EP1458252B1 - Tabac et/ou substitut de tabac en combinaison avec du tabac s'utilisant comme tabac a priser dans la cavite buccale - Google Patents

Tabac et/ou substitut de tabac en combinaison avec du tabac s'utilisant comme tabac a priser dans la cavite buccale Download PDF

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EP1458252B1
EP1458252B1 EP02795287A EP02795287A EP1458252B1 EP 1458252 B1 EP1458252 B1 EP 1458252B1 EP 02795287 A EP02795287 A EP 02795287A EP 02795287 A EP02795287 A EP 02795287A EP 1458252 B1 EP1458252 B1 EP 1458252B1
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Prior art keywords
nicotine
tobacco
composition according
release
membrane
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German (de)
English (en)
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EP1458252A2 (fr
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Henri Hansson
Lars Hovgaard
Christer Spegel
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Galenica AB
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Galenica AB
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    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B13/00—Tobacco for pipes, for cigars, e.g. cigar inserts, or for cigarettes; Chewing tobacco; Snuff
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes

Definitions

  • the present invention relates to a novel composition for the use as snuff in the oral cavity, the composition comprising tobacco and/or tobacco in combination with a tobacco substitute encapsulated in a membrane material comprising one or more membranes at least one of which being water permeable and water-insoluble.
  • a novel composition enables a selective release of e.g. nicotine while it at the same time reduces the release of substances, which normally lead to unwanted side effects.
  • the novel compositions may be used as a healthier alternative to snuff and other tobacco products such as, e.g., cigarettes, cigars and pipe.
  • the invention also relates to methods for giving up smoking, reducing nicotine craving, reducing side effects normally related to smoking and snuffing of tobacco as well to a method for the preparation of a composition according to the invention.
  • various buffer systems may be added, e.g. carbonates.
  • the moist snuff is either packed loosely, as bulk in a box or as single doses in small non-woven bags. A number of the filled and sealed bags are then packed in a box.
  • the moist snuff as a single dose has become popular due to the ease of use compared to the bulk product.
  • the popularity of moist snuff is most probably due to its pharmacological nicotine absorption profile.
  • the dose of nicotine and speed of absorption is approximately 10 ng per ml over 10 minutes.
  • Plasma nicotine concentrations rapidly increase within the first few minutes of the use of snuff and reach levels comparable to those obtained from smoking cigarettes within 30 min of use. Measurements of plasma nicotine concentrations after a single day of moist snuff consumption also yielded levels similar to cigarette use.
  • the kinetics is slightly slower compared to the kinetics when smoking tobacco, such as e.g. cigarettes and cigars; however, the overall amount of nicotine absorbed is higher when snuff is employed.
  • snuff is the vast number of compounds, more or less harmful to the body, e.g. different tobacco-specific nitrosamines, which are compounds known to cause different diseases such as, e.g., gastro-intestinal disorders and cancer.
  • US 4,141,369 describes a method of inhaling the nicotine from tobacco without combustion of the tobacco.
  • Another way of avoiding the harmful substances contained in tobacco is to substitute tobacco with nicotine.
  • Various devices have also be constructed in order to deliver nicotine from a tobacco composition placed in the oral cavity:
  • US 5,346,734 describes a perforated latex oral pouch for loose, moist snuff, the pouch serving as a barrier to avoid direct physical contact between the tobacco product and the gum.
  • the pouch has to be filled by the user, cut to fit the mouth cavity of the user and is re-usable.
  • US 6,162,516 describes a shield, which also has to be filled with snuff by the user, the shield acting as a barrier to reduce tobacco contact with the sensitive inner cheek lining and gum surfaces while using snuff.
  • the present invention provides a composition wherein the release of nicotine from snuff can be designed freely, even though the release of unwanted and harmful substances from the tobacco is dramatically reduced.
  • the present invention provides a composition for use in the oral cavity comprising tobacco and/or tobacco in combination with a tobacco substitute encapsulated in a membrane material comprising one or more membranes at least one of which being water permeable and water-insoluble.
  • the gist of the invention is the employment of a membrane material which makes it possible to deliver nicotine and/or a nicotine derivative, analog, salt, solvate or a mixture thereof in a predetermined manner and - at the same time - has the properties of withholding the substances which are unwanted to such a degree that the side-effects normally observed in connection with the use of snuff in the oral cavity are dramatically reduced.
  • the tobacco used in the novel snuff composition according to the invention may be natural tobacco leaves in order to preserve the authentic taste and feeling of tobacco.
  • the tobacco plant belongs to the family Solanaceae and the genus Nicotiana. More than 60 tobacco species exists, the most commonly used in smoking or snuffing tobacco products being Nicotiana tabacum and Nicotiana rustica.
  • To manufacture moist snuff the tobacco, which typically has a content of from about 1% to 8% nicotine, is dried, milled and mixed with a fermentative solution. The mixture is then fermented, typically for 5 days to 4 weeks at elevated temperature. After this the tobacco mass is mixed with a suitable buffer, such as e.g.
  • the water content in the final product may lie in the range from about 10 % to about 60 %.
  • additional compounds may be added, such as e.g. sweeteners, aroma substances and other taste additives, detergents and preservative, release modifying agents, and other liquids such as oil, organic solvents and herbal extracts.
  • the natural fermented tobacco may be partly substituted with a tobacco substitute, such as, e.g., nicotine and/or a nicotine derivative, analog, salt, solvate or a mixture thereof selected from the group consisting of nor-nicotine, lobeline, methylanabasine, anabasine, nicotine hydrochloride, nicotine dihydrochloride, nicotine sulphate, nicotine monotartrate, nicotine bitartrate, nicotine salicylate or nicotine zinc chloride monohydrate.
  • a tobacco substitute such as, e.g., nicotine and/or a nicotine derivative, analog, salt, solvate or a mixture thereof selected from the group consisting of nor-nicotine, lobeline, methylanabasine, anabasine, nicotine hydrochloride, nicotine dihydrochloride, nicotine sulphate, nicotine monotartrate, nicotine bitartrate, nicotine salicylate or nicotine zinc chloride monohydrate.
  • some additional filler may be added, such as, e.g., non-digestible fibers.
  • the tobacco and/or tobacco substitute may preferably have a content of nicotine and/or a nicotine derivative, analog, salt, solvate or a mixture thereof, from about 0% w/w to about 30% w/w such as, e.g., from about 0.5% w/w to about 25% w/w, from about 0.1% w/w to about 20% w/w, from about 0.1% w/w to about 15% w/w, from about 0.1% w/w to about 10% w/w, from about 0.1% w/w to about 9% w/w or from about 0.1% w/w to about 8% w/w.
  • a content of nicotine and/or a nicotine derivative, analog, salt, solvate or a mixture thereof from about 0% w/w to about 30% w/w such as, e.g., from about 0.5% w/w to about 25% w/w, from about 0.1% w/w to about 20% w/w, from about 0.1% w/w to about 15%
  • the tobacco and/or tobacco substitute is enclosed in a membrane material.
  • the membrane material may comprise one or more membranes.
  • membrane describes a thin polymeric film having natural pores and acting as a selective permeability barrier. The term does not include papermade material or polymeric materials in which not-naturally occurring openings have been made.
  • At least one of the membranes may be water-insoluble to prevent spreading of the snuff in the oral cavity, and to maintain the beneficial properties of the selective membrane material during use, with respect to the withholding of unwanted substances.
  • At least one of the membranes may be water permeable in order to allow water to diffuse into the encapsulated tobacco and/or tobacco substitute and to allow e.g. nicotine to diffuse through the polymeric membrane material and thus becoming available for absorption.
  • the membranes may have a predominantly hydrophilic or hydrophobic nature.
  • the hydrophilic or hydrophobic nature of the membrane has an effect on the release of substances such as, e.g., nicotine through the membrane, since the flow of substances through the membrane is dependent on the ability of the membrane to hydrate, e.g. create hydro-channels through the membrane. These hydro-channels are a prerequisite for molecular transport when dry polymeric membranes are used.
  • the flow of hydrophilic substances through a hydrophobic membrane is slower compared to a hydrophilic membrane. This is probably due to less swelling of the hydrophobic membrane pores, i.e. in the hydrophobic membranes nicotine diffusion occurs through well-organized polymeric material and hydrophobic organized water.
  • One or more of the membranes used for making the composition may be a synthetic or semi-synthetic membrane.
  • a synthetic or semi-synthetic membrane As is given some examples of natural, synthetic and semi-synthetic hydrophilic and hydrophobic membranes, which may be used in a novel snuff composition according to the invention.
  • membranes are membranes made of cellulose acetate and derivates thereof, carboxymethyl cellulose membranes, polycellulose ester membranes, other cellulose derivatives such as, e.g., ethylcellulose, propylcellulose, polyethylene membranes, polypropylene membranes, polystyrene membranes, polyvinyl chloride membranes, polyvinyl acetate membranes, membranes made of polymers of methacrylates and acrylates, natural rubber membranes, polycarbonate membranes, polyethylene terephthalate membranes, polyester membranes, polyamide membranes and nylon membranes.
  • cellulose acetate and derivates thereof such as, e.g., ethylcellulose, propylcellulose, polyethylene membranes, polypropylene membranes, polystyrene membranes, polyvinyl chloride membranes, polyvinyl acetate membranes, membranes made of polymers of methacrylates and acrylates, natural rubber membranes, polycarbonate membranes, polyethylene tere
  • At least the outer membrane in the membrane material enclosing the tobacco and/or tobacco substitute may be made from a biocompatible and physiologically acceptable polymeric material, since the novel snuff composition has to be placed close to or in contact with the mucous membrane in the oral cavity during use.
  • At least one of the membranes in a membrane material may be surface treated with e.g. polycarbophils to obtain a bioadhesiveness of the novel snuff composition in the oral cavity.
  • the molecular weight cut off of the membrane material used in the novel snuff composition may be varied to obtain a desired release of nicotine and other substances through the membrane material.
  • the molecular weight cut-off of a membrane is defined as the molecular weight of the smallest molecule of which 90 % will be prevented from permeating the membrane.
  • the exact permeability of a molecule is dependent on the shape, the degree of hydration and the charge of the molecule.
  • At least one of the membranes comprising the membrane material may have a molecular weight cut-off from about 500 to about 40,000 such as, e.g., from about 500 to about 5,000, from about 800 to about 4,000, from about 1,000 to about 3,500; or from about 2,000 to about 40,000, from about 3,000 to about 30,000, from about 5,000 to about 25,000, from about 7,500 to about 20,000 or from about 10,000 to about 20,000.
  • a molecular weight cut-off from about 500 to about 40,000 such as, e.g., from about 500 to about 5,000, from about 800 to about 4,000, from about 1,000 to about 3,500; or from about 2,000 to about 40,000, from about 3,000 to about 30,000, from about 5,000 to about 25,000, from about 7,500 to about 20,000 or from about 10,000 to about 20,000.
  • the release of nicotine and/or other substances through the membrane material is also dependent on the thickness of the membrane materiel.
  • the diffusion process of molecules through the membrane is decreased when the membrane thickness is increased and vice versa.
  • the thickness of the membrane material may be varied in respect of obtaining a desired release of nicotine and other substances through the membrane material.
  • the lower limit for the membrane material thickness is determined by what is possible from a practical point of view, and the upper value is restricted by what will allow a comfortable fit of the novel snuff composition in the oral cavity of the user.
  • At least one of the membranes comprising the membrane material may have a thickness of from 2 to about 200 ⁇ m such as, e.g., from about 5 to about 100 ⁇ m, from about 7.5 to about 50 ⁇ m, from about 7.5 to about 40 ⁇ m, from about 7.5 to about 35 ⁇ m, from about 7.5 to about 30 ⁇ m or from about 7.5 to about 25 ⁇ m.
  • nicotine or a nicotine derivative, analog, salt, solvate or a mixture thereof, selected from the group consisting of nor-nicotine, lobeline, methylanabasine, anabasine, nicotine hydrochloride, nicotine dihydrochloride, nicotine sulphate, nicotine monotartrate, nicotine bitartrate, nicotine salicylate or nicotine zinc chloride monohydrate, has to be released from the composition.
  • the release profile may be designed with respect to the rate and amount of nicotine and unwanted substances released by the membrane.
  • the release of nicotine and/or a derivative, analog, salt, solvate or a mixture thereof from a novel snuff composition may be designed to be released in a sufficient amount and/or a sufficient rate to enable a desired effect and on the other hand be designed to retain substances, which normally give rise to side-effects, such as, e.g., nitrosamines, and/or to release such substances in a substantially low amount and/or at a substantially slow rate.
  • the Impurity Index- IPI - is introduced.
  • the IPI is calculated from the UV-spectra recorded from 200 nm to 900 nm as described in Example 2, and is defined as the ratio of the sum of peak heights other than that of nicotine (i.e. thus including unwanted and harmful substances) to the peak height of nicotine. In other words, a low IPI reflects that a large amount of nicotine is released through the membrane compared to the amount of unwanted substances.
  • the impurity index IPI is at the most 3.0 such as, e.g. at the most 2.75, at the most 2.5, at the most 2.0, at the most 1.75, at the most 1.5, at the most 1.5 or at the most 1.4 when measured after 90 min.
  • the release profile of nicotine and/or a derivative, analog, salt, solvate or a mixture thereof from the invention could e.g., be fast and equivalent to the release of nicotine from the commercially available moist snuff, while maintaining a low IPI value, i.e. limiting the release of unwanted substances.
  • a composition according to the invention can be designed to release nicotine and/or a derivative, analog, salt, solvate or mixture thereof in a controlled manner such as, e.g., fast (faster than from the reference product employed in the examples herein), relatively fast (i.e. similar or almost similar to the reference product employed in the examples herein), delayed (i.e. with a lag time in which period no nicotine is released followed by a release of nicotine), prolonged or sustained (i.e. a relatively slower release than the reference product to avoid any peak concentration and to obtain a relatively constant plasma concentration of nicotine after application).
  • fast fast
  • relatively fast i.e. similar or almost similar to the reference product employed in the examples herein
  • delayed i.e. with a lag time in which period no nicotine is released followed by a release of nicotine
  • prolonged or sustained i.e. a relatively slower release than the reference product to avoid any peak concentration and to obtain a relatively constant plasma concentration of nicotine after application.
  • the release of nicotine or a derivative, analog, salt, solvate or a mixture thereof may be delayed compared to the commercially available moist snuff, to mimic the effect of nicotine replacement products such as, e.g., patches.
  • the release of nicotine or a derivative, analog, salt, solvate or a mixture thereof may be determined by the release test described in Example 1, but other suitable methods for determining the release of nicotine may also be used, i.e. the embodiments of the invention described below referrer to Example 1 without limiting the relevant release tests to the one described in Example 1.
  • the tobacco and/or tobacco in combination with a tobacco substitute composition may be designed so that at least about 50% w/w of the total content of nicotine and/or a derivative, analog, salt, solvate or a mixture thereof is released within at the most 60 min when subject to the release test described in Example 1 below.
  • the tobacco and/or tobacco substitute composition may be designed so that at the most 25% w/w of the total content of nicotine and/or a derivative, analog, salt, solvate or a mixture thereof is released within at the most 60 min when subject to the release test described in Example 1 below.
  • the tobacco and/or tobacco substitute composition may be designed so that at least about 50% w/w of the total content of nicotine and/or a derivative, analog, salt, solvate or a mixture thereof is released within at the most 120 min when subject to the release test described in Example 1 below.
  • release profiles for compositions according to the invention are described as %w/w released of total nicotine content as a function of time, measured at 0, 3, 30, 90 and 180 minutes.
  • the release profiles according to the invention also includes profiles described by only one or any combination of the values below, i.e. a release profile according to the invention could be defined by e.g. the %w/w release of nicotine at 3 minutes and 90 min, or at 3 and 90 and 180 minutes, or at 90 and 180 minutes or any possible combination of the values shown below.
  • a composition according to the invention is suitable designed to release nicotine and/or a derivative, analog, salt, solvate or a mixture thereof from the tobacco or tobacco in combination with the tobacco substitute with the following characteristics: time (min) % w/w released of total nicotine content 0 from about 0 to about 20 such as, e.g., from about 0 to about 15 or from about 0 to about 10, 3 from about 0 to about 40 such as, e.g., from about 0 to about 35, from about 0 to about 30, from about 0 to about 25, from about 0 to about 20, 30 from about 2 to about 100, such as, e.g., from about 2 to about 90, from about 2 to about 80, from about 2 to about 70, from about 2 to about 65, from about 2 to about 60, from about 5 to about 60, from about 5 to about 55, from about 7.5 to about 55 or from about 10 to about 50, op til 100 90 from about 10 to about 100 such as, e.g., from about 10 to about 95, from about
  • a composition according to the invention releases nicotine and/or a derivative, analog, salt, solvate or a mixture thereof from the tobacco or the tobacco in combination with a tobacco substitute with the following release profile characteristics: time (min) % w/w released of total nicotine content 0 from about 0 to about 15 3 from about 1 to about 25 30 from about 7.5 to about 55 90 from about 35 to about 80 180 from about 65 to about 100 and the release is determined as described herein in Example 1.
  • a composition according to the invention releases, nicotine and/or derivative, analog, salt or solvate thereof from the tobacco or the tobacco in combination with a tobacco substitute with the following release profile characteristics: time (min) % w/w released of total nicotine content 0 from about 0 to about 10 3 from about 1 to about 20 30 from about 10 to about 50 90 from about 40 to about 90 180 from about 70 to about 100 and the release is determined as described herein in Example 1.
  • a composition according to the invention releases nicotine and/or a derivative, analog, salt, solvate or a mixture thereof from the tobacco or the tobacco in combination with a tobacco substitute with the following release profile characteristics: time (min) % w/w released of total nicotine content 0 from about 0 to about 10 3 from about 1 to about 20 30 from about 30 to about 50 90 from about 65 to about 90 and the release is determined as described herein in Example 1.
  • membrane material properties such as hydrophobicity, hydrophilicity, molecular weight cut-off and membrane thickness may be used in designing a desired release profile for nicotine or a derivative, analog, salt, solvate or mixture thereof.
  • a multi-layer membrane is e.g. designed to contain one membrane material being hydrophilic and a second membrane material being lipophilic. Both membrane components are chosen in such a manner that the membrane material has a molecular cut off large enough for the relatively small nicotine molecule to pass through with ease.
  • amphiphilic nature of nicotine enables it to pass both hydrophilic and hydrophobic materials while a majority of both hydrophilic and lipophilic unwanted and harmful substances are excluded from permeation through the membrane material.
  • Many other combinations of different types of membranes are of course possible and based on the disclosure herein a skilled person will know how to chose different membranes in order to obtain a suitable release.
  • compositions according to the invention are a composition wherein the membrane material is a bi-layer membrane with one membrane being preferentially hydrophilic and one membrane being predominantly hydrophobic. Both membranes possess high permeability to nicotine while maintaining low aqueous pore diffusion.
  • the release profile of nicotine could either be identical to the release profile of original snuff or it could be designed to have a prolonged or sustained release. The unwanted and harmful substances from the tobacco should substantially be maintained inside the membrane.
  • a composition according to the invention may attain all possible sizes and shapes, such as, e.g. round, circular, oblong, elliptical, square, rectangular or trapezoidal.
  • the shape and/or size chosen may be such as to allow a comfortable fit in the oral cavity.
  • the location in the oral cavity of a composition according to the invention may be centered or to the sides under the upper front lip, centered or to the sides under the lower front lip, under the tongue or in the cheeks.
  • the invention also relates to use of a composition according to the invention as a smoke substitute and it can be used by persons who suffer from nicotine craving or who want to give up or reduce smoking.
  • the content of tobacco and/or a tobacco substitute is adjusted to the individual purposes and it is possible to design a kit comprising compositions according to the invention with different concentrations of tobacco and/or a tobacco substitute.
  • Such compositions in a kit could e.g. contain compositions with a decreasing content of tobacco or nicotine.
  • Membranes made of regenerated cellulose acetate dialysis tubing with varying MW cut-off together with vinyl and polyethylene membranes with various thicknesses were tested with respect to the diffusion profiles over the membranes of nicotine released from tobacco.
  • snuff tobacco SVENSKT SNUS, GOTHIATEK, General
  • PBS phosphate buffered saline according to Ph. Eur.
  • PBS with a pH of 6.6 was placed in the receiver chamber.
  • the cells of the diffusion chamber were kept at a temperature of 37°C ⁇ 0.5°C by attachment to a water bath. The temperature control was made in order to simulate the environment of the oral cavity.
  • Diffusion profiles were constructed by sampling from the receiver chamber at 0, 3, 30, 60, 90, 120, (110 min for the polyethylene membrane) and 180 min after the start of the diffusion experiment.
  • the concentration of nicotine in the receiver chamber was measured by HPLC, using a C-18, 5 ⁇ , 4.5 mm x 15 cm column, employing a mobile phase consisting of 70 % v/v 0.1 M phosphate buffer (pH 4.5), 30 % acetonitrile, and 2.3 g sodium dodecyl sulphate/liter at a flow rate of 1 ml /min and a temperature of 40°C.
  • the sample volume was 10 ⁇ l and detection was carried out using a UV-detector running at 260 nm.
  • the membranes used were regenerated cellulose acetate dialysis tubing with varying MW cut-off and vinyl and polyethylene membranes with varying thickness.
  • Table I shows a comparison of the release profile of nicotine for a commercial non-woven snuff-bag, and a piece of filter paper used as reference in the experiments. The measurements were performed as described above, and the results are the mean of 2 single runs. Table I. Comparison of the nicotine release profile for a commercial non-woven filter and a reference paper filter Filter type Nicotine released (mg/ml) 15 sec. 30 min. 60 min. 90 min. Reference paper filter 11.5 64.4 92.0 202.4 Commercial non-woven filter 9.4 65.8 90.1 205.5
  • Hydrophobic membranes e.g. vinyl and polyethylene membranes
  • the slower profile is probably due to less swelling of the hydrophobic membrane pores, i.e. in the hydrophobic membranes nicotine diffusion occurs through well-organized polymeric material and hydrophobic organized water rather than through aqueous pores.
  • Figure 1 shows that the release of nicotine over a hydrophilic membrane made of regenerated cellulose acetate dialysis tubing is high and close to the nicotine release over the reference filter paper.
  • Figure 1 also shows that the physical properties, i.e. the molecular weight cut-off and thickness of the hydrophilic membrane, affect the permeability of nicotine as stated below.
  • a membrane with a relatively small molecular weight cut-off tends to have a sigmoid release profile for nicotine.
  • a considerable lag time is expected before the nicotine starts to permeate the membrane, even though the size of a nicotine molecule is significantly smaller than the molecular weight cut-off of 3,500.
  • a membrane with a higher molecular weight cut-off e.g. a molecular weight cut-off of 13,000, seems to have a release profile for nicotine that is very close to the release profile for nicotine of the reference filter paper.
  • This difference may be due to a much lower aqueous mobility of nicotine in the membrane with a molecular weight cut-off of 3,500, compared to the membrane with a molecular weight cut-off of 13,000.
  • Figure 1 also shows that when the thickness of a membrane increases, then the flux of nicotine through the membrane decreases.
  • Example 1 shows that it is possible to design a polymeric membrane which gives rise to a release profile of nicotine from moist tobacco through the membrane very similar to the release profile through a commercial non-woven snuff-bag, i.e. with respect to the shape of the profile and the individual release data (time, percentage released). Especially, it seems that a hydrophilic membrane material is suitable. Furthermore, the release profile is dependent of the molecular weight cut-off of the membrane, the thickness of the membrane and of the membrane material itself.
  • Example 1 also shows that some hydrophobic membranes, e.g. vinyl and polyethylene membranes, have a slower nicotine release profile compared to the hydrophilic membranes.
  • hydrophobic membranes e.g. vinyl and polyethylene membranes
  • membranes which enable a specific release of nicotine, i.e. it is possible to design membranes having desired release characteristics e.g. a quick or a slow release of nicotine dependent on the purpose of the composition.
  • desired release characteristics e.g. a quick or a slow release of nicotine dependent on the purpose of the composition.
  • the specific features of a membrane or a membrane material can be used to design a controlled and well-defined release profile for the release of nicotine from a composition according to the invention.
  • Membranes made from regenerated cellulose acetate dialysis tubing with varying thickness and molecular weight cut-off were tested for their selectivity in transporting nicotine across the membrane, while unwanted and potentially harmful substances are retained in the tobacco.
  • the Impurity Index - lPl - was introduced as a measure for the selective release of nicotine.
  • the IPI is calculated from the UV-spectra recorded from 200 nm to 900 nm, and is defined as the ratio of the sum of peak heights other than that of nicotine (i.e. thus including unwanted and harmful substances) to the peak height of nicotine. All measurements are performed in the receiver chamber, i.e. after permeation through the membrane in question. The IPI is measured 3, 30 and 90 min after start of the experiment, cf. above. In those cases where any additionally substances are added to the tobacco composition such as, e.g., sweeteners, flavors, detergents, buffers, etc. the peak heights of these are normally not included when calculating the sum of peak height as described above.
  • IPI Impurity index
  • the decrease in lPl is not merely a result of a decrease in the overall release rate. Accordingly, the release profiles relating to nicotine and employing cellulose membranes with a molecular weight cut-off of 13,000 are only a few percent lower than the release profile for the reference filter paper. Thus, employment of such membranes enables a release, which permits release of wanted substances (i.e. nicotine) while retaining unwanted substances.
  • Example 2 shows that no significant loss in membrane selectivity is observed as the membrane thickness is being decreased. Therefore, further studies to investigate the relationship between membrane thickness, molecular weight cut-off of the membrane and amount of nicotine transferred over the membrane were performed by analyzing selected data from Example 1.
  • the maximum slope for each release profile has been deduced.
  • the maximum slope i.e. percentage nicotine release per time unit, dR/dt represents the maximum flux of nicotine through the membranes (see Table 4).
  • Figure 3 shows a plot of the maximum flux as a function of membrane thickness for the cellulose membrane with a molecular weight cut-off of 13,000.
  • the Figure shows that the flux of nicotine through a membrane is approaching the flux through a reference filter paper, which practically has no barrier to the nicotine diffusion, at a membrane thickness of about 10 ⁇ m.
  • a hydrophilic membrane with a molecular cut off about 13,000 does not seem to give rise to any boundary layer/membrane effects or any major diffusion limitations for nicotine.
  • a thickness of approx.10 ⁇ m will give a release profile equal to the original commercially available non-woven moist snuff pouches.
  • the sensation of taking up nicotine into the blood stream from the oral cavity was scored using a scale rating from zero to five, with zero indicating no feeling and 5 indicating a very strong feeling of uptake, leading to dizziness and nausea.
  • the results show that the effect of nicotine uptake from the novel snuff composition is slightly delayed compared to the sensation of nicotine uptake from the commercially available bag snuff.
  • the volunteers feel an effect rated 5 after 8 to 10 minutes.
  • the volunteers feel the maximum effect between 12 to 16 minutes.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Manufacture Of Tobacco Products (AREA)
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Claims (39)

  1. Composition destinée à être utilisée dans la cavité orale, comprenant un matériau choisi dans l'ensemble constitué par le tabac et le tabac en combinaison avec un substitut du tabac, le matériau étant encapsulé dans un matériau de membrane comprenant une ou plusieurs membranes, au moins l'une de celles-ci étant perméable à l'eau et insoluble dans l'eau, et dans laquelle l'indice d'impureté de la composition - quand il est déterminé comme décrit ici - est d'au plus 3,0, comme par exemple d'au plus 2,75, d'au plus 2,5, d'au plus 2,0, d'au plus 1,75, d'au plus 1,5, d'au plus 1,5 ou d'au plus 1,4 quand il est mesuré après 90 minutes.
  2. Composition selon la revendication 1, pour une utilisation sous la forme d'une prise.
  3. Composition selon la revendication 1 ou 2, laquelle composition n'est pas sous la forme d'une gomme à mâcher.
  4. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins une membrane est une membrane synthétique ou semi-synthétique.
  5. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins une membrane est faite en caoutchouc naturel.
  6. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins une membrane est une membrane biocompatible.
  7. Composition selon l'une quelconque des revendications précédentes, dans laquelle la membrane est en un matériau polymère par exemple choisi dans l'ensemble constitué par l'acétate de cellulose et ses dérivés, la carboxyméthylcellulose, les polyesters cellulosiques, d'autres dérivés de cellulose comme par exemple l'éthylcellulose, la propylcellulose, le polyéthylène, le polypropylène, le polystyrène, le poly(chlorure de vinyle), le poly(acétate de vinyle), les polymères de méthacrylates et d'acrylates, le caoutchouc naturel, les polycarbonates, le poly(téréphtalate d'éthylène), les polyesters, les polyamides et le nylon.
  8. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins l'une des membranes a un caractère principalement hydrophile.
  9. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins l'une des membranes a un caractère principalement hydrophobe.
  10. Composition selon l'une quelconque des revendications précédentes, dans laquelle de la nicotine et/ou un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges est libéré par le tabac ou le substitut du tabac.
  11. Composition selon la revendication 10, dans laquelle la libération est une libération contrôlée.
  12. Composition selon la revendication 10 ou 11, dans laquelle la nicotine et/ou un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges est choisi dans l'ensemble constitué par la nor-nicotine, la lobéline, la méthylanabasine, l'anabasine, le chlorhydrate de nicotine, le dichlorhydrate de nicotine, le sulfate de nicotine, le monotartrate de nicotine, le bitartrate de nicotine, le salicylate de nicotine ou le zinc-chlorure de nicotine monohydraté.
  13. Composition selon l'une quelconque des revendications précédentes, qui i) est conçue pour libérer de la nicotine et/ou un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges en une quantité suffisante et/ou à un débit suffisant pour permettre un effet souhaité et ii) est conçue pour retenir les substances qui conduisent normalement à des effets secondaires et/ou pour libérer ces substances en une quantité sensiblement faible et/ou à un débit sensiblement faible.
  14. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins l'une des membranes comprenant le matériau de membrane a une séparation des masses moléculaires d'environ 500 à environ 40 000, comme par exemple d'environ 500 à environ 5 000, d'environ 800 à environ 4 000, d'environ 1000 à environ 3 500, ou d'environ 2 000 à environ 40 000, d'environ 3 000 à environ 30 000, d'environ 5 000 à environ 25 000, d'environ 7 500 à environ 20 000 ou d'environ 10 000 à environ 20 000.
  15. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins l'une des membranes comprenant le matériau de membrane a une épaisseur d'environ 2 à environ 200 µm, comme par exemple d'environ 5 à environ 100 µm, d'environ 7,5 à environ 50 µm, d'environ 7,5 à environ 40 µm, d'environ 7,5 à environ 35 µm, d'environ 7,5 à environ 30 µm ou d'environ 7,5 à environ 25 µm.
  16. Composition selon l'une quelconque des revendications précédentes, dans laquelle au moins 50 % en poids de la teneur totale en nicotine et/ou dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges est libéré au plus dans les 60 minutes quand elle est soumise au test de libération décrit ici.
  17. Composition selon l'une quelconque des revendications 1 à 15, dans laquelle au plus 25 % en poids de la teneur totale en nicotine et/ou dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges est libéré au plus dans les 60 minutes quand elle est soumise au test de libération décrit ici.
  18. Composition selon l'une quelconque des revendications 1 à 15 ou 17, dans laquelle environ 50 % en poids de la teneur totale en nicotine et/ou dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges sont libérés au plus dans les 120 minutes quand elle est soumise au test de libération décrit ici.
  19. Composition selon l'une quelconque des revendications précédentes, dans laquelle la libération de nicotine et/ou dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges à partir du tabac ou du substitut de tabac a les caractéristiques suivantes :
    Temps (min) % en poids libéré de la teneur totale en nicotine
    0 d'environ 0 à environ 20, comme par exemple d'environ 0 à environ 15 ou d'environ 0 à environ 10
    3 d'environ 0,5 à environ 40, comme par exemple d'environ 0,5 à environ 35, d'environ 0,5 à environ 30, d'environ 1 à environ 25 ou d'environ 1 à environ 20
    30 d'environ 2 à environ 65, comme par exemple d'environ 2 à environ 60, d'environ 5 à environ 60, d'environ 5 à environ 55, d'environ 7,5 à environ 55 ou d'environ 10 à environ 50
    90 d'environ 10 à environ 100, comme par exemple d'environ 10 à environ 95, d'environ 15 à environ 90, d'environ 20 à environ 90, d'environ 25 à environ 85, d'environ 30 à environ 80, d'environ 35 à environ 80 ou d'environ 40 à environ 80
    180 d'environ 40 à environ 100, comme par exemple d'environ 45 à environ 100, d'environ 50 à environ 100, d'environ 55 à environ 100, d'environ 60 à environ 100, d'environ 65 à environ 100 ou d'environ 70 à environ 100
    et la libération est déterminée comme décrit ici.
  20. Composition selon l'une quelconque des revendications précédentes, dans laquelle la libération de nicotine et/ou dérivé, analogue, sel, solvate de nicotine
    ou un de leurs mélanges à partir du tabac ou du substitut de tabac a les caractéristiques suivantes : Temps (min) % en poids libéré de la teneur totale en nicotine 0 d'environ 0 à environ 15 3 d'environ 1 à environ 25 30 d'environ 7,5 à environ 55 90 d'environ 35 à environ 80 180 d'environ 65 à environ 100
    et la libération est déterminée comme décrit ici.
  21. Composition selon l'une quelconque des revendications précédentes, dans laquelle la libération de nicotine et/ou dérivé, analogue, sel, solvate de nicotine
    ou un de leurs mélanges à partir du tabac ou du substitut de tabac a les caractéristiques suivantes : Temps (min) % en poids libéré de la teneur totale en nicotine 0 d'environ 0 à environ 10 3 d'environ 1 à environ 20 30 d'environ 10 à environ 50 90 d'environ 40 à environ 90 180 d'environ 70 à environ 100
    et la libération est déterminée comme décrit ici.
  22. Composition selon l'une quelconque des revendications précédentes, dans laquelle la libération de nicotine et/ou dérivé, analogue, sel, solvate de nicotine
    ou un de leurs mélanges à partir du tabac ou du substitut de tabac a les caractéristiques suivantes : Temps (min) % en poids libéré de la teneur totale en nicotine 0 d'environ 0 à environ 10 3 d'environ 1 à environ 20 30 d'environ 30 à environ 50 90 d'environ 65 à environ 90
    et la libération est déterminée comme décrit ici.
  23. Composition selon l'une quelconque des revendications précédentes, dans laquelle le tabac est transformé à partir des feuilles de la famille de plantes Solanaceae et du genre Nicotiana, comme par exemple Nicotiana tabacum et Nicotiana rustica.
  24. Composition selon l'une quelconque des revendications précédentes, comprenant de la nicotine et/ou un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges selon la revendication 12, conjointement avec du tabac sous la forme de tabac à priser et/ou une substance de charge appropriée.
  25. Composition selon l'une quelconque des revendications précédentes, laquelle composition comprend en outre des édulcorants, des arômes, des additifs de goût, des détergents, des substances d'ajustement du pH, des conservateurs, des tampons, des agents modifiant la libération et/ou des charges.
  26. Composition selon l'une quelconque des revendications précédentes, laquelle composition comprend en outre des composés chimiques qui permettent et amplifient la libération de nicotine à partir du tabac, comme par exemple des tampons de régulation du pH, par exemple de l'huile de tampons carbonates, des solvants organiques et des extraits d'herbes.
  27. Composition selon l'une quelconque des revendications précédentes, dans laquelle le tabac ou le substitut du tabac contient de la nicotine et/ou un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges à une concentration d'environ 0 % en poids à environ 30 % en poids, comme par exemple d'environ 0,5 % en poids à environ 25 % en poids, d'environ 0,1 % en poids à environ 20 % en poids, d'environ 0,1 % en poids à environ 15 % en poids, d'environ 0,1 % en poids à environ 10 % en poids, d'environ 0,1 % en poids à environ 9 % en poids ou d'environ 0,1 % en poids à environ 8 % en poids.
  28. Composition selon l'une quelconque des revendications précédentes, dans laquelle le matériau de membrane est composé d'au moins deux types de membranes en ce qui concerne par exemple l'épaisseur, la séparation des masses moléculaires, la nature hydrophile/hydrophobe et la perméabilité à l'eau.
  29. Composition selon l'une quelconque des revendications précédentes, laquelle composition a une taille et/ou une forme qui conviennent pour une application sous la lèvre supérieure d'un humain.
  30. Composition selon l'une quelconque des revendications précédentes, contenant un mélange de tabac et d'un substitut du tabac.
  31. Composition selon l'une quelconque des revendications précédentes, destinée à être utilisée en tant que substitut du tabac à fumer.
  32. Composition selon la revendication 30 ou 31, destinée à être utilisée pour réduire l'état de manque à la nicotine et/ou l'abstinence à la nicotine.
  33. Procédé pour contrôler la libération de nicotine et/ou d'un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges, à partir de tabac ou d'un substitut du tabac dans la cavité orale, le procédé comprenant l'encapsulation d'un matériau choisi dans l'ensemble constitué par le tabac et le tabac en combinaison avec un substitut du tabac dans un matériau de membrane comprenant une ou plusieurs membranes, au moins l'une de celles-ci étant perméable à l'eau et insoluble dans l'eau, de façon que la nicotine et/ou le dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges soit libéré en une quantité suffisante et/ou à un débit suffisant pour i) permettre un effet souhaité et ii) retenir les substances qui conduisent normalement à des effets secondaires et/ou libérer ces substances en une quantité sensiblement faible et/ou à un débit sensiblement faible.
  34. Procédé pour délivrer de la nicotine et/ou un dérivé, analogue, sel, solvate de nicotine ou un de leurs mélanges à une personne en ayant besoin, le procédé comprenant l'application d'une composition selon l'une quelconque des revendications 1 à 32 dans la cavité orale.
  35. Procédé pour arrêter de fumer, le procédé comprenant l'application d'une composition selon l'une quelconque des revendications 1 à 32 à la cavité orale.
  36. Utilisation d'une composition selon l'une quelconque des revendications 1 à 32 dans la fabrication d'un médicament pour réduire l'état de manque à la nicotine, par application de ladite composition à la cavité orale.
  37. Utilisation d'une composition selon l'une quelconque des revendications 1 à 32 dans la fabrication d'un médicament pour réduire les effets secondaires liés au fait de fumer et/ou de priser du tabac, par application de ladite composition à la cavité orale.
  38. Utilisation d'une composition selon l'une quelconque des revendications 1 à 32, en alternative et/ou en remplacement du tabac à fumer.
  39. Procédé pour la préparation d'une composition selon l'une quelconque des revendications 1 à 32, le procédé comprenant l'encapsulation de tabac et/ou d'un substitut du tabac dans un matériau de membrane comprenant une ou plusieurs membranes, dont au moins l'une est une membrane perméable à l'eau et insoluble dans l'eau.
EP02795287A 2001-12-21 2002-12-17 Tabac et/ou substitut de tabac en combinaison avec du tabac s'utilisant comme tabac a priser dans la cavite buccale Expired - Lifetime EP1458252B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK200101945 2001-12-21
DKPA200101945 2001-12-21
PCT/EP2002/014853 WO2003053175A2 (fr) 2001-12-21 2002-12-17 Composition de substitut de tabac et/ou de tabac ameliore s'utilisant comme tabac a priser dans la cavite buccale

Publications (2)

Publication Number Publication Date
EP1458252A2 EP1458252A2 (fr) 2004-09-22
EP1458252B1 true EP1458252B1 (fr) 2008-01-23

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US (1) US20050061339A1 (fr)
EP (1) EP1458252B1 (fr)
AT (1) ATE384450T1 (fr)
AU (1) AU2002360097A1 (fr)
DE (1) DE60224832T2 (fr)
DK (1) DK1458252T3 (fr)
WO (1) WO2003053175A2 (fr)

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DK1458252T3 (da) 2008-05-13
US20050061339A1 (en) 2005-03-24
DE60224832D1 (de) 2008-03-13
AU2002360097A8 (en) 2003-07-09
EP1458252A2 (fr) 2004-09-22
WO2003053175A2 (fr) 2003-07-03
AU2002360097A1 (en) 2003-07-09
DE60224832T2 (de) 2009-01-22
ATE384450T1 (de) 2008-02-15
WO2003053175A3 (fr) 2003-10-09

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