DE2136119A1 - Tobacco substitutes - Google Patents

Description

¹ di- present invention relates to substitutes for Eauchwaren to be chewed and are particularly valuable for facilitating the transition to Non smoking and / or to reduce the need to smoke.

Intake of nicotine, usually from smoking cigarettes, cigars, or pipes, can be stimulating. However, smoking can be detrimental to health, so a different mode of nicotine administration is desirable to find those to facilitate smoking cessation and / or as a substitute for smoking can be used.

Nicotine or alkaloid-containing products with an effect similar to smoking products that are chewed or snorted are known, but they are not very

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satisfactory. Examples of such products are found in U.S. Patent specifications 865 02b and 904 521 can be found.

According to these patents, a meal will be yours 'i' tobacco, e.g., snuff, mixed into chewing gum; further the use of a tobacco extract becomes unidentified Composition mentioned. However, it has now been found that when nicotine or others are incorporated • Fabacalkaloids in common chewing gucimi compositions the type commonly used today, the release of the alkaloid takes place very quickly. This is disadvantageous for two reasons: If the alkaloid is released too quickly, the alkaloid concentrations in the blood will be higher than in ordinary blood Smoking produces; Furthermore, the effect of the replacement product is too short.

It is an object of the present invention to provide a chew which is a tobacco alkaloid such as nicotine or slowly releasing a similar alkaloid, so that the product would take up the effect of a nicotine Breathing is imitated satisfactorily.

Under "l'abakalkaloid" are according to the present description Nicotine or nicotine-like alkaloids such as lior-hikotine, lobeline and the like, in the form of the free base or understood pharmacologically acceptable acid addition salts. Sources of alkaloids of this type are the plant species Nicotiana (for nicotine and ITor-hikotine), Lo beliaceae (Indian tobacco) and lobelia (for lobeline) and the like.

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An ideal substitute for tobacco products in the form of a chew ;; umrais should have the following properties:

(a) The release of the tobacco alkaloid should be uniform take place during a period that is not too short;

(b) the release of the tobacco alkaloid should be almost the same ;; * done when different rubber bases are used;

\ ·) Without changing the gum composition, the i''roi. '; From the rate of growth of the tobacco alkaloid should be able to be changed, since it may be desirable, for example, when using; ··, · - ·:;':] "πγογ amounts of alkaloid to increase the λ · -; ... aüo.eGciiv / indlgkeit something, including the. "■ -. -auc .ei · J-.u satisfy;

' -, ^ v, irei- OGütate alkaloid should not only produce a "(dec Kauchena". because oo ± absorption of the alkaloid without GeriCiü..ackijijüniJation an excessive use of the substitute product oxine the satisfaction achieved during diving can occur, which can result in a relapse to habitual smoking;

(e) The incorporation of the alkaloid into the chewing gum should be easy to accomplish while ensuring a substantially even distribution.

It has now surprisingly been found that all of these

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parts can be achieved by using a tobacco alkaloid a cation exchanger binds and in this form in the generation of the caused by smoking Satisfying sufficient amount incorporated into a chewing gum mixture. The present invention thus becomes a A soft commodity substitute is provided which comprises a gum base and a tobacco alkaloid which is cation exchanger is kept in dispersion. The amount of Ta-P bakalkaloid such as nicotine, ITor-ificotine and / or lobeline in a chewing gum unit can vary within wide limits. So can from about 0.05 to about 2 percent by weight Tobacco alkaloid based on the weight of the gum base and calculated as the free base. Usually chewing gum units contain about 1-10 mg of an alkaloid, preferably about 1 to about 5 mg. Preferably the abdominal product substitute is made acidic by adding a pharmacologically acceptable acidulant.

When working with an alkaloid bonded to a cation exchanger, a variety of chewing gum compositions can be used be used. The chewing gum manufacturer can thus use the solid complex of alkaloid and cation exchanger incorporate into its existing composition without having to change it. It is also possible to satisfy different tastes.

The rate of release of the alkaloid from the composition can be altered by turning the on a given amount of the cation exchanger-bound amount of alkaloid varies. Relatively larger amounts of alkaloid result in a faster delivery and vice versa. Under the

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_ 5 -

The term "slow release ¹¹ " means that the majority of the alkaloid from the tobacco substitute is released essentially uniformly over the course of several minutes and preferably over the course of at least 10 minutes. The release time is particularly preferably at least 20 minutes.

It is well known that nicotine is absorbed through the mucous membranes in the form of nicotine base. It has now been found that the "feeling of smoking" is weaker when the alkaloid from the rubber is used as the base is released. This is presumably due to the fact that the alkaloid is present on the parts, i.e. in the part of the mouth that directly contacts the gum is absorbed very quickly. So only one is relative small amount of the alkaloid transported to other parts of the mouth including the throat. The throat seems very sensitive to nicotine. If, as in the case of the compositions according to the invention, the nicotine when nicotine cation is released, absorption does not occur as quickly, so some of the nicotine will leave other parts the oral cavity and throat, bringing the sensation of smoking including the sensation of a a slight burning sensation, which is generally felt to be pleasant by the smoker, is achieved to a certain extent.

The complex containing an alkaloid bound to the cation exchanger is preferably in a particular Made up-to-date. The complex produced in this way is easy to handle, and thus sources of error in the listening position are grounded of the finished chewing gum product is kept to a minimum.

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It could also be shown that the complex works as a lubricant acts so that the mixing of the individual components is facilitated to form the "cumin mass. One obtains in this way easily a homogeneous product.

The ion exchanger must have cationically exchanging groups so that it forms a complex with the alkaloid forms. These groups are preferably in the hydrogen ion form prior to complex formation.

The exchanger can also contain anionic groups, in which case a polyampholyte is present.

The cationic exchanger groups can be strongly acidic, weakly acidic or moderately acidic. Synthetic cationic exchangers containing such groups are therefore referred to as strongly acidic, weakly acidic or moderately acidic cation exchangers, depending on the strength of the acid from which the functional groups are derived. Examples of suitable acidic groups are the carboxylic acid groups, sulfonic acid groups, phosphonous acid groups, phosphonic acid groups, phosphoric acid groups, iminodi acetic acid groups or phenolic groups. In the case of phenolic groups, the arrangement or the content is preferably such that the acid strength is relatively high. Ion exchangers containing such phenolic groups have been described by Adams, BA and Holmes, EL, J. Soc. Chem. Ind * 54> IT (193.5). It is possible to implement any desired release scheme simply by using a suitable mixture of counter-ions in the same ion exchanger or a suitable mixture of different ion exchangers, including genuinely bound ion exchange.

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shear and polyampholytes. It is also possible the release certificate by changing the amount of alkaloid that is attached to a given amount of the ion exchanger is bound to change.

Of course, the generally synthetic cation exchanger must be un toxic in the amounts used Furthermore, it should not impart any undesirable taste to the finished products. These demands result not a difficult problem, however, as it binds a sufficient amount of nicotine or other alkaloid required amount of ion exchanger is small.

The acidic groups of the ion exchanger, which can be referred to as ion exchange resin, can be attached to a cross-linked polymer such as an addition polymer Styrene and divinylbenzene, divinylbenzene and methacrylic acid, Divinylbenzene and acrylic acid, phenolic resin, or on e.g. cellulose crosslinked by epichlorohydrin, dextran or be bound to pectin *

The acidic groups can be linked to insoluble linear polyneses, e.g. cellulose, bound with nitrogen oxide gases, whereby mainly uronic acid groups are formed. Such compounds are from Ott, E. and Spurlin, H.H., Cellulose and Cellulose Derivatives, Part I, Interscience, New York (195 * f). Also carboxymethyl cellulose, Sulphoethyl cellulose, cellulose sulfate and the like. can be used. To ensure that the cellulose polymers containing the acidic groups in the saliva are insoluble must be the number of acidic groups

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be relatively low, e.g. a maximum of 1 in 3 Glucose units. Compounds of this type are from Ott, E. and Spurlin, H.M., Cellulose and Cellulose Derivatives, Part II, Interscience, ITew York (195 ^ f). Typical cation exchangers suitable for use in the present invention are as follows Table I compiled:

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Table I:

(D
OO
W.

iiame

Representative cation exchangers for the purposes of the present invention.

crosslinked polymer

Amberlite IRC 50 Amberlite IRP 6k Amberlite IRP 6ifM BIO-REZ 70 Amberlite IR 118 Amberlite IRP 69 Amberlite IRP o9M BIO-RSX 40 Amberlite IR 120 Dowex 50
Dowex 50Ϋ /
Duolite C 25 Lewatit JS 100

Ionac C 22fO Wofatit EPS 200 Amberlyst 15 Duolite C-3 Duolite C-IO

Divinylbenzene methacrylic acid

Divinylbenzene acrylic acid Styrene-divinylbenzene

Phenolic styrene divinylbenzene

-M-

-M-

-M- -M- -M-

Phenolic

-M-

f unlit io nolle Manufacturer groups Carboxylic acid Rohm St Haas Vo. -M- -II- -M- -M- -M- BIO-EAD Lab. Sulfonic acid Rohm & Haas Co. -M- - "-!. - »t_ _M_ _M_ ΒΙΟ-RAD Lab. -M- Rohm & Haas Co. -M- Dow Chemical Co. -M- -M_ -M_ Chemical Process Co. -M- Paint factories Bayer -M- Ionac Chemical Co. -M- I.G. Farben Wolfen -M- Rohm & Haas Co. -M- Chemical Process Co. -M-

Table I (continued):

Groves crosslinked polymer Functional
groups Manufacturer H
O Lewatit KS Phenolic Sulfonic acid Paint factories Bayer Cerolite 215 -H- -II- The Permutit Co. Duolite ES-62 Styrene divinyl benzene Plio spho ni gic acid e Chemical Process Co. 3Ι0-3ΞΧ 63 -H_ Phosphonic acid BIO-RAD Lab. Duolite ES-63 -H- Chemical Process Co. Duolite ES-65 Phenolic phosphoric acid Chelex 100 Styrene-divinylbenzene Iminodiessig
acid BIO-PJlD Lab.

Dow Chelating Resin - "- A-I

CM Sephadex C-25 dextran

SE Sephadex C-25

- "- Dow Chemical Co.

Carboxy-methyl-Pharmacia Fine Chemicals

Sulfoethyl - "-

The following are the properties and characteristics of if ion exchange resins !!, which are particularly suitable for the purposes of the present invention, listed :

iiame manufacturer

Amberlite IHP 6 if

Amberlite IRP 6ifM

Amberlite IEP 69M S3 Rohm & Haas Co., Philadelphia

BIO-RAD Lab., Richmond, Cali Fornia

. type

:; c :; v. ^r ach α au er, Me tha ^r ; r, yl; j: luro-

Functional groups

Carboxylic acid groups

H. COCTH ⁺

üvar: sour, poly-

nittolcauer, polystyrene type II . SO ₇ "H ⁺

H.PO ₃ "(H ⁺ )

^r »Ionian form

hydrogen

-H-

Crosslinking, ^ divinylbenzene

not published, according to the manufacturer: "Because gel resin", it acts as a "resin relative high porosity ".

-H-

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Mr. Ionic form

Networking, % Divinylbenzene

3 · Na converted into hydrogen

not published, according to the manufacturer the resin acts like a resin with ^lf conventional gel porosity ".

not published, according to the manufacturer. the resin acts like a resin "of high porosity" ¹ .

Kr. Apparent pK value exchange capacity m-eq. / G in 1 m-KCl solution of the oven-dried resin

10.3

6.6

1. Approx. 6.0 2. 3. approx. 1.3 4th not known

i \ ^T r.

Particle size .M,

% external V / ater

1. 150-40 maximum 5.0 2. 95 % < 40 3. 95 % <40 maximum 10.0 4th 150-75 maximum 4.0

The amount of alkaloid, e.g. nicotine, nor-liikotin, Lobeline or their acid addition salts and mixtures thereof, which are bound to the ion exchanger, can can be varied depending on the working conditions and the type of ion exchanger used.

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It has been found that alkaloid ion exchange complexes with a content of nicotine or other alkaloid of about 2-60%, and preferably suitably from about 5 ~ 35% for incorporation into the inventive mixtures. For ion exchangers with carboxylic acid groups, the preferred range is about 5-35 %, while ion exchangers with phosphonic acid groups are preferably in amounts of about
5-30 % and ion exchangers with sulfonic acid groups are preferably used in amounts of about 5-25 % .
A portion of the nicotine, nor-uicotine and / or lobeline may be bound to the ion exchanger by "surface absorption" instead of an actual ion exchange reaction. Suitable and preferred amounts of various
Alkaloids in complexes with various ion exchange resins are summarized vile follows:

Alkaloid ion exchange complex% by weight of alkaloid in the complex

Amber tail IEP 64M liikotin complex

Anberlice IP ₁ P 6 ^ fM-Hor-Nicotine Complex

Amberlite IRP 64M lobeline complex Amberlite IR llS wikotin complex LIO-HEIX 63-iicotine complex

(2-60

(preferably 5-35 (2 - 60

(preferably 5-35 (2-60

(preferably 5-35 (2- -yy

(, preferably 5-20 (2- / 4O

(preferably 5-30

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"? AD ORIGINAL

Alkaloid ion exchanger complex Gei; t.% Alkaloid, in Κοη-

-. . riles:

ΒΙΟ-HEX 63- ^ iOr-iiicotine complex (2-40

BIO-EEX 63 lobelin complex (2-40

Amberlite ISP o9M-i'Tiiiotin-Kociplex (2-3 ~

Amberlite IRP 69M-IiOr-NIkOtIn- (2-j $>

Complex (

Amberlite Il-jp 69M Lobeline Complex (

Amberlite IEP 64 nicotine complex (2-SO Aiiiberlite IRG 50-Liko cin-Komplo :: (2— ^ 0 Amberlite IRP o9-ilicotine complex

JlO-EE3 {40-iiikotlii-ComplGX {2.-Z ~ j

ilO-REX 70-Hikotin-Koraplex (2-oO

ovrolae 5-35

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Alkaloid ion exchanger complex wt.% Alkaloid in the com-

Duolite ES-iiikotln-Konrolex Imolite SS-iiicotine complex

Uli el ex 100 -Jüiko t in-Ko mplex

GIi Sophade :: G-25-l. ^r ikotin complex hauu :: G-2 "> - i; ikotin-Ko mplex

(2-35

(preferably ^ -Z ^ (2-25

(preferably 5-15 (2-25

(preferably 5-15 (2-30

(preferably 5-20 (2-15

(preferably 5-10

lil'j Kauru:.; .. j.-Koi: ^ onente der orrindunfßgöiüüß zu.-ja, .... j. ^ iJ. ':,.; - /., ϊ; ]: a-: ..olicui ' ^- oi · Be kind, vorzugGweiso ver - ""-.' ^ -: -a: i 'jl .: all;';:; Gin erii; ^: .ltlichea, aandolsiiblicJioc Ov ...:.; i. D: I '-. "O Ko: .i ^ ono; ito i: ann zU a Guiii.äbarjis natur-Ii-j.ion odor cynthOwioclion Ur3prun, f, G aufweiijon. Suitable aaLurlic:; c uUi:;. .iir:: jina 2..1 ;. -lie Chiole-, Jdubong-, Lcchi <■ '_'. ο Cacpi-, Sch-, Siak-, Katiau-, Sorwa-, iialata-, Pendaro-, Porillo- , Malaya and Percha-uumniic, natural rubber v / ic Krupp, latex and j? 'Cl.le, natural resins such as darauar and mastic. Synthetic rubber bases are poly vinyl acetate ("7innapas"), "Dreyco", polyvinyl ester, Polyisobutylene and non-toxic butadiene-styrene-Laticc.-j and the like .. In the commercial Kaugauiirni base plasticizers are incorporated in a conventional manner to the

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Viscosity of the rubber mixture up to the desired one Reduce consistency and improve texture * Some of the common plasticizers are: Lecitin, Lanolin, hydrogenated coconut oil, hydrogenated cottonseed oil, mineral oil, olive oil, petroleum jelly, carnauba wax, Candelilla wax, paraffin, beeswax, stearic acid, Glycerin monostearate, glycerin, honey, propylene glycol, hexylene glycol and sorbitol. These plasticizers also work at the same time as a humectant. Various other possible additives for chewing gum are: cerelose, mannitol, diastatic malt, starch, calcium carbonate, talc, defatted cocoa, flavors and food colors. Sugar in The form of cane sugar and commercial glucose (corn syrup) make up the bulk of a chewing gum formulation off, but completely sugar-free and / or glucose-free chewing gum formulations can also be produced according to the invention.

For the purposes of the present invention, the chewing gum component Can be formulated with the following ingredients in varying amounts: The rubber base can be natural or synthetic, preferably synthetic, in origin and in the chewing gum formulation in one Amount from about 15 to about 80 weight percent, preferably from about 50 to about 80 percent by weight and particularly preferably from about 60 to about 75 percent by weight * present «

Icing sugar, preferably sorbitol powder, can be present in amounts of about 15 to about 80 percent by weight, preferably from about 16 to about 1 percent by weight and particularly preferably from about 20 to about 32 percent by weight.

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to be

Corn syrup, usually at about 41 ° to 2 + 6 ° BaumS, preferably an about 70% aqueous sorbitol solution, can be used in amounts of about 1 to about 30 percent by weight, preferably about 1 to about 10 percent by weight and particularly preferably about 5 up to about 8 percent by weight. There are also special formulations for chewing gum, e.g. sugar-free compositions, with a concentration of up to 80 % chewing gum base, preferably of synthetic origin (see preparation 13 below) ·

Changes in consistency, on the one hand the initial consistency at the beginning of chewing and on the other hand the secondary consistency after some chewing can be achieved simply by varying the proportions in the above formulation achieved. The consistency and adhesion of the chewing gum can be improved by adding various substances of the type mentioned above can be influenced.

Compositions of the invention can be made by simply adding the chewing gum mass with it the alkaloid ion exchange complex, preferably together with an excess of a suitable acidifying agent. If the complex is directly in the form of a finely divided ion exchanger, then it can be used directly mixed with the rubber. However, if the complex is in the form of coarser ion exchange particles, then it is advisable to marry them first. Mixing is preferably carried out at suitable elevated levels

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Temperatures that depend on the viscosity of the gum mass depend ^ because higher temperatures lower the viscosity of the rubber, so that the alkaloid ion exchange complex can unite evenly and intimately with the chewing gum. The particle size of the complex the gum should be small enough so that damage to the teeth when chewing is avoided.

The compositions according to the invention are expediently prepared directly when other additives such as corn syrup, sugar, sorbitol and flavors are incorporated into the chewing gum mass. For example, the composition can be prepared in a suitable kettle such as a steam jacketed mixer. This is heated, the gum base is added and mixed until there are practically no lumps left. Then sorbitol or corn syrup and sugar are added.

Depending on the physical properties of the pharmacologically acceptable acid, which is used as a further additive can be incorporated according to the present invention, their addition, for example in the case of Recommend sulfuric acid, along with sorbitol solution or corn syrup. In the case of malic acid, for example, a Added together with the solid sorbitol powder or sugar. Finally, flavoring agents, plasticizers and other additives poured in and well distributed. The mass is cooled, rolled out, cut and sufficiently hardened, if necessary overlaid, before it is finally wrapped or analyzed. Storage rooms with controlled humidity provide a suitable /

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Moisture content safe and prevent the gum from exuding. Preferably just enough heat is supplied to soften the gum base to the extent necessary for mixing. By adding sugar and syrup, the temperature is lowered, and the Al kaloid - ion exchange complexes and optionally arolueii v / earth only added when the mixture cools down sufficiently is. This significantly reduces uncontrollable losses of alkaloid and / or aroma.

The weight of a chewing gum unit, for example a stick, a ball or the like, can be between 0.5 and 0.1 and is preferably between 1.0 and 1.0 . , the weights being of the conventional type.

Doi · weight fraction of the alkaloid ion exchanger K. 1jxo individually or in mixtures, based on the Ge-.j.-; . owichc dec rubbers, is not critical, moves

- ■ λ between an upper and lower limit for the respective formulation spe- ". ':; Uen. It has been found that α ·· .' Compositions with about 0.1 to 10, preferably 'j.' .: ■ .. 0, "d to 5 and particularly preferably about 0.5 to 2. Weight percent alkaloid ion exchanger complex, based on the total weight of the rubber, are free.

Preparation 1 illustrates the production of an according to the invention usable ion exchange complex, while preparations 2 to 13 are suitable chewing gum compositions indicate. However, such compositions are not required for the purposes of the present invention be preformed, but they can be formed simultaneously with the incorporation of the complex.

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Nicotine ion exchange complex with 200 mg nicotine in 800 mg Amberlite IRP 64M.

The ion exchanger was dried in an oven at 10.5 ° C. to constant weight.

100.0 g of the ion exchanger are placed in a beaker ^ which contains 25.0 g of nicotine (calculated as 100%) and is made up to a total volume of 500 ml with distilled water. The mixture is at least Stirred for 1 hour with a magnetic stirrer or the like. The loaded ion exchanger is then filtered off or centrifuged. The filter cake is broken into pieces and placed in a fan at around 20 C Drying chamber dried. The nicotine ion exchange complex is then after careful mixing and sieving analyzed for its nicotine content by a sieve with a mesh size of 0.059 mm.

The preparation of other alkaloid ion exchanger P complexes can be carried out according to the instructions in the above example ■ take place. In the following preparations, all percentages relate to the weight,

Preparation 2:

Granulated sugar l * f _f 5 %

Condensed sugared milk

(low fat content) Z _1. , 5 %

Glucose powder 30.0 %

' Chicle gum 20.0 %

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Powdered sugar 30 »O

ToIu balm 1.0 %

Preparation ^:

"Dreyco", synthetic, commercially available Rubber base 16.9%

Glucose powder 22.5 %

Powdered sugar 60.0 %

Water 0.3 %

Glycerine ... 0.3 / 6

preparation k '

Natural rubber base 22.0%

Icing sugar 6Jf, 0 %

Corn syrup 45 ° Baume '14.0 %

Preparation 5;

Natural rubber base 22.0 %

Diastatic malt 1.0 %

Corn syrup 44 ° Baume 15.0 %

Powdered sugar 60.0%

Calcium carbonate 2.0 %

Preparation 6;

Natural rubber base 22.0 %

Diastatic malt 2.0 %

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Invert sugar 5.0 % Corn syrup l \ l ± tree S. 13.0 % powdered sugar 51.0% Cerelose 7.0 % Preparation Ji (summer formula lation) Natural guinrni base 22.0% powdered sugar 50.0 % Corn Syrup 45 Tree§ 2if, 0 % Calcium carbonate 2.0 % Starch powder 2.0 % Preparation 8: (winter formula lation) Natural rubber base 22.0 % powdered sugar 53.0 % Corn syrup l + k ° tree S. 21.0 % Calcium carbonate 2.0 % Starch powder 2.0 %

preparation 9:

Sticky gum base Icing sugar Glucose powder Corn syrup i \ 5 ° Baumf Glycerin aromatis. oil

19.9 %

9.9 % 14.9 % 0.2 - 0.5 % 0.6 %

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Preparation 10: (Bubble-gum)

Bubble gum base 18.0 % powdered sugar 55.9% Glucose powder 9.0 % Corn syrup ^ 5 ° tree! 16.2 % Glycerin 0.2-0.7 % aromat. oil 0.6% Preparation 11: (gum with sugar coating) Rubber base with sugar coating 22.0 % powdered sugar 55.1% Glucose powder 5.5% Corn syrup k5 trees 16.5 % Glycerin 0.2-0.5 % aro;.: atis. oil 0.7 %

The chewing gum is coated with sugar or colored sugar in conventional coating drums.

Preparation 12: (sugar and glucose free)

Natural rubber base 29.2 %

Sorbitol powder 45.8%

Calcium carbonate 8.5%

Sorbitol, 70% aqueous solution 16.5%

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Preparation 13; Sugar- and glucose-free formulation with high concentrations of chewing gum

Synthetic rubber base 73.7%

Sorbitol powder 19.8%

Sorbitol, 70% aqueous solution 3.8 %

Glycerine 0.7%

aromatis. Oil 2.0 %

The following examples illustrate the invention Compositions. Each of these compositions is made by heating the rubber base in a kettle and Addition of the various additives prepared according to the general method given above.

Example 1:

Chewing gum with a 10 % -lgen complex, made from 3 mg nicotine, which is bound to Amberlite IEP 6 ^ -M. Chewing gum mass according to preparation 4, 1000 pieces from 1,970 g of the mass. 30.0 g of the 10% Mkotin-Amberlite IEP 6ZfM complex.

Example 2;

Chewing gum with a 10 # complex of 2.5 mg nicotine, bound to Amberlite IEP 64M, as well as a 20% Complex, from 2.5 mg nicotine, also on Amberlite IRP 6ifM bound. Chewing gum mass according to preparation 4, 1,000

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Pieces from 1,835 g of the mass. 25.0 g of the 10% and 12.5 g of the 20% nicotine-amberlite IKP 64M complex.

example J> '>

30% complex chewing gum made from 1 mg Nicotine bound to Amberlite IRP 64M. Chewing gum mass according to preparation 6, 1,000 pieces from 3,325 of the mass. 3.33 S of the 30% nicotine-amberlite IRP 64M complex.

Example 4?

Chewing gum with a 20% complex made from 3 mg nicotine bound to Amberlite IRP 69M. Chewing gum mass according to preparation 4, 1,000 pieces from 1,485 g of the mass. 15.0 g of the 20% nicotine-r Amberlite IEP 6 9M-Ko mpl exes.

Example 5?

Chewing gum containing a 15% complex, made from 4 mg nicotine, bound to BIO-REX 63, leads over into the hydrogen form. Chewing gum mass according to preparation 4, 1,000 pieces from 2 025 g of the mass. 26.7 g of the 15% nicotine-BIO-REX 63 complex.

Example 6;

Chewing gum with a 30% complex made from 2 mg lobeline bound to Amberlite IRP 64M. Chewing gum -

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mass according to preparation 3 »1,000 pieces from 3 3 ^ -5 g of the mass. 6.67 g of the 30% lobeline amberlite IRP 64M complex.

Example 7?

Chewing gum with a 20% complex made from 1 mg lobeline bound to Amberlite IRP 64M, and a 35% complex made from 1 mg nicotine, also bound to Amberlite IRP 64M. Chewing gum mass according to preparation 12, 1,000 pieces from 1 565 S of the mass. 5.0 g of the 20% lobeline amberlite IRP 64M complex and 2.86 g of the 35 % nicotine amberlite IRP 64M complex.

Example 8;

Chewing gum with a 10% complex made from 5 mg of nor-nicotine bound to Amberlite IRP 64M. Chew gum according to preparation-2, 1,000 pieces from 450 g of the mass. 50.0 g of 10% Nor-liikotin-Amberlite IRP 64M complex.

Example 9 «

Chewing gum containing a 15% complex, produced from 2 mg nicotine, bound to Amberlite IRP 69M, chewing gum mass according to preparation 13, 1,000 pieces from 987 g of the mass. 13.33 S of the 15% nicotine-amberlite IRP 69M complex.

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- 2.Ί -

Example 10;

Chewing gum containing a 15 # complex from 2 mg nicotine, bound to Amberlite IRP 64M, as well as a 10% complex, made from 1 mg nor-nicotine, also bound to Amberlite IEP 64M. Chewing gum according to preparation 4, 1,000 pieces of 2,975 g the crowd. 13.33 g of the 15 # nicotine complex and 10.0 g of the 10 # nor-nicotine complex.

The manufacture of chewing gum with the other alkaloid ion exchange complexes mentioned above individually or in a mixture according to the procedure of the above examples, subject to application of the Skilled minor changes.

Looking at the results of previous experiments, there is the slow and controlled release of the alkaloid from the compositions according to the invention surprisingly. It has been found to have a satisfactory release rate of the alkaloid from alkaloid ion exchange complexes does not occur in the absence of chewing gum. The following Table II shows the results of screening of the amount of nicotine released as a function of time.

Table II:

Released Nicotine in Weight, - % in Addiction from the Time. Time (mn.) Al A2 D. E.

18 % 18 % 54% 64%

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- 28 Table II (continued):

Time (min.) Al A2 D. E. 5 36 % 39 % 70 % 66% 10 61 % & 5% 70 % 66 % 20th 91 % 92 % 70 % 66 $ j

Al; Chewing gum containing 20 mg Amberlite IRP 6ifM resin, bound with the nicotine base (20 percent by weight nicotine) and 1 g of high concentration chewing gum on a gum base, manufactured according to preparation 13 · The release occurs when chewing. A distinct sense of Smoking was observed.

A2: chewing gum with 20 mg Amberlite IRP 64M, with nicotine base (20 percent by weight nicotine) complexed and 3 g chewing gum with a low concentration of gum base, manufactured according to preparation Zf. Approval is given ^ while chewing. A distinct feeling of smoking was observed.

D: Amberlite IRP 64M resin complexed with hicotine base (10 percent by weight nicotine). Release with about 10 ml synthetic saliva No. 2 (see below), in contact with 50 mg of the complex at 37 ° C.

E: The same complex as for D, released with 10 ml of physiological saline solution, that with 50 ml of the complex came into contact at 37 ° C.

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The following desorption and chewing tests were carried out:

Desorption tests.

Desorption tests were carried out in vitro with the alkaloid-cation exchanger complexes without being incorporated into chewing gum. In a series of experiments, 25 mg of the respective complex, which contained 5 mg of nicotine, was shaken for various times with 10 ml of water, physiological sodium chloride solution, 20% (weight / volume) sugar solution and saliva. It was shaken in a thermostat at 20 ^ 0,1 ⁰ 0,1 ⁰ C and at 37- C ge. Samples of the filtered solutions were analyzed for nicotine by UV examination. The ion exchange resins Amberlite IRP 6 ^ M and IRP 69M gave the results shown below. Similar results are achieved with other ion exchangers.

Results;

Total amount of nicotine released in mg / 10 ml.

medium IRP water NaCl solution IRP 69M *
Ion off
exchangers 20 ° Gk M IRP 69 M IRP 64 M 20 ° 37 ° temperature 37 ° 20 ° 37 ° 20 ° 37 ° Time,
Minutes 0.22 1.90 2 0.23 3.68 1.93 2.00 5 0.23 0.21 3.88 4.01 1.95 10 0.25 3.96 1.96 15th 3.98

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medium water 69 M. Ion off
exchangers IRP 64 M IRP 37 ° temperature ZQ ⁰ 37 ° 20 ° Time,
Minutes 20th 0.25 0.0 30th 0.27 0.25 0.01 medium Sugar solution

riaCl solution 20 ° 37 ° 20 ° 3.98 1.97

Saliva 1

Ion exchanger IRP 64M IRP 69M

Temperature 20 ° 37 °

20 IRP 64M IRP 69M 20 ° 37 ° 20 ° 37 °

Time,
Minutes 0.39 0.43 2.94 IRP 3.40 2 , 24 2.21 2 0.46 3.21 20 ° 2 , 26 5 0.47 10 0.50 2 , 30 15th 0.50 0.44 0.02 3.46 2 , 30 2.70 20th 0.59 saliva 2 30th IRP 64M 69M medium 20 ° 37 ° 37 ° Ions
exchanger temperature Time,
Minutes

3.24

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medium

- 31 -

Saliva 2

Ions
exchanger IRP 64M IRP 69M temperature 20 ° 37 ° ' 20 ° 37 ° Time,
Minutes vji 1.51 IO 3.45 4.57 4, 15th 20th 30th 3.46 4.60 1.57 4, Media:

Water: 2 χ ion exchangers, distilled water Physiological NaCl solution: 0.9% in distilled water,

Sugar solution: sucrose, 20 % in water

Saliva 1: gelatin 2 g Glycine 1 g Aspartic acids 1 g Phytin (Ciba) 0.5 g NaHCO, 1 g NaCl 0.5 g KSCN 0.1 g water ad 1000 ml Saliva 2: NaCl 0.45 g CaCl ₂ .6H ₂ O 0.12 g CaCO-z 1.0 g

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Saliva 2: 'Na ^ HPO, (dry) 0.07 g

Mucin '2.5 g

Taka diastase 16.0 g

Cholesterol 0.06 g

Water to 1000 ml

It can be seen from the above results that the equilibrium is reached very quickly. After 2 minutes there is no further release. The addition of sugar affects the release does not. The ion exchange resin Amberlite IEP 69H apparently binds nicotine more strongly than the ion exchange resin IRP 6 ^ -M. The strength of the bond is in saliva and physiological sodium chloride solution of the same order of magnitude, but considerably less than in water and sugar solution.

With regard to the release at 20 and 37 ° C, with Except for one case, no significant difference was observed. When tested with artificial saliva No. 2 was a faster release achieved at a higher temperature. This saliva solution No. 2 contains mucin, which is also found in natural Saliva is present. It is therefore likely that the presence of miicin in the human Saliva provides a reasonable basis for explaining the surprising effect of the initially rather rapid release of Nicotine, Kor-Nicotine, "Lobelin" or the like Chewing the tobacco substitute products according to the invention is observed. Without mucin, desorption for any bulky use must be too slow, especially in terms of generating the desired taste sensation.

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The phenomenon is particularly surprising with the strongly acidic cation exchangers, e.g. Amberlite IRP 69M, due to the fact that alkaloids are usually so tightly bound to it that they can only with difficulty can be eluted therefrom.

Chewing tests.

Di ^Q following analytical values for nicotine refer to Kautests. 2 people chewed the gum for different lengths of time, the analysis results were recorded and the mean values were determined.

The chewing gums used in the tests were formulated as follows;

Natural gum base 22, Q ^ powdered sugar 6if, Q %

Corn syrup if5 ° tree $ ~ 14> ° %

Each individual chewing gum consisted of 3> 0 g of this mass and a certain amount of an alkaloid ion exchange complex with each 5> Q mg of the alkaloid.

The relationship between nicotine and Ionenaustau was shear with the different raw materials, _t which were used in the following samples,

Example 11:

190 mg nicotine per g Amberlite JRP 6ifM nicotine com, plex.

OWGiHAL INSPECTED Chewing time mean value of nicotine released (mg)

Q 0

2 1.9

5 2.6

± 9 3.2

15 3.3

20 4.2

3P 4.4

Example 12;

105 mg Nikqtin per g Awtierlite IBP 64M-N3iiQtin-Koraplex,

Chewing time (minutes) Mean value of the released Niko- - ""'-. ^ R ---- ?. ■ .. · tins (mg)

Q 0

2 Q, 6-

3 1.2 IQ 2.3 15 2.7

20 3.3

3P 4.1

example

179 fflg Ifikotip prp g Afflfeerlite IRP 64-lfil5: otin complex.

Chewing time (minutes ) Mean value of the released nicotine (mg )

Q P

2 2.0

5 2.2

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10 3.3

15 3.6

20 4.0

30 4.2

Example 14?

210 mg nicotine per g Amberlite IEP 69M nicotine complex. ^ Chewing time (minutes) Mean value of the released nicotine

(mg) 0 0 2.3 2 2.6 5 3.5 10 4.1 15th 4.3 20th 4.7 30th Example 15:

333 mg nicotine per g Amberlite IRP 64M nicotine complex.

Chewing time (minutes) Mean value of the released nicotine (mg)

0 0

2 3.1

5, 3.8.

10 4.4 ■ ''

15 4.5

ZO 4.6

30 4.8

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In the following examples, a chewing gum was made according to Preparation 13 used. Each piece contained 1.0 g this composition.

Example 16:

170 mg nicotine per g AmberIite IEP 64M nicotine complex, 1.5 mg of nicotine per chewing gum.

Chewing time (minutes) Mean value of the released nicotine (mg)

0 0

2 0.02

5 0.26

10 0.70

15 0.98

20 1.14

30 1.32

Example 17;

175 mg nicotine per g Amberlite IKP 64M nicotine complex,
4 mg of nicotine per chewing gum.

Chewing time (minutes) Mean value of the released nicotine (mg)

0 0

2 0.72

5 ■ l, ¥ i-

10 2, Mf

20 3.6k

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- 37 Example 18:

88 mg nicotine per g BIO-EEX 63 nicotine complex, 2 mg nicotine per chewing gum.

Chewing time (minutes) Mean value of the released nicotine (mg)

0 0

2 0.13

5 0.1?

10 0.50

20 "1.25

30 '1.68

The quantitative determination of nicotine was carried out by titration with perchloric acid.

The IR spectrum was used for identification, Determination of nicotine bound to ion exchangers.

Regarding the method, see Off, Meth.Anal., Der A.O.A.C., 9th edition, 1960, pp. 94-95.

Heagentien: Alkali-Sals-Solution: 300 g sodium hydroxide

are dissolved in 700 ml of water, then saturated with sodium chloride,

Hydrochloric acid: 1 part concentrated hydrochloric acid is mixed with L \. Share distilled V / asters diluted.

Device: steam distillation plant (i.e. a device those for nitrogen determination according to

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Kjedahl is used), Beckmann spectrophotometer YOU.

Determination: A sample corresponding to 5 mg nicotine is weighed and transferred to the distillation flask * 50 ml hydrochloric acid (1 + k) are placed in a 500 ml flask that serves as a template and the latter is arranged so that the cooling tube is immersed in the solution . 50 ml of the alkali-salt solution are added to the sample in the distillation flask and then a steam distillation is carried out, during which the condenser is fully utilized. The escaping condensate should not be higher than the edge temperature. The distillation flask is heated to keep the volume in it constant. 480 ml of condensate are collected and made up accordingly with water. In the spectrophotometer the absorption is measured at 259 (max), 236 (min) and 2.82. mu, read.

The following formulas are used for the calculation:

³ Wr = ³ W " ¹ Z ² ^ mIn ⁺² SS ₂ > 5

for E-, _c ^ (corr) was found to be 338 ;

^E corr ^x 5 °° * 1000

338 x 100 χ (sample weight, g)

Nicotine determination in chewing gum. Device: Beckmann DU spectrophotometer.

Determination: A chewing gum is homogenized with 20 g of sea sand in a mortar under ether. The homogeneous mixture

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is transferred to a glass column with a glass wool plug at the bottom. The pillar is with Approx. 100 ml of ether is eluted and the eluate is collected in a separating funnel. Then the column is as far as possibly freed from ether. The ether in the separating funnel is extracted 3 times with 15 ml of 0.1 η hydrochloric acid each time and the extracts are combined in a 250 ml flask. Then the ether phase is discarded. The almost dry one. The column is then eluted with 0.1 η hydrochloric acid, the eluate is added to the combined extracts until the total volume is 250 ml.

In the spectrophotometer the absorptions are read off at 259 (mas), 236 (min) and 282 mu .

Calculation;

^E corr ^{= E} raax " ^{1/2 (E} min ⁺

for E ^ cm ( ^corr ) ^{νΛ1Γ {1θ} 338 determined;

^E corr ^{x 100} ° ^x ^ ^w = mg nicotine§chewing gum 338 χ 100

The method can also be used on chewed gums to stimulate the residual nicotine.

Example 19:

A nicotine ion exchange complex with Amberlite IRP 6ifM was prepared according to the method of preparation 1, the resulting complex contained 10 % nicotine.

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h3k S natural rubber base were placed in a mixer equipped with a heating jacket and stirrer. The mixer was heated with approximately 1.05 atmospheric steam. The stirrers were turned on periodically to invert the gum base. To avoid overheating of the Guinmi base, a low vapor pressure was chosen. After the base has completely melted, the steam is switched off and cold water is passed through the jacket to reduce the temperature of the flask contents to around 85 ° C. Then 840 g of powdered sugar (particle size 0.059 mm) and 276 g of corn syrup with k3 ° tree! added, then the mass is mixed for another 15 minutes. The mixture then has a temperature between 60 and 75 ° C.

Another 420 g of powdered sugar and 30 g of the nicotine ion exchange complex, Particle size in each case below 0.059 now, v / earth mixed and then as a powder mixture dem molten mixture is added, then stirring is continued for 5 minutes so that the total mixing time is about 15 minutes amounts to.

The temperature in the boiler has dropped to 40-6O C after the end of the mixing process. It is advisable, cool the composition as much as possible before mixing is complete, but the viscosity increases decreasing temperature, and you have to stop the mixing process, © he the mass becomes too stiff. In practice it will the mixing process is less related to the thermometer reading than to the consistency of the mixture completed"

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After mixing, the batch is cut into pieces which are fed to the existing extruder can. The extruder jacket is usually heated to 45 - 50 C with warm water more uniform extrusion than heating with steam, and better temperature control. The extruded Gum should be sufficiently dusted with starch or a mixture of granulated sugar and starch, so that sticking to forming rollers and cutting devices is avoided. With the rollers, the desired Thickness achieved. The cutting devices preferably operate at about 25 ° C.

The shaping in the extruder and the further treatment are conventional. These stages are to be set up according to the desired shape and size of the rubber pieces. The individual pieces generally weigh between 1 and 3 S · In the present example, 1000 pieces of 2 g each are produced by conventional extrusion and cutting. The pieces are then also packaged and stored in a conventional manner. The Einwickelraum is preferably at 20 C and a relative humidity of 45 - 50% retained, and the Stüekchen are preferably stored at 18-20 ⁰ C and a relative humidity of 45-50%. Of course, other combinations of alkaloid ion exchanger complexes and other gums can also be used, and various other flavoring agents, sweeteners, binders and the like can also be added.

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As already mentioned, the tobacco substitute products according to the present invention should preferably be acidic be. This is supposed to increase the feeling of smoking, since the nicotine cation-nicotine base balance is in an acidic environment

+ H

is shifted to the left, so that the rate of absorption of nicotine at the caustic site is reduced and a The part of the released nicotine can be found in other parts of the oral cavity or the throat. It turned out to be For the purposes of the present invention, it is desirable to keep the pH at the caustic site below about 7, preferably from about 5 to about 4, which is achieved by adding a pharmacologically acceptable acidulant to the compositions admits.

According to a preferred embodiment of the invention, the cation exchanger, originally in ionic hydrogen form, is only partially loaded with nicotine or a similar alkaloid. When chewed, the four then released from the cation exchanger hydrogen ions and the pH of the saliva on the occlusal site is reduced, this reduction affects in turn the acid-base balance. It is also possible to use a cation exchange resin fully loaded with nicotine

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To mix in cation exchange resin in acid form, whereby the desired activity is achieved at the chewing point, or a cation exchange resin completely loaded with nicotine to mix with a pharmacologically acceptable organic or inorganic acid, or with a combination of a cation exchange resin in the acid form and a pharmacologically acceptable one organic or inorganic salt.

The amount of pharmacologically acceptable acid can be between about 1.5 and about 10 equivalents of acid per mole Alkaloid base, preferably from about 1.5 to about 6 equivalents of acid per mole of alkaloid base, and particularly preferred about 2 to about one-half equivalents of acid per mole of alkaloid base be. In terms of the alkaloid as a neutral salt, the amount of acid can be about 0.5 to about 9 equivalents of acid per mole of neutral alkaloid salt, preferably about 0.5 to about 5 equivalents of acid per mole neutral alkaloid salt, and more preferably from about 1 to about 3 equivalents of acid per mole of neutral alkaloid salt turn off.

According to the invention, suitable acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, as well as organic acids such as succinic acid, fumaric acid, glutaric acid, adipic acid, malic acid, tartaric acid, Ascorbic acid, citric acid, mixtures of these acids, and the like. Organic acids are preferred.

The acid can or can be added to the chewing gum composition at any mixing stage

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previously mixed with a water-soluble portion of the mixture e.g. the sorbitol, whereupon the resulting mixture is worked into the chewing gum mass.

When administering the tobacco substitute products according to the invention very good results were obtained on habitual smokers. In numerous cases, when using From 6 to 20 pieces of chewing gum per day the breathing is completely given up, in other cases at least a considerable reduction was possible.

BATH ORIGINAL

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Claims (12)

Patent claims: 1. Chewable whiff product, characterized by a gum base and a tobacco alkaloid, which bound to a cation exchanger dispersed in the base is. 2. Product according to claim 1, characterized in that the gum base in an amount of et v / a 15 to about 80 percent by weight and the tobacco alkaloid in an amount from about 0.05 to about 2 percent by weight based on the weight of the gum base and calculated as the free base, is present. 3. Product according to claim 2, characterized in that the gum base in an amount of about 50 to 80 percent by weight is present. 4. The product of claim 2 characterized in that the gum base is present in an amount of from about 60 to about 73 percent by weight. 5. Product according to one of claims 1 to i \., Characterized in that it also contains a pharmacologically acceptable stimulant in such an amount that the dor'pH value at the chewing point when chewing is less than oi; v / a V. ORJGiNAL 1 i) il Β 8 7 / \ 2 I Ü 6. Product according to claim 5> characterized in that that the acidulant in an amount sufficient to achieve a pH of about 5 to about. Zj. before lies. 7. Product according to one of claims 5 or 6, characterized characterized in that the acidifying agent is a pharmacological permissible acid or a cation exchanger in hydrogen ο rni is and in an amount of about 1.5 to about 10 equivalents of acid per mole of alkaloid, calculated as the free base, is present. 8. Product according to claim 7> characterized in that the acidifying agent in an amount of about 1.5 to about 6 equivalents of acid per mole of alkaloid, calculated as the free base, is present. 9. Product according to claim 7, characterized in that the acidifying agent is present in an amount of about 2 to about k equivalents of acid per mole of alkaloid, calculated as the free base. 10. Product according to one of claims 1 to 9, characterized characterized in that the cation exchanger is a weakly acidic methacrylic type resin and is functional Contains carboxyl groups or is a strongly acidic resin of the polystyrene type and has functional sulfonic acid groups contains or a medium acidic resin of the polystyrene-i'yp is and functional phosphonic acid groups on v / eist. BAD ORiGINAL 109887/1218 11. Product according to one of claims 1 to 10, characterized in that it is nicotine as an alkaloid, nor-nicotine, Contains lobeline or a pharmacologically acceptable salt of one of these alkaloids. 12. A process for the production of a chewable substitute for artificial goods according to one of claims 1 to 11, characterized in that an I ¹ ab al: alkaloid bound by a cation exchange is dispersed in a gum base. For: Aktiebolaget Leo Ke chtsanv / old BATH ORIGINAL 109887/1210