Nicotine Delivery Product and Method for Producing It

Abstract

A nicotine delivery product comprising the reaction product of a nicotine/cation exchange resin complex and an organic polyol; and a method for preparing it comprising (a) mixing an aqueous suspension of a nicotine/cation exchange resin complex with an organic polyol or an aqueous solution thereof, and (b) removing water from the mixture to produce said nicotine delivery product. The nicotine delivery product has a nicotine release rate of at least 80% over a 10 minute period. It is particularly suited for use in smoking substitution devices delivering nicotine such as chewing gum, patches, lozenges, melting tablets and tablets for chewing.

Description

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, a nicotine delivery product, methods for preparing such nicotine delivery product, and compositions containing such nicotine delivery product are provided. The nicotine in the nicotine delivery product herein has a release rate of not less than 80% over a period of 10 minutes. The method by which such release rate is determined is described in more detail in the U.S.P. Official Monograph, Volume 26, pages 1309-1310.

The product produced by the process according to the present invention contains, in addition to the above disclosed nicotine, a cation exchange resin and an organic polyol.

The higher release rate for products according to the present invention is surprising and, without being bound by any theory, we may offer the following explanation:

In a product without polyol, the binding between nicotine and the cationic resin is dominated by ionic bonds.

The same type of binding is found in the product according to the present invention, but is expected to be covered by the added polyol giving a high concentration of polyol on the surface of the particles.

In the process disclosed in U.S. Pat. No. 6,586,449 a fraction of the ionic binding sites are physically blocked by the polyol which will also penetrate deeper into the resin particles before the loading of nicotine. The particles will therefore have a relatively high concentration of polyol in the center with nicotine on the surface.

In the release test according to the U.S.P. monograph the product is treated with a solution containing sodium chloride ions, which will start an ion exchange reaction with the nicotine resin complex resulting in the release of the ionically bound nicotine.

It is believed that the polyol will act as an humectant during the release test and thus give rise to a better contact between the resin complex and the test solution. This effect will be more pronounced in the product according to the present invention due to the very high concentration of polyol on the surface of the resin complex particles, which may explain the observed difference in release rates.

Any non-ionic pharmaceutical grade cationic ion exchange resin used to bind anionic molecules at the ion exchange sites may be employed in this invention. Examples of such cationic materials are: those bearing a carboxylic acid group, such as a weakly acidic type of resins containing carboxylic functional groups (these resins are typically derived from polymers or copolymers of methacrylic acid or polymethacrylic acid); the strongly acidic type of resins containing sulfonic functional groups (these resins are typically derived from polymers of styrene or copolymers of styrene and divinylbenzene); or the intermediate acidic type of resins containing phosphonic acid functional groups (these resins are typically derived from polymers of styrene or copolymers of styrene and divinylbenzene).

Cationic ion exchange resins are well known in the art and the present invention encompasses all of these. Representative cation exchange resins of use in accordance with the present invention are disclosed in U.S. Pat. No. 3,901,248. The preferred cation exchange resins are those known in the art as the Amberlite® resins and include, for example, Amberlite® IR20, Amberlite® IRP69, Amberlite® IRP64, Amberlite® IRP58, Amberlite® IRC50, Amberlite® IRP69, etc.

The product in accordance with the present invention also contains an organic polyol. The organic polyol is a non-toxic C₂ to C₁₂ linear or branched hydrocarbon having at least 2 hydroxy groups or a non-toxic C₅ to C₁₂ cyclic or heterocyclic hydrocarbon having at least 2 hydroxy groups.

The presence of a polyol also facilitates improved handling of the nicotine delivery product because it reduces the dust from the material.

Preferably the nicotine delivery product is an intermediate product for used in the manufacture of a final nicotine delivery product such as a chewing gum. The chewing gum additionally can comprise further polyols.

Examples of such polyols are:

C3

1,2 Propanediol (propylene glycol), 1,3 propanediol (trimethylene glycol), 1,2,3 propanetriol (glycerol);

C4

Erythritol;

C5

Xylitol;

C6

Sorbitol, mannitol, 1,6 hexanediol, cyclohexanehexol (inositol);

C12

Maltitol, maltitol syrup, lactitol, isomalt;

Mono- and disaccharides

Glucose, glucose syrup, fructose, sucrose.

In the first step of the process according to the present invention an aqueous solution of nicotine is mixed with the cation exchange resin to form a slurry of nicotine resin complex in water. The ratio of cation exchange resin to nicotine is from about 1:1 to about 10:1, preferably from 2:1 to 6:1, and most preferably about 4:1.

To ensure a fast and complete reaction between nicotine and the cation exchange resin it is important to include a sufficient amount of water in the mixture. The percent of total added water in the process before drying is suitably from 15 to 90% by weight, preferably from 25 to 65% by weight. In the process according to this invention the organic polyol is adsorbed to the nicotine cation exchange resin complex. The ratio of resin to polyol is from about 1:1 to about 10:1, preferably from 2:1 to 8:1, and most preferably about 2,4:1.

The resulting aqueous slurry of the nicotine/cation exchange resin complex with adsorbed organic polyol is then dried to remove the water. Such drying can be carried out by any conventional means, i.e. dried over a purge of nitrogen, dried under vacuum, etc. However, during the drying procedure temperatures in excess of 75-80° C. should be avoided as this may cause loss of nicotine. Preferably, the temperature should be kept below 60° C.

The dried product is typically milled and/or sieved to a substantially uniform particle size before being used.

The nicotine delivery product according to this invention is particularly suited for use in smoking substitution devices delivering nicotine such as chewing gum, patches, lozenges, melting tablets and tablets for chewing.

The following Examples illustrate the method of the present invention and the nicotine delivery product resulting from such method. These Examples should not be regarded as limiting the invention in any sense.

EXAMPLES

Procedure A

A 40 liter Stephan mixer equipped with scraper and stirrer was charged with 4.32 kg of ion exchange resin Amberlite® IRP64. In a separate container 1.08 kg of nicotine was mixed with 8.75 kg of water for ½ to 1 minute and the solution added to the mixer. The nicotine container was rinsed with further 2 kg of water which was also added to the mixer. The mixer was closed and stirred for 60 minutes.

Then, a mixture of 1.80 kg of glycerol and 1 kg of water was added to the mixer, and the slurry was stirred for 20 minutes.

Thereafter, the slurry was dried by heating to max. 60° C. under vacuum at a pressure of about 30-100 mbar (about 25-75 mmHg) with stirring. The drying process was stopped when the water content was about 3% by weight.

Results

The dried sample was analysed for nicotine content and release rate according to the method specified in the U.S.P. Official Monograph, Volume 26, pages 1309-1310.

Content of nicotine	Water content	Release of nicotine
% by weight	% by weight	% over 10 min
14.9	3.4	86

Procedure B

A 20 liter Diosna laboratory mixer VAC 20 equipped with scraper and stirrer was charged with 5.00 kg of water. 0.60 kg of nicotine was added and the nicotine container was rinsed with further 0.50 kg of water and was also added to the mixer.

The mixer was closed and stirred for 5 minutes.

Then 2.40 kg of ion exchange resin Amberlite® IRP64 was added to the mixer.

Then, a mixture of 1.00 kg of glycerol and 0.5 kg of water was added to the mixer, and the slurry was stirred for 15 minutes.

Thereafter, the slurry was dried by heating to max. 60° C. under vacuum at a pressure of about 30-100 mbar (about 25-75 mmHg) with stirring. The drying process was stopped when the water content was about 3% by weight.

Claims

1. A nicotine delivery product comprising an intimate mixture of the reaction product of a nicotine/cation exchange resin complex forming reaction and an organic polyol.

2. A nicotine delivery product according to claim 1, in that wherein the ratio of resin to polyol is from about 1:1 to about 10:1, preferably from 2:1 to 8:1 and most preferably about 2.4:1.

3. A method of preparing a nicotine delivery product, said method comprising (a) mixing an aqueous suspension of a nicotine/cation exchange resin complex with an organic polyol or an aqueous solution thereof, and (b) removing water from the mixture to produce said nicotine delivery product.

4. A method of preparing a nicotine delivery product, said method comprising (a) mixing an aqueous solution of nicotine with a cation exchange resin thereby forming a nicotine/cation exchange resin complex, (b) admixing with said complex of step (a) in aqueous suspension an organic polyol or an aqueous solution thereof to form an aqueous slurry of nicotine/cation exchange resin complex incorporating polyol, and (c) removing water from said slurry to produce said nicotine delivery product.

5. A method according to claim 3, wherein the cation exchange resin is selected from the group consisting of: (i) a methacrylic, weakly acidic type of resin containing carboxylic functional groups(ii) a polystyrene, strongly acidic type of resin containing sulfonic functional groups, and(iii) a polystyrene, intermediate acidic type of resin containing phosphonic functional groups.

6. The method according to claim 5, wherein the cation exchange resin is a methacrylic, weakly acidic type of resin containing carboxylic functional groups.

7. The method according to claim 6, wherein the cation exchange resin is polacrilex (Amberlite® IRP64).

8. A method according to claim 3, wherein the organic polyol is a non-toxic C2 to C12 linear or branched hydrocarbon having at least 2 hydroxy groups.

9. A method according to claim 8, wherein the organic polyol is selected from the group consisting of 1,2-propanediol, 1,3-propanediol, 1,6-hexanediol, glycerol and sorbitol.

10. A method according to claim 3, wherein the organic polyol is a non-toxic C5 to C12 cyclic or heterocyclic hydrocarbon having at least 2 hydroxy groups.

11. A method according to claim 10, wherein the organic polyol is selected from the group consisting of hexahydroxy cyclohexane (inositol) and mono- and disaccharides.

12. A method according to claim 11, wherein the organic polyol is glucose, fructose or sucrose.

13. The method according to claim 3, wherein the concentration of nicotine in said aqueous solution of nicotine is from about 5% by weight to about 50% by weight.

14. The method according to claim 3, wherein the ratio of cation exchange resin to nicotine is from 1:1 to 10:1.

15. The method according to claim 14, wherein the ratio of cation exchange resin to nicotine is from 2:1 to 6:1.

16. The method according to claim 14, wherein the ratio of cation exchange resin to nicotine is about 4:1.

17. The method according to claim 3, wherein the ratio cation exchange resin to organic polyol is from 1:1 to 10:1.

18. The method according to claim 17, wherein the ratio of cation exchange resin to organic polyol is from 2:1 to 8:1.

19. The method according to claim 17, wherein the ratio of cation exchange resin to organic polyol is about 2.4:1.

20. A method of preparing a nicotine delivery product having a nicotine release rate of at least 80% over a 10 minute period, said method comprising:

21. A nicotine delivery product obtainable by a method according to claim 20.

22. A chewable gum composition comprising a chewing gum base and a nicotine delivery product according to claim 1, wherein the nicotine delivery product is substantially uniformly distributed in said chewing gum base.