were placed in water in a test tube made of clear glass with or without stirring. The visual color index is determined as follows: VCI VCI VCI Clear solution 1 No opalization 1 No particles 1 Slight light 2 Tendency to 2 Some particles 2 brown solution opalization Light brown 3 Slight opalization 3 Particles 3 solution Brown solution 4 Opalizing 4 Particles giving 4 gives tendencies to sedimentation Dark brown 5 White opalescent 5 Particles as 5 solution gives sediment Dark dark 6 White opalescent 6 Particles as 6 brown solution cloudy gives clear sediment 10 15 ordinary business, which gives the following 28 529 462 The visual color index has been tested for the refined tobacco and ordinary Swedish snus bought in any Result; the sum of each VCI index when tested; time is summarized; min The invented tobacco VCI Ordinary "snus" brand VCI Clear solution, no 3 Clear solution, no 3 O opalization, no opalization, no particles particles Clear solution, no. 3 Slightly light brown solution, 4 1 opalization, no no opalization, no particles particles Clear solution, none 3 Light brown solution, none 5 2 opalization, no opalization, no particles particles Clear solution, tendency 3 Brown solution, none 8 5 to opalization, no opalization, particles particles Clear solution, tendency 3 Dark brown solution, none 11 10 for opalization, no opalization, particles that particles give sediment Clear solution, tendency 3 Dark dark brown solution, 16 20 for opalization, no particles opalization, particles that give sediment The color index gives a product that has less risk of staining the teeth and less smell from the tobacco .

EXAMPLE 11 MEASUREMENT OF HEAVY METALS, NITRITES AND NITRATES Furthermore, the nicotine product and the tobacco product (Example 5) will have a reduced amount of one or more of substances such as Pb, As and / or Cd, measured using atomic absorption. The following metals were measured: Fe Al B V Mo Ti Hg Cu Cr As Bi W Se Co Pb P S Zn Cd Mn Ni Sr Na Mg Ca K nitrates nitrites The method is a standard method described in Swedish or international standard (SS 028183, ISO). The dried and / or moisture-containing tobacco is treated according to standards and analyzed by atomic absorption, ICP optical, ICP-MS and / or ICP-OES. The results are seen below in Table 2. 529 462 NN NNN NN NN m5 N_N NN NN 35 NNN5 v NN NNH NNNNz NN NS NN NH N NN NN NN NN NN5 NNN5 v NS NNH NNNNz NN NNN 3 NNH NN NN NN NN NN N35 NN NNNNz NN Ni NN Nï NN N_N NN NN NN5 N35 v NN NN NNNNz N \ N1 N \ NN N \ N1 N \ N1 N \ N1 NB: N \ N1 N \ N1 N \ N1 N \ N1 Nää N \ N1 z nu N: mz az en wm mm oz É mm Hz Q fi mm N5 N35 N NN5 N HN5v NN5 3N5v NNNNz NN5 N35 .N NN5 N NN5 * NN5 N35v NNNNz NNN5 N N35 N NN5 ä, NN5v N35 N35 N35 v NNN N NN v NNN NN5 * N35 N35 N NNNNz ^ N5 ^ N5 ^ N5 NN5 ANJ: QNNN | N5N LTNN | H5v »N5vv | N5N: Bämïmvwz m5 N5 N5 NN5 N5 Reach m5 N NN5 Reach äwc fi w m \ @ 1 @ \ © 1 m \ @ 1 m \ @ 1 m \ m1 m \ @ 1 mc mumm Nz vu sm m4 Hu Nm N Haw fl mß 529 462 Öl OH m va »må ïšmz md wâ Éomz 3 wá Nøomz Û Ü» Somz m \ m1 m \ m1 HEQ .HNUHHn- ... nz HÜUNHUHZ .HC mwßw

Claims (8)

10 15 20 25 30 35 529 462 32 PATENT REQUIREMENTS 1. A nicotine product comprising; a. less than 0.5 pg nitrosamines / mg nicotine, and b. a carrier, diluent or excipient. The nicotine product according to claim 1, wherein the nitrosamine content is less than 0.3 pg / mg nicotine. The nicotine product according to claim 1, wherein the nitrosamine content is less than 0.1 pg / mg nicotine The nicotine product according to any one of the preceding claims, wherein the nitrosamine content is less than 0.01 pg / mg nicotine. The nicotine product according to any one of the preceding claims, wherein the nitrosamines comprise at least N'-nitrosonoricotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB) and 4- (N-methylnitrosamino) -1-) 3 pyridyl) -1-butanone (NNK) and 4- (methylnitrosamino) -1- (3-pyridyl) -1-butanone. The nicotine product according to any one of the preceding claims, wherein the carrier is selected from the group consisting of polacrilex, cyclodextrin, starch, cellulose and cellulose derivatives, chewing gum bases, gelatin, sodium laginate, PVP and fibers. The nicotine product of claim 6, wherein the fibers are tobacco fibers. The nicotine product according to claim 6, wherein the nicotine product is selected from the group consisting of tablet, capsule,