NICOTINE POUCH

Abstract

A product for oral delivery of nicotine comprising a powder composition of a nicotine source, at least one pH adjusting agent, and at least one filler, contained in a pouch which is permeable to saliva and to components of the powder composition once dissolved in saliva, wherein the composition has a solubility of less than 5 g/100 ml. The invention also relates to a method for preparing said product and also the use of said product.

Claims

1.-16. (canceled)

17. An oral dosage pouch, comprising: a powder composition, comprising: nicotine; at least one pH adjusting agent; and one or more fillers, wherein at least one filler is microcrystalline cellulose in the amount of 40-80 wt % by weight of the powder composition; wherein the powder composition has a solubility of less than 5 g/100 ml; and a pouch which is permeable to saliva and to components of the powder composition once dissolved in saliva.

18. The pouch of claim 17, wherein the pouch is a non-woven pouch.

19. The pouch of claim 17, wherein the nicotine is in a nicotine source, and the nicotine source is 0.5-2 wt % by weight of the powder composition calculated as nicotine base.

20. The pouch of claim 17, wherein the nicotine is stabilized in the form of a nicotine salt.

21. The pouch of claim 20, wherein the nicotine salt is nicotine benzoate or nicotine maleate.

22. The pouch of claim 17, wherein the nicotine is bound to an ion exchange resin.

23. The pouch of claim 22, wherein the ion exchange resin is a weak cation exchange resin.

24. The pouch of claim 22, wherein the ion exchange resin is polacrilex.

25. The pouch of claim 17, wherein the pH adjusting agent is a buffer comprising carbonates, bicarbonates, borates, glycinates, ammonium, phosphates, hydroxides, tris, or mixtures thereof.

26. The pouch of claim 17, wherein the pH adjusting agent is 4-15 wt % by weight of the powder composition.

27. The pouch of claim 17, further comprising one or more polyalcohols, sweeteners, polysaccharides, cellulose, natural fibers, flavors, or mixtures thereof.

28. The pouch of claim 27, wherein at least one sweetener is present, the sweetener comprising one or more of mannitol, xylitol, maltitol, sucralose, acesulfam potassium, aspartame, steviol glycosides, or mixtures thereof.

29. The pouch of claim 17, wherein the solubility of less than 5 g/100 ml is a solubility in water at pH 7 and 25° C.

30. The pouch of claim 29, wherein the solubility of less than 5 g/100 ml is a solubility of less than 2.5 g/100 ml.

31. The pouch of claim 29, wherein the solubility of less than 5 g/100 ml is a solubility of less than 1.0 g/100 ml.

32. The pouch of claim 17, wherein the pouch has a nicotine release fraction of 50-100% after 30 min.

33. An oral dosage pouch, comprising: a powder composition, comprising: nicotine bound to a weak cation exchange resin; at least one pH adjusting agent in the amount of 4-15 wt % by weight of the powder composition; and one or more fillers, wherein at least one filler is microcrystalline cellulose in the amount of 40-80 wt % by weight of the powder composition; wherein the powder composition has a solubility of less than 5 g/100 ml in water at pH 7 and 25° C.; and a non-woven pouch containing the powder composition, wherein the pouch is permeable to saliva and to components of the powder composition once dissolved in saliva.

34. The pouch of claim 33, wherein the weak cation exchange resin is polacrilex.

35. The pouch of claim 33, wherein the pH adjusting agent is a buffer comprising carbonates, bicarbonates, borates, glycinates, ammonium, phosphates, hydroxides, tris, or mixtures thereof.

36. The pouch of claim 33, further comprising one or more polyalcohols, sweeteners, polysaccharides, cellulose, natural fibers, flavors, or mixtures thereof.

Description

SHORT DESCRIPTION OF THE DRAWINGS

[0050] In the figures below, the nicotine release from products according to the disclosed invention as well as reference products are presented.

[0051] FIG. 1 shows nicotine release profiles for the pouch products according to the present invention: Example 1 (Batch A, filled squares); Reference 1A (2 mg Nicotine, left triangles) and Reference 1B (4 mg Nicotine, right triangles); Reference 2A (3 mg Nicotine, up triangles) and Reference 2B (6 mg nicotine, down triangles).

[0052] FIG. 2 shows nicotine release data for the pouch product according to the present invention, Example 1 (Batch B, filled circles with error bars) and stability data: 1 month, T=21-22° C., 60-62% RH (black empty circle with corresponding error bars).

[0053] FIG. 3 shows nicotine release data for the analyzed pouch products from different batches (A, B and C) according to the present invention, Example 1. Pouch products with different concentration range for the buffer agents (Example 2, black star with error bars), nicotine polacrilex (Example 3, black cross with error bars) and fillers (Example 4, black pentagram with error bars) are analyzed and compared for the nicotine release at 30 min.

[0054] FIG. 3 shows nicotine release data for the analyzed pouch products with different fillers and moisturizing agents (Example 5, open circle with error bars) are analyzed and compared for the nicotine release at 30 min.

[0055] FIGS. 4A-C show the results from the degradation study of the pouch of the present invention, the chromatograms from the HPLC-UV analysis of the pouch sample stored at 21-22° C./60-62% RH for up to 3 months (FIG. 4A), sample with the same excipients but without nicotine API (FIG. 4B) and sample of nicotine polacrilex 20% API (FIG. 4C).

[0056] FIGS. 5A-B show the results from the degradation study of the pouch of the present invention, the chromatograms from the HPLC-UV analysis of a pre-stressed sample of nicotine (FIG. 5A) was compared to the chromatogram of nicotine bitartrate dihydrate spiked into the reference sample without API (FIG. 5B).

DETAILED DESCRIPTION OF THE INVENTION

[0057] Although individual features may be included in different embodiments, these may possibly be combined in other ways, and the inclusion in different embodiments does not imply that a combination of features is not feasible. In addition, singular references do not exclude a plurality. In the context of the present invention, the terms “a”, and “an” do not preclude a plurality.

[0058] The design of a nicotine delivering pouch require co-optimization of several properties, in particular nicotine stability and release as well as taste masking. Surprisingly, it has been found that a pouch based on nicotine polacrilex according to the present invention is both stable and can release nicotine as fast as a pouch based on a typical salt such as nicotine tartrate. Polacrilex is an insoluble, weakly acidic cation exchange resin. The matrix contains methacrylic acid capable of exchanging hydrogen for nicotine cations, e.g. Amberlite IRP64® or Doshion P-551®.

[0059] The pouch according to the present invention contains a powdered mix of a nicotine source, at least one pH controlling agent and at least one filler, such as microcrystalline cellulose, as well as sweeteners and flavors.

[0060] In a preferred embodiment according to the present invention, the buffer powder is directly mixed with the other powder components of the pouch to facilitate rapid pH adjustment upon contact with the saliva.

[0061] Nicotine may be derived either by extraction from tobacco or from chemical synthesis. In comparison with the synthetic nicotine, the extracted material contains small amounts of tobacco-derived non-nicotine alkaloids. While these impurities may be toxic, they likely contribute difficulties for the taste masking of the product. Although both sources of nicotine are acceptable embodiments of this invention, the synthetic material provides additional advantages in terms of taste setting. Hence, in one preferred embodiment the nicotine is derived from chemical synthesis. In an advantageous embodiment of the present invention the purity of nicotine is in the range of 99.00-99.99%, preferably in the range of 99.60-99.99%.

[0062] According to one embodiment of the present nicotine may be in the form of nicotine polacrilex or a nicotine salt, such benzoate or maleate. In another embodiment nicotine polacrilex is preferred due to the favorable combination of nicotine stability and fast release affected by the direct mix with the pH controlling agent.

[0063] Further, the pH controlling agent according to the present invention may be a carbonate buffer, such as sodium carbonate, sodium bicarbonate, potassium carbonate, or mixtures thereof. In other preferred embodiments the buffer may be a borate, such as sodium tetraborate; phosphate, such as mono-, di- or trihydrogenphosphate; or tris(hydroxymethyl)aminomethane (tris). Preferred buffer agents according to the present invention are mixtures of sodium carbonate and sodium bicarbonate.

[0064] In addition to the nicotine source and pH controlling agents, the pouch of the present invention also contains at least one filler.

[0065] Fillers according to the present invention may include polyalcohols, sweeteners, polysaccharides, cellulose, microcrystalline cellulose, natural fibers, flavors. Polyalcohols, or sugar alcohols are a class of polyols that are commonly obtained by the hydrogenation of sugars. Further, the polyalcohols comprise a lower caloric content than sugars and are also, in general, less sweet. Polysaccharides are polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages, and on hydrolysis give the constituent monosaccharides or oligosaccharides. They range in structure from linear to highly branched. Examples include storage polysaccharides such as starch and glycogen, and structural polysaccharides such as cellulose, chitin and alginate. Cellulose is a very common natural polymer and it is the largest component of plant cell walls. The cellulose usually consists of polymer chains that are 10,000-15,000 molecules long. Microcrystalline cellulose (MCC) is synthetically made and consists of chains that are between 100 and 300 molecules long. With natural fibers means fibers that are produced by plants, animals, or geological processes.

[0066] The at least one filler of the present invention may be microcrystalline cellulose, such as Avicel PH-200, which may have solubility of less than 5 g/100 ml. Fillers with poor water solubility limit the water solubility of the powder composition in the pouch and, therefore, do not allow the pouch content to be completely dissolved when in contact with water supplied in the form of saliva. Thus, the use of fillers with poor water solubility, such as Avicel PH-200, may result in a relatively slow release and direct absorption of nicotine through the mucus membrane in the mouth. In a preferred embodiment the water solubility of microcrystalline cellulose is less than 2.5 g/100 ml, more preferable less than 1.0 g/100 ml, even more preferable less than 0.75 g/100 ml, most preferable less than 0.58 g/100 ml measured in H.sub.2O at 25° C. and pH 7. This contributes greatly to the advantageous nicotine release profile of the pouch according to the present invention.

[0067] The at least one filler in one embodiment of the present invention may be microcrystalline cellulose, such as Avicel PH-200. In another embodiment of the present invention, the at least one filler may comprise a mixture of microcrystalline cellulose 90M(102) and the polysaccharide sodium alginate. Both embodiments of the present invention may have a water solubility of less than 5 g/100 ml. Fillers with poor water solubility limit the water solubility of the powder composition in the pouch and, therefore, do not allow the pouch content to be completely dissolved when in contact with water supplied in the form of saliva. Thus, the use of fillers with poor water solubility, such as Avicel PH-200 or Hicel 90M(102), may result in a relativley slow release and direct absorption of nicotine through the mucus membrane in the mouth. In a preferred embodiment the water solubility of microcrystalline cellulose is less than 2.5 g/100 ml, more preferable less than 1.0 g/100 ml measured in H.sub.2O at 25° C. This contributes greatly to the advantageous nicotine release profile of the pouch according to the present invention.

[0068] Sweeteners according to the present invention may comprise mannitol, xylitol, maltitol, sucralose, acesulfam potassium, aspartame, steviol glycosides, or mixtures thereof. Flavors according to the present invention may include menthol, cinnamon, mint, peppermint, spearmint, apple, cherry, melon, mango, peach, passion fruit, orange, blood orange, grape fruit, mandarin, tangerine, licorice, ginger, vanilla, wintergreen, lemon, lime, strawberry, raspberry, salmonberry, lingonberry, cranberry, blueberry, muscadine berry, sea buckthorn, chocolate, coffee, mocha, or mixtures thereof.

[0069] In an advantageous embodiment of the present invention, the distinct balance of microcrystalline cellulose and polyalcohol levels contribute to the favorable release profile of nicotine from the matrix.

EXAMPLES

[0070] The formulation of the present invention is exemplary and should be considered as an inspiration to obtain a similar outcome within the scope of the present invention. A specification of suppliers for the different ingredients used in the present application is disclosed in Table 1.

[0071] A specification of suppliers for the different ingredients used in the present application is disclosed in Table 1B.

TABLE-US-00001 TABLE 1 Specification of suppliers for the different ingredients. Ingredients Supplier Form Particle size Solubility in water Function Nicotine Polacrilex Siegfried Solid/white 96%: <710 μm Insoluble Nicotine source (NPR) 20% fine powder 90%: <210 μm Xylitol Sigma-Aldrich Solid/white — Very soluble Filler Sweetener crystalline 642 mg/ml at 25° C. powder D-Mannitol Sigma-Aldrich Solid/white — Very soluble Filler Sweetener crystalline 216 mg/ml at 25° C. powder Avicel PH-200 FMC Solid/white 200 μm Insoluble Filler Microcrystalline free-flowing (water soluble cellulose powder substances: NMT 12.5 mg/5 g (0.25%) at 25° C.) Sodium Carbonate Sigma-Aldrich Solid/white — Very soluble Buffering agent Monohydrate powder 307 mg/ml at 25° C. Sodium Bicarbonate Sigma-Aldrich Solid/white — 103 mg/ml at 25° C. Buffering agent powder L-Menthol Sigma-Aldrich Solid/transparent — Low soluble Flavoring agent large crystals 0.49 mg/ml at 25° C. Apple flavor Firmenich Solid/colored — — Flavoring agent powder Cinnamon flavor Firmenich Solid/colored — — Flavoring agent powder Acesulfame K Celanese Solid/white Min 95%: <1000 μm High solubility: Sweetener crystalline 270 mg/ml at 20° C. powder

TABLE-US-00002 TABLE 1B Specification of suppliers for the different ingredients. Ingredients Supplier Form Particle size Solubility in water Function Nicotine Polacrilex Siegfried Solid/white 96%: <710 μm Insoluble Nicotine source (NPR) 20% fine powder 90%: <210 μm Xylitol Sigma-Aldrich Solid/white — Very soluble Filler Sweetener crystalline 642 mg/ml at 25° C. powder D-Mannitol Sigma-Aldrich Solid/white — Very soluble Filler Sweetener crystalline 216 mg/ml at 25° C. powder Avicel PH-200 FMC Solid/white 200 μm Insoluble Filler Microcrystalline free-flowing (water soluble cellulose powder substances: NMT 12.5 mg/5 g (0.25%) at 25° C.) Hicel 90M (102) Brenntag Solid/white  90 μm Insoluble Filler Microcrystalline free flowing (water soluble cellulose powder substances: <0.24%) Satialgine S 900NS Brenntag Solid/creamy- — Soluble Filler Sodium Alginate white to light- brown powder Sodium Carbonate Brenntag Solid/white — Very soluble Buffering agent Monohydrate powder 307 mg/ml at 25° C. Sodium Bicarbonate Sigma-Aldrich Solid/white — 103 mg/ml at 25° C. Buffering agent powder L-Menthol Sigma-Aldrich Solid/transparent — Low soluble Flavoring agent large crystals 0.49 mg/ml at 25° C. Menthol flavor Firmenich Solid powder — — Flavoring agent Flavors Firmenich Solid/white — — Flavoring agent or colored powder Acesulfame K Celanese Solid/white Min 95%: <1000 μm High solubility: Sweetener crystalline 270 mg/ml at 20° C. powder Ammonium Chloride Brenntag White — — Taste enhancer crystalline powder Propylene glycol Caldic Clear colorless — Soluble Moisturizing agent odorless liquid

[0072] Product Manufacturing

[0073] A product with a composition according to the present invention is manufactured in the following manner: all ingredients, that are in powder form, are mixed and sieved into the final powder mixture. The resulting powder is filled into a pouch made of a non-woven material or cloth. Non-woven material, cloths or fabrics may be defined as sheet or web structures bonded together by entangling fibers or filaments, and by perforating films, mechanically, thermally, or chemically. They are flat, porous sheets that are made directly from separate fibers or from molten plastic or plastic film. They are not made by weaving or knitting and do not require converting the fibers to yarn. The whole manufacture process is performed at ambient conditions of temperature and relative humidity (RH), ranging between 21-25° C. and 30-60% RH, respectively.

[0074] Solubility in Water

[0075] The water used for solubility measurements is either distilled or filtered via a Millipore Milli-Q system. An unused pouch with weight P0 (g) is placed in a test tube containing 20 ml of water and left on the shaker at room temperature for 1 h. The pouch is isolated and dried to constant weight Pe (g) in air at room temperature. Three replicates for each batch are used in the solubility measurements. The water solubility of the pouch composition is then (P0-Pe) (g) per 20 ml water.

[0076] In-Vitro Release Experiments

[0077] An experimental method for the determination of the nicotine release from pouch was performed using UV spectrophotometric methodology. Pouch sample preparation and method of analysis were adapted and modified from the published methods for pouch analysis (see U.S. Pat. No. 9,402,810).

[0078] Briefly, a pouch sample is placed on the middle of the filter paper which is pre-soaked in 20 ml water phase in a Petri dish. The whole setup is covered by lid to maintain the relative humidity level and prevent water evaporation. As the pouch starts to absorb the water, the nicotine polacrilex is dissolved by liquid and the released nicotine diffuses into the external water phase.

[0079] This is conducted at specific incubation times, i.e. 10, 20 and 30 min (note a new pouch for each time). Three replicates from each batch of Example 1 are used in the experiment for each time. After each analyzed timepoint, the pouch sample is placed into the test tube containing 15 ml of water and left on the shaker for 1.5-2 hours.

[0080] A number of unused pouches from the same batch are also placed into the test tube, containing 15 ml purified water, and left on the shaker for 1.5-2 hours for analysis of the total nicotine content.

[0081] Afterwards, the water phase containing nicotine is analyzed for the residual content of nicotine using the UV spectrophotometer (Shimadzu, UV1800). First, each sampling of the water phase from the test tube is filtered using the 0.45 μm filter unit. The filtered solution is then diluted to the suitable concentration, and the sample absorbance is measured. The measurements are conducted at photometric mode with fixed wavelength of 260 nm.

[0082] The nicotine concentration for the analyzed samples (non-used and used pouches) is calculated from a calibration curve, and the total and residual nicotine content is determined. The release of nicotine at specific time is calculated by subtracting the ‘residual nicotine content’ from the ‘total nicotine content’ and dividing it by the ‘total nicotine content’. Table 2 shows four different example compositions (Examples 1-4) according to the present invention that have been analyzed. Table 3 summarizes the obtained data for the nicotine release for the four example compositions of the present invention and reference pouch samples. The obtained data are plotted and shown in FIGS. 1-3.

[0083] Table 2B shows five different example compositions (Examples 1-5) according to the present invention that have been analyzed. Table 3B summarizes the obtained data for the nicotine release for the five example compositions of the present invention and reference pouch samples. The obtained data are plotted and shown in FIGS. 1-3.

TABLE-US-00003 TABLE 2 Formulation compositions of the present invention. The pouch weight is 0.4 g. The nicotine dose corresponds to the 4 mg per pouch (Examples 1, 2 and 4) and 8 mg per pouch (Example 3). Example Example Example Example Content 1 2 3 4 NPR 20%* 5 5 10 5 Xylitol 16 16 16 4 Mannitol 16 16 16 4 Avicel 48 53.2 43 72 PH-200 Sodium 4.0 2.0 4.0 4.0 Carbonate Sodium 6.4 3.2 6.4 6.4 Bicarbonate Menthol 0.2 0.2 0.2 0.2 Apple flavor 2.0 2.0 2.0 2.0 Cinnamon 2.14 2.14 2.14 2.14 flavor Ace K** 0.26 0.26 0.26 0.26 *NPR—Nicotine polacrilex; **Ace K—Acesulfame potassium.

TABLE-US-00004 TABLE 2B Formulation composition of the present invention. The pouch weight is 0.4 g (Examples 1-4) and 0.6 g (Example 5). The nicotine dose corresponds to the 4 mg per pouch (Examples 1, 2, 4 and 5) and 8 mg per pouch (Example 3). Example Example Example Example Example Content 1 2 3 4 5 NPR 20%* 5 5 10 5 3.3 Xylitol 16 16 16 4 0 Mannitol 16 16 16 4 0 Sodium 0 0 0 0 5 Alginate Avicel 48 53.2 43 72 0 PH-200 Hicel 90M 0 0 0 0 48.9 (102) Sodium 4.0 2.0 4.0 4.0 2.5 Carbonate Sodium 6.4 3.2 6.4 6.4 0 Bicarbonate Water 0 0 0 0 20.0 Propylene 0 0 0 0 14.5 glycol L-Menthol 0.2 0.2 0.2 0.2 0 Menthol 0 0 0 0 0.7 flavor Apple flavor 2.0 2.0 2.0 2.0 0 Cinnamon 2.14 2.14 2.14 2.14 0 flavor Peppermint 0 0 0 0 3.0 flavor Spearmint 0 0 0 0 1.0 flavor Ace K** 0.26 0.26 0.26 0.26 0.6 Ammoinium 0 0 0 0 0.5 chloride *NPR—Nicotine polacrilex; **Ace K—Acesulfame potassium.

TABLE-US-00005 TABLE 3 Pouches according to the present invention together with reference pouches and their respective measured nicotine release at specific timepoints. Nicotine Nicotine Release fraction (%) source/ dose/pouch X.sub.released(time) Sample ID Conc % mg 10 min 20 min 30 min In-Vitro Example 1 Batch A NPR/1.0% 4 35 54 75 34 54 66 35 48 78 Mean value ± Std 35 ± 0.6 52 ± 3.5 73 ± 6.2 Example 1 Batch B NPR/1.0% 4 38 63 61 51 55 76 39 56 69 Mean value ± Std 43 ± 7.2 58 ± 4.3 69 ± 7.5 Stability study: — — 61 1 month 62 (T = 21 − 22° C., 77 60-62% RH), Batch B Mean value ± Std — — 67 ± 8.9 Example 1 Batch C NPR/1.0% 4 22 60 71 32 49 72 32 54 86 Mean value ± Std 29 ± 5.8 54 ± 5.5 76 ± 8.4 Example 2 NPR/1.0% 4 — — 69 84 84 Mean value ± Std — — 79 ± 8.7 Example 3 NPR/2.0% 8 — — 53 49 61 Mean value ± Std — — 54 ± 6.1 Example 4 NPR/1.0% 4 — — 68 61 60 Mean value ± Std — — 63 ± 4.3 Reference 1A NPR/1.1% 2 32 32 43 (Zonnic) Reference 1B NPR/2.2% 4 31 31 34 (Zonnic) Reference 2A Nicotine 3 48 70 77 (ZYN mini dry) Salt/0.75% Reference 2B Nicotine 6 47 53 65 (ZYN mini dry) Salt/1.5%

TABLE-US-00006 TABLE 3B Pouches according to the present invention together with reference pouches and their respective measured nicotine release at specific timepoints. Nicotine Nicotine Release fraction (%) source/ dose/pouch X.sub.released(time) Sample ID Conc % mg 10 min 20 min 30 min In-Vitro Example 1 Batch A NPR/1.0% 4 35 54 75 34 54 66 35 48 78 Mean value ± Std 35 ± 0.6 52 ± 3.5 73 ± 6.2 Example 1 Batch B NPR/1.0% 4 38 63 61 51 55 76 39 56 69 Mean value ± Std 43 ± 7.2 58 ± 4.3 69 ± 7.5 Stability study: — — 61 1 month 62 (T = 21 − 22° C., 77 60-62 % RH), Batch B Mean value ± Std — — 67 ± 8.9 Example 1 Batch C NPR/1.0% 4 22 60 71 32 49 72 32 54 86 Mean value ± Std 29 ± 5.8 54 ± 5.5 76 ± 8.4 Example 2 NPR/1.0% 4 — — 69 84 84 Mean value ± Std — — 79 ± 8.7 Example 3 NPR/2.0% 8 — — 53 49 61 Mean value ± Std — — 54 ± 6.1 Example 4 NPR/1.0% 4 — — 68 61 60 Mean value ± Std — — 63 ± 4.3 Example 5 NPR/0.66% 4 — — 67 68 70 Mean value ± Std — — 68 ± 1.5 Reference 1A NPR/1.1% 2 32 32 43 (Zonnic) Reference 1B NPR/2.2% 4 31 31 34 (Zonnic) Reference 2A Nicotine 3 48 70 77 (ZYN mini dry) Salt/0.75% Reference 2B Nicotine 6 47 53 65 (ZYN mini dry) Salt/1.5%
1) Pouch Analysis: a Comparison with Commercially Available Reference Pouches.

[0084] FIG. 1 shows that the pouch products of the present invention—Example 1 (filled squares with error bars) results in similar nicotine release at 10 min and higher release of nicotine at 20 min and 30 min as compared to the nicotine release for Reference 1 pouch products containing nicotine polacrilex (right and left triangles). Moreover, all the examples of the pouch products according to the present invention show similar release of nicotine as compared to Reference 2 pouch product, containing nicotine salt (up and down triangles) at 20 min and 30 min.

[0085] Pouch based on nicotine polacrilex according to the present invention can release nicotine as fast as a pouch based on a typical salt such as nicotine tartrate. Moreover, pouch based on nicotine polacrilex according to the present invention can release higher amount of nicotine in comparison to other nicotine polacrilex based pouch products.

2) Stability Study:

[0086] nicotine release at 30 min [0087] degradation product
Pouch samples from Example 1 were stored in a plastic container with closed (but not hermetically sealed) lid at 21-22° C./60-62% RH for up to 3 months. The release of nicotine at 30 min for the pouch product stored for 1 month at 21-22° C./60-62% RH was analyzed, using the UV spectrophotometrical method described above.

[0088] FIG. 2 shows the obtained results where no changes in the nicotine release are observed for the pouch product samples (Example 1) stored for one month at 21-22° C./60-62% RH (black empty circle).

[0089] Pouch samples from Example 1 were also analyzed for the detection of potential degradation products, using HPLC-UV method (Agilent 1200 series HPLC). Samples with the same excipients but without the nicotine API and samples with the nicotine API was used to identify reference (blank) peaks. A pre-stressed sample of nicotine was prepared (using elevated temperature and light) to reveal any peaks originating from heat- and light-induced degradation of nicotine. FIGS. 4A-C show the chromatograms from the HPLC-UV analysis of the pouch sample of the present invention stored at 21-22° C./60-62% RH for up to 3 months (FIG. 4A), a pouch sample with the same excipients but without nicotine API (FIG. 4B) and a sample of nicotine polacrilex 20% API (FIG. 4C). The obtained chromatograms show no peaks for the potential degradation products in analyzed samples. The obtained peaks in the chromatogram corresponds to nicotine or solvent injection peak. The chromatogram from the HPLC-UV analysis of pre-stressed sample of nicotine (FIG. 5A), which was compared to the chromatogram of nicotine bitartrate dihydrate spiked into the reference sample without API (FIG. 5B). No additional peaks from potential degradation products were observed in the chromatogram of the pre-stressed sample (FIG. 5A).

[0090] Pouch based on nicotine polacrilex according to the present invention is stable and release the same amount of nicotine after 1 month storage as a freshly manufactured pouch based on nicotine polacrilex according to the present invention. Pouch based on nicotine polacrilex according to the present invention is stable and show no potential degradation products in analyzed pouch samples from example 1, stored at 21-22° C./60-62% RH for up to 3 months.

3) Concentration Range for the Components:

[0091] Buffer (reduced twice) [0092] Nicotine polacrilex (increased twice) [0093] Filler (polyalcohols reduced 4 times) [0094] Filler (no polyalcohols, addition of polysaccharide and/or moisturizing agents)
FIG. 3 shows similar nicotine release at 30 min even if the content of buffer agents is reduced twice in the current pouch formulation recipe (black star with error bars, Example 2).

[0095] If the nicotine content is increased twice in the current pouch formulation recipe (Table 2, Example 3), the release of nicotine at 30 min is lower as compared to the release of nicotine of Examples 1, 2 and 4 at 30 min (Table 2). However, similar trend could be observed in the analyzed reference pouch products with higher amount of nicotine (FIG. 1, black triangles). For example, analysis of Reference 1B pouch containing 4 mg NPR (FIG. 1, right triangles) results in lower nicotine release at 30 min as compared to the Reference 1A pouch containing 2 mg NPR (FIG. 1, left triangles). Similar scenario is observed for Reference 2 pouch products: pouch, containing 6 mg nicotine salt (FIG. 1, down triangles) shows lower release of nicotine at 30 min than pouch containing 3 mg nicotine salt (FIG. 1, up triangles).

[0096] FIG. 3 shows slightly lower release of nicotine at 30 min if the content of polyalcohols is reduced four times in the current formulation recipe (black pentagram with error bars, Example 4).

[0097] FIG. 3 shows similar nicotine release even if the content of polyalcohols reduced to zero but with the addition of polysaccharides such as sodium alginate and moisturizing agents (open circle with error bars, Example 5).

[0098] FIG. 3 also shows batch-to-batch variation according to the present invention, Example 1. There is a relatively high batch-to-batch variation (filled circles, squares and diamonds with error bars) of the nicotine at 10 min.

[0099] A pouch based on nicotine polacrilex with reduced amount of buffer agents according to the present invention, Example 3, has the same release of nicotine at 30 min as compared with a pouch based on nicotine polacrilex according to the present invention, Example 1. It appears that a pouch based on nicotine polacrilex with reduced amount of buffer agents according to the present invention, Example 3, has similar release of nicotine at 30 min as compared with a reference pouch based on a nicotine salt such as nicotine tartrate. A pouch based on nicotine polacrilex with reduced amount of polyalcohols according to the present invention, Example 4, has slightly lower release of nicotine at 30 min as compared with a pouch based on nicotine polacrilex according to the present invention, Example 1. A pouch based on nicotine polacrilex with reduced amount of polyalcohols according to the present invention, Example 4, has higher nicotine release as compared with a reference pouch based on nicotine polacrilex.

[0100] The pH of the nicotine containing water phase from the test tube for the examined pouch samples of Example 1 was also measured. The obtained pH values are summarized in Table 4.

[0101] Table 4 shows that the pH for the pouch based on nicotine polacrilex according to the present invention is above pH 8.

[0102] The pH of the nicotine containing water phase from the test tube for the examined pouch samples of Example 1 and Example 5 was also measured. The obtained pH values are summarized in Table 4B.

[0103] Table 4B shows that the pH for the pouch based on nicotine polacrilex according to the present invention is above pH 8.

TABLE-US-00007 TABLE 4 pH values of the water phase containing nicotine in the test tube for the examined pouch samples at specific timepoint. Specific timepoint, Min pH values In-Vitro 0(non-used) 8.62 10 8.47 20 8.42 30 8.49

TABLE-US-00008 TABLE 4B pH values of the water phase containing nicotine in the test tube for the examined pouch samples at specific timepoint. Specific timepoint, Min pH values In-Vitro Examples 1 5 0(non-used) 8.62 9.67 10 8.47 — 20 8.42 — 30 8.49 9.58