Nicotine pouch

Abstract

The present invention relates to a method for preparing the product, and further to uses of the product. ...

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a pouch for the oral delivery of nicotine. [Background technology]

[0002] Technical background Tobacco smoking is associated with adverse health effects, but these adverse health effects are not related to the administration of nicotine itself. Although nicotine is highly addictive, the most important risks associated with tobacco use result from the numerous substances formed and released during tobacco combustion, such as carcinogens, such as nitrosamines and various tar components.

[0003] It is generally accepted that the difficulty of quitting smoking is due to the smoker's dependency on the ingredient nicotine. It is therefore desirable to use alternative means of delivering nicotine to facilitate smoking reduction or cessation. Such products should provide nicotine without or with minimal amounts of other potentially harmful ingredients associated with tobacco use. Several alternative nicotine administration forms are known, such as gums, patches, nasal or oral sprays, lozenges and oral pouches. For these products, the purity of the ingredient nicotine is important for potential toxicity aspects. Also, the taste of the product is obviously important for consumer acceptance and preference.

[0004] During cigarette smoking, nicotine is easily absorbed into the smoker's blood via the large surface of the lungs and begins to affect the brain within 10 seconds. This results in increased levels of epinephrine and dopamine, the neurotransmitter that controls the pleasure centers of the brain, leading to "smoker's satisfaction" among other things. In contrast, products such as nicotine gums, patches, sprays, lozenges and pouches release nicotine in the oral cavity, where it is quickly absorbed through the oral mucosa or is partially swallowed, which may slow down and make absorption from the stomach less efficient. In these products, the speed and location of nicotine release (oral mucosa vs. stomach) are clearly important. Even with a concentrated and optimized release of nicotine to the oral mucosa, the onset of action is on the order of minutes rather than seconds, as would be facilitated by absorption via the lungs.

[0005] In addition to the taste, purity and expression of action mentioned above, the chemical stability of the nicotine molecule is important for its performance in an oral delivery system. In its free base form, nicotine is volatile and undergoes rapid oxidation, leading to discoloration and partial loss of activity. To address these issues, the nicotine base may be absorbed on a suitable carrier and / or non-covalently bound with a salt or complexed with an ion exchange resin. This improves the stability of the component nicotine, but also clearly affects the rate of nicotine release from the delivery system. Absorption of the nicotine molecule through the oral mucosa requires the neutral form to prevail only at pH values ​​above 8. Therefore, most delivery systems contain pH control substances such as buffers that bring the pH to the desired range once nicotine is released from the delivery system. The rate of local pH adjustment in the mouth becomes yet another parameter that determines the overall performance of the nicotine delivery system.

[0006] US Patent No. 9,402,810 describes a pouch based on nicotine extracted from tobacco and then stabilized in the form of tartrate. The pouch described in US Patent No. 9,907,748 is also based on nicotine extracted from tobacco, in this case stabilized by binding with polacrilex resin. However, for stability reasons, US Patent No. 9,907,748 teaches that a pH control agent is adsorbed onto an inert cellulose carrier to avoid contact with the nicotine salt in the dry pouch. Furthermore, WO2018 / 233795 also uses nicotine extracted from tobacco, and sugar alcohol sweeteners are often used as carriers for nicotine. Summary of the Invention [Problem to be solved by the invention]

[0007] One object of the present invention is to provide an improved nicotine pouch that overcomes at least some of the shortcomings associated with products currently on the market. [Means for solving the problem]

[0008] Summary of the Invention The above objectives are: Nicotine source; at least one pH adjuster; and At least one bulking agent This is achieved by a nicotine oral delivery product comprising a powder composition consisting of: a) a nicotine oral delivery product that is contained in a pouch that is permeable to saliva and to components of the powder composition dissolved in saliva, and the solubility of the powder composition is less than 5 g / 100 ml. In a preferred embodiment, the solubility of the powder composition is less than 2.5 g / 100 ml, more preferably less than 1.0 g / 100 ml.

[0009] The above objectives are: Nicotine source; at least one pH adjuster; and At least one bulking agent This can be achieved by a nicotine oral delivery product comprising a powder composition consisting of: a) a nicotine oral delivery product comprising: a powder composition contained in a pouch that is permeable to saliva and to components of the powder composition dissolved in saliva, the powder composition having a solubility of less than 5 g / 100 ml in water at 25 degrees Celsius and pH 7. In a preferred embodiment, the solubility of the powder composition is less than 2.5 g / 100 ml, more preferably less than 1.0 g / 100 ml.

[0010] In connection with the above, it should be emphasized that neither the pouches described in US Pat. No. 9,402,810 nor US Pat. No. 9,907,748 provide an optimal combination of nicotine stability, release and uptake profile. In US Pat. No. 9,402,810, nicotine is used in salt form. In contrast, nicotine bound to an ion exchange resin promotes controlled release and helps maximize the proportion of the dose that is absorbed through the mucous membrane in the mouth rather than swallowed. In US Pat. No. 9,907,748, nicotine bound to a polacrilex resin is employed. However, to minimize contact between the nicotine polacrilex (NPR) and the buffer in the dry pouch, the buffer is adsorbed onto an inert cellulose carrier. In the presence of saliva, this increases the time it takes for the buffer to come into contact with the nicotine polacrilex. As shown herein, the pouches described in US Pat. No. 9,907,748 release nicotine relatively slowly and more poorly through a 30 minute window.

[0011] Furthermore, the pouches described in WO 2018 / 233795A1 use an excess of polyalcohol, which acts both as a nicotine carrier and to increase the aqueous solubility of the composition in the pouch, and since it is difficult to control the supply of water in the form of saliva of each end user, a large amount of soluble carrier may lead to loss of nicotine to the stomach by swallowing rather than absorption through the mucous membrane in the mouth.

[0012] In WO2018 / 233795A1, release modifiers such as magnesium stearate are required to slow the release of nicotine from compositions containing high levels of polyalcohol, whereas the proportions of microcrystalline cellulose and (lower levels of) polyalcohol used herein allow for controlled nicotine release without the need for specific release modifiers such as magnesium stearate.

[0013] In contrast, the proportions of microcrystalline cellulose and much lower levels of polyalcohol used herein allow for controlled nicotine release without the need for specific release modifiers such as magnesium stearate.

[0014] In one embodiment, the present invention relates to a product in which the nicotine source is obtained by extraction from tobacco or by chemical synthesis. The nicotine source according to the present invention can be stabilized in the form of a nicotine salt or bound to an ion exchange resin.

[0015] In one embodiment of the present invention, the ion exchange resin may be a weak cation exchange resin, such as polacrilex.

[0016] In one embodiment of the invention, the nicotine source can be nicotine polacrilex.

[0017] In another embodiment of the present invention, the nicotine source may be nicotine benzoate or nicotine maleate.

[0018] In a further embodiment, the present invention relates to a product in which at least one pH adjuster is a buffer comprising carbonate, bicarbonate, borate, glycinate, ammonium, phosphate, hydroxide, Tris, or mixtures thereof. The pH adjuster of the present invention can be a buffer comprising sodium carbonate, sodium bicarbonate, potassium carbonate, or mixtures thereof.

[0019] In yet another embodiment, the present invention relates to a product in which the at least one bulking agent comprises a polyalcohol, a sweetener, a polysaccharide, a cellulose, a microcrystalline cellulose, a natural fiber, a flavor, or a mixture thereof. In one embodiment of the present invention, the at least one bulking agent may comprise a microcrystalline cellulose, such as Avicel PH-200.

[0020] In another embodiment, the at least one bulking agent may comprise a mixture of microcrystalline cellulose 90M (102) and the polysaccharide sodium alginate.

[0021] The sweetener of the present invention may be selected from the group consisting of mannitol, xylitol, maltitol, sucralose, acesulfame potassium, aspartame, steviol glycosides, or mixtures thereof.Furthermore, the flavor of the present invention may be selected from the group consisting of menthol, cinnamon, mint, peppermint, spearmint, apple, cherry, melon, mango, peach, passion fruit, orange, blood orange, grapefruit, mandarin, tangerine, licorice, ginger, vanilla, wintergreen, lemon, lime, strawberry, raspberry, salmonberry, lingonberry, cranberry, blueberry, muscadine berry, sea buckthorn, chocolate, coffee, mocha, or mixtures thereof.

[0022] In some embodiments, the pouch material may further comprise an additional moisture component in the form of water, propylene glycol, glycerin, or mixtures thereof. In this invention, all reported weight percentages of powder components are based on total weight (including additional moisture component, if any).

[0023] In one embodiment, the present invention relates to a product in which the weight percentages of the powder composition are 0.5-2% by weight of a nicotine source, calculated as nicotine base, 4-15% by weight of a pH adjuster and 70-85% by weight of at least one bulking agent. The product of the present invention may comprise microcrystalline cellulose in an amount of 40-80% by weight, preferably 43-75% by weight. Furthermore, the product of the present invention may comprise nicotine in an amount ranging from 0.5-2% by weight, calculated as nicotine base. Furthermore, the product of the present invention may comprise at least one pH adjuster in an amount ranging from 4-15% by weight, preferably 5-13% by weight, more preferably 5-11% by weight. The product of the present invention may comprise at least one polyalcohol in an amount ranging from 5-50% by weight, preferably 6-45% by weight, more preferably 8-40% by weight. The weight percentage of the nicotine source relative to the amount of pH adjuster and bulking agent (especially microcrystalline cellulose) is very important to achieve optimal nicotine release from the pouch.

[0024] In another embodiment, the present invention relates to a product in which the weight percentages of the powder composition are 0.15-2% by weight of a nicotine source, calculated as nicotine base, 2-15% by weight of a pH adjuster and 40-85% by weight of at least one bulking agent. The product of the present invention may comprise microcrystalline cellulose in an amount of 40-80% by weight, preferably 30-70% by weight. Furthermore, the product of the present invention may comprise nicotine in an amount ranging from 0.15-2% by weight, calculated as nicotine base. Furthermore, the product of the present invention may comprise at least one pH adjuster in an amount of 1-15% by weight, preferably 2-11% by weight. The product of the present invention may optionally comprise at least one polyalcohol in an amount of 0-50% by weight, preferably 0-40% by weight, a humectant such as propylene glycol and / or glycerin in an amount of 0-15% by weight, and water in an amount of 0-35%.

[0025] In one preferred embodiment, the present invention relates to a product in which at least one bulking agent comprises microcrystalline cellulose, such as Avicel PH-200 or Hicel 90M (102).

[0026] In a preferred embodiment, the present invention relates to a product in which the weight proportions of the powder composition are 0.15 to 2% by weight of a nicotine source, calculated as nicotine base, 2 to 15% by weight of a pH adjuster and 40 to 85% by weight of at least one bulking agent.

[0027] In a preferred embodiment, the present invention relates to a product comprising microcrystalline cellulose in an amount of 30-80% by weight.

[0028] In a preferred embodiment, the present invention relates to a product in which the pouch has a nicotine release rate of 50-100% after 30 minutes.

[0029] Additionally, the present invention also relates to a product in which the pouch is made of a nonwoven material. In another embodiment, the pouch is made of a biodegradable material. In a preferred embodiment, the pouch is made of a home compostable material.

[0030] Another aspect of the invention is a process for preparing a product according to the invention, comprising the steps of: a) providing the nicotine source, the at least one pH adjusting agent and the at least one bulking agent in powder form; b) mixing the powders provided in step a); c) optionally sieving the powder mixture of step b) into a powder composition; and d) Optionally, filling the powder composition into a pouch. The present invention relates to a method comprising the steps of:

[0031] Another aspect of the invention is a process for preparing a product according to the invention, comprising the steps of: a) providing the nicotine source, the at least one pH adjusting agent and the at least one bulking agent in powder form; b) mixing the powders provided in step a); c) optionally sieving the powder mixture of step b) into a powder composition; and d) Optionally, filling the powder composition into a pouch. e) optionally adding a moisture component to step b) in the form of water, propylene glycol, glycerin, or mixtures thereof. The present invention relates to a method comprising the steps of:

[0032] In a further aspect, the present invention relates to the use of a product according to the invention for the oral delivery of nicotine.

[0033] In the figure below, nicotine release from a product according to the disclosed invention as well as a reference product is shown. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 shows the nicotine release profiles for pouch products according to the invention: Example 1 (Batch A, closed squares); Reference 1A (2 mg nicotine, left triangle) and Reference 1B (4 mg nicotine, right triangle); Reference 2A (3 mg nicotine, up triangle) and Reference 2B (6 mg nicotine, down triangle). [Diagram 2] FIG. 2 shows nicotine release data for a pouch product according to the invention (Example 1) (Batch B, filled circles with error bars) and stability data: 1 month, T=21-22° C., 60-62% RH (open circles with corresponding error bars). [Diagram 3] Figure 3 shows nicotine release data for analyzed pouch products (Example 1) from different batches (A, B and C) according to the invention. Pouch products with different concentration ranges for buffer (Example 2, black star with error bar), nicotine polacrilex (Example 3, black cross with error bar) and bulking agent (Example 4, black five-pointed star with error bar) are analyzed and compared for nicotine release at 30 minutes. Figure 3 shows nicotine release data for analyzed pouch products with different bulking agents and humectants (Example 5, open circle with error bar) are analyzed and compared for nicotine release at 30 minutes. [Figure 4A-C]4A-C show results from a degradation study of the pouches of the present invention. Chromatograms from HPLC-UV analysis of pouch samples stored at 21-22 °C / 60-62% RH for up to 3 months (Figure 4A), a sample with the same excipients but no nicotine API (Figure 4B), and a sample with nicotine polacrilex 20% API (Figure 4C). [Figure 5A-B] 5A-B show results from a degradation study of a pouch of the invention. A chromatogram from an HPLC-UV analysis of a prestressed nicotine sample (FIG. 5A) was compared to a chromatogram of an API-free reference sample spiked with nicotine bitartrate dihydrate (FIG. 5B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description of the Invention Although individual features may be included in different embodiments, they may possibly be combined in other ways, and 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 exclude a plurality.

[0036] The design of nicotine delivery pouches requires the simultaneous optimization of several properties, especially nicotine stability and release, and taste masking. Surprisingly, it has been found that the nicotine polacrilex-based pouches according to the present invention are stable and can release nicotine as fast as typical salt-based pouches such as nicotine tartrate. Polacrilex is an insoluble, weakly acidic cation exchange resin. The matrix contains methacrylic acid that can exchange hydrogen with nicotine cations (e.g., Amberlite IRP64® or Doshion P-551®).

[0037] A pouch according to the present invention comprises a powder mixture of a nicotine source, at least one pH controlling agent and at least one bulking agent, such as microcrystalline cellulose, as well as sweeteners and flavors.

[0038] In a preferred embodiment according to the present invention, the buffer powder is mixed directly with the other powdered components of the pouch to facilitate rapid pH adjustment upon contact with saliva.

[0039] Nicotine can be obtained by extraction from tobacco or by chemical synthesis. Compared to synthetic nicotine, the extracted material contains small amounts of non-nicotine alkaloids from tobacco. These impurities can be toxic and can make the product difficult to taste. Although both sources of nicotine are acceptable embodiments of the invention, the synthetic material offers additional advantages in terms of taste setting. Thus, in a preferred embodiment, the nicotine is obtained from chemical synthesis. In an advantageous embodiment of the invention, the purity of the nicotine is in the range of 99.00-99.99%, preferably in the range of 99.60-99.99%.

[0040] According to one embodiment, the nicotine can be in the form of nicotine polacrilex or a nicotine salt such as the benzoate or maleate salt. In another embodiment, nicotine polacrilex is preferred due to its favorable combination of nicotine stability and rapid release affected by direct mixing with a pH control agent.

[0041] Furthermore, the pH control agent according to the present invention may be a carbonate buffer, such as sodium carbonate, sodium bicarbonate, potassium carbonate, or a mixture thereof. In other preferred embodiments, the buffer may be a borate, such as sodium tetraborate; a phosphate, such as monohydrogen phosphate, dihydrogen phosphate, or trihydrogen phosphate; or tris(hydroxymethyl)aminomethane (Tris). A preferred buffer according to the present invention is a mixture of sodium carbonate and sodium bicarbonate.

[0042] In addition to a nicotine source and a pH controlling agent, the pouches of the present invention also include at least one bulking agent.

[0043] Bulking agents according to the present invention may include polyalcohols, sweeteners, polysaccharides, cellulose, microcrystalline cellulose, natural fibers, and flavors. Polyalcohols, or sugar alcohols, are a class of polyols that are typically obtained by hydrogenation of sugars. Furthermore, polyalcohols have a lower calorie content than sugars and are generally less sweet. Polysaccharides are polymeric carbohydrate molecules composed of long chains of monosaccharide units linked by glycosidic bonds that, upon hydrolysis, produce the constituent monosaccharides or oligosaccharides. Their structures range from linear to highly branched. Examples include storage polysaccharides such as starch and glycogen and structural polysaccharides such as cellulose, chitin, and alginates. Cellulose is a common natural polymer and is the largest component of plant cell walls. Cellulose is typically composed of polymer chains 10,000-15,000 molecules long. Microcrystalline cellulose (MCC) is synthetic and composed of chains 100-300 molecules long. By natural fibers is meant fibers produced by plants, animals, or geological processes.

[0044] At least one bulking agent of the present invention may be microcrystalline cellulose, such as Avicel PH-200, which may have a solubility of less than 5 g / 100 ml. A bulking agent with poor water solubility limits the water solubility of the powder composition in the pouch and therefore may not completely dissolve the pouch contents when contacted with water provided in the form of saliva. Thus, the use of a bulking agent with poor water solubility, such as Avicel PH-200, allows for a relatively slow release and direct absorption of nicotine through the mucous membrane in the mouth. In a preferred embodiment, the water solubility of microcrystalline cellulose is less than 2.5 g / 100 ml, more preferably less than 1.0 g / 100 ml, even more preferably less than 0.75 g / 100 ml, and most preferably less than 0.58 g / 100 ml, measured in H2O at 25°C and pH 7. This contributes greatly to the advantageous nicotine release profile of the pouch according to the present invention.

[0045] The at least one bulking agent 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 bulking agent may comprise a mixture of microcrystalline cellulose 90M (102) and polysaccharide sodium alginate. The aqueous solubility of both embodiments of the present invention may be less than 5 g / 100 ml. A bulking agent with poor aqueous solubility limits the aqueous solubility of the powder composition in the pouch and therefore may not completely dissolve the pouch contents when contacted with water provided in the form of saliva. Thus, the use of a bulking agent with poor aqueous solubility, such as Avicel PH-200 or Hicel 90M (102), allows for a relatively slow release and direct absorption of nicotine through the mucous membrane in the mouth. In a preferred embodiment, the aqueous solubility of microcrystalline cellulose is less than 2.5 g / 100 ml, more preferably less than 1.0 g / 100 ml, measured in H2O at 25°C. This contributes significantly to the advantageous nicotine release profile of the pouches according to the invention.

[0046] Sweeteners according to the present invention may comprise mannitol, xylitol, maltitol, sucralose, acesulfame potassium, aspartame, steviol glycosides, or mixtures thereof.Flavors according to the present invention may comprise menthol, cinnamon, mint, peppermint, spearmint, apple, cherry, melon, mango, peach, passion fruit, orange, blood orange, grapefruit, mandarin, tangerine, licorice, ginger, vanilla, wintergreen, lemon, lime, strawberry, raspberry, salmonberry, lingonberry, cranberry, blueberry, muscadine berry, sea buckthorn, chocolate, coffee, mocha, or mixtures thereof.

[0047] In advantageous embodiments of the present invention, the unique balance of microcrystalline cellulose and polyalcohol levels contributes to a favorable release profile of nicotine from the matrix. EXAMPLES

[0048] The formulations of the present invention are exemplary and should be considered as inspiration for obtaining similar results within the scope of the present invention. Supplier specifications for the various components used in this application are disclosed in Table 1.

[0049] Supplier specifications for the various components used in this application are disclosed in Table 1B.

[0050] [Table 1]

[0051] [Table 2]

[0052] Manufacturing of products A product having a composition according to the invention is manufactured as follows: all ingredients (which are in powder form) are mixed and sieved into a final powder mixture. The resulting powder is filled into pouches made of nonwoven materials or fabrics. Nonwoven materials, fabrics or textiles can be defined as sheet or web structures bonded together by entangling fibers or filaments and by mechanically, thermally or chemically perforating films. They are flat porous sheets made from separate fibers or directly from molten plastic or plastic films. They are not made by weaving or knitting and do not require the conversion of fibers into yarns. The entire manufacturing process is carried out at ambient conditions, with temperature and relative humidity (RH) ranging from 21-25°C and 30-60% RH, respectively.

[0053] Solubility in water The water used for the solubility measurements is distilled or filtered through a Millipore Milli-Q system. An unused pouch of weight P0 (g) is placed in a test tube containing 20 ml of water and placed on a shaker at room temperature for 1 hour. The pouch is separated and air-dried at room temperature to a constant weight Pe (g). Three replicates are used for each batch in the solubility measurements. The water solubility of the pouch composition is then (P0-Pe) (g) per 20 ml of water.

[0054] In-Vitro Release Experiment The experimental method for measuring nicotine release from the pouches was carried out using UV spectrophotometry. The pouch sample preparation and analysis methods were adapted and modified from published methods for pouch analysis (see U.S. Patent No. 9,402,810).

[0055] Briefly, a pouch sample is placed in the center of a filter paper pre-soaked in 20 ml of aqueous phase contained in a Petri dish. The entire setup is covered with a lid to maintain humidity levels and prevent water evaporation. As the pouch starts to absorb water, the nicotine polacrilex dissolves in the liquid and the released nicotine diffuses into the external aqueous phase.

[0056] This is done at specific incubation times, i.e. 10, 20 and 30 minutes (note new pouches each time). Each experiment uses 3 replicates from each batch of Example 1. After each time point analyzed, the pouch samples are placed in test tubes with 15 ml water and placed on a shaker for 1.5-2 hours.

[0057] Additionally, multiple unused pouches from the same batch were also placed in a test tube containing 15 ml of purified water and placed on a shaker for 1.5 to 2 hours for analysis of total nicotine content.

[0058] The nicotine-containing aqueous phase is then analyzed for the remaining amount of nicotine using a UV spectrophotometer (Shimadzu, UV1800). First, each sample of the aqueous phase from the test tube is filtered using a 0.45 μm filter unit. The filtered solution is then diluted to a suitable concentration and the absorbance of the sample is measured. The measurement is performed in photometric mode using a fixed wavelength of 260 nm.

[0059] The nicotine concentrations for the analyzed samples (unused and used pouches) are calculated from the calibration curve to determine the total and residual amounts of nicotine. The release of nicotine at a particular time is calculated by subtracting the "residual amount of nicotine" from the "total amount of nicotine" and dividing it by the "total amount of nicotine". Table 2 shows the four different exemplary compositions according to the invention (Examples 1-4) that were analyzed. Table 3 summarizes the data obtained for the nicotine release of the four exemplary compositions according to the invention and the reference pouch sample. The data obtained are plotted and shown in Figures 1-3.

[0060] Table 2B shows five different exemplary compositions according to the invention (Examples 1-5) that were analyzed. Table 3B summarizes the data obtained for the nicotine release of the five exemplary compositions according to the invention and the reference pouch sample. The data obtained are plotted and shown in Figures 1-3.

[0061] [Table 3]

[0062] [Table 4]

[0063] [Table 5]

[0064] [Table 6]

[0065] 1) Pouch analysis: Comparison with a commercially available reference pouch.

[0066] 1 shows that the pouch product of the present invention (Example 1) (black squares with error bars) provides a similar nicotine release at 10 minutes and a greater nicotine release at 20 minutes and 30 minutes compared to the nicotine release of Reference 1 pouch product (right and left triangles) containing nicotine polacrilex. Additionally, all examples of pouch products according to the present invention show a similar nicotine release at 20 minutes and 30 minutes compared to Reference 2 pouch product containing nicotine salt (upper and lower triangles).

[0067] The nicotine polacrilex-based pouches of the present invention can release nicotine as fast as typical salt-based pouches such as nicotine tartrate. Furthermore, the nicotine polacrilex-based pouches of the present invention can release a larger amount of nicotine compared to other nicotine polacrilex-based pouch products.

[0068] 2) Stability study: Nicotine release at 30 minutes ·Decomposition products Pouch samples from Example 1 were stored in closed (not sealed) plastic containers at 21-22°C / 60-62% RH for up to 3 months. Pouch products stored for 1 month at 21-22°C / 60-62% RH were analyzed for nicotine release at 30 minutes using the UV spectrophotometric method described above.

[0069] FIG. 2 shows the results obtained, with no change in nicotine release observed for pouch product samples (Example 1) stored at 21-22° C. / 60-62% RH for 1 month (filled circles).

[0070] The pouch samples of Example 1 were also analyzed for detection of potential degradation products using the HPLC-UV method (Agilent 1200 series HPLC). A sample with the same excipients but without nicotine API and a sample with nicotine API were used to identify the reference (blank) peak. A prestressed nicotine sample was prepared (using high temperature and light) to reveal peaks due to heat and light induced nicotine degradation. Figures 4A-C show chromatograms from HPLC-UV analysis of a pouch sample of the present invention (Figure 4A), a pouch sample with the same excipients but without nicotine API (Figure 4B) and a sample of Nicotine polacrilex 20% API (Figure 4C) stored at 21-22°C / 60-62% RH for up to 3 months. The resulting chromatograms do not show peaks of potential degradation products in the analyzed samples. The resulting peaks in the chromatograms correspond to peaks of nicotine or solvent injection. The chromatogram from the HPLC-UV analysis of the prestressed nicotine sample (Figure 5A) was compared to the chromatogram of a reference sample containing no API and spiked with nicotine bitartrate dihydrate (Figure 5B). No additional peaks due to potential degradation products were observed in the chromatogram of the prestressed sample (Figure 5A).

[0071] The nicotine polacrilex-based pouches according to the present invention are stable and release the same amount of nicotine after one month of storage as freshly prepared nicotine polacrilex-based pouches according to the present invention.The nicotine polacrilex-based pouches according to the present invention are stable and do not show potential degradation products in analyzed pouch samples of Example 1 stored at 21-22°C / 60-62% RH for up to three months.

[0072] 3) Concentration range of ingredients: Buffer (half) Nicotine polacrilex (2x) · Bulking agent (1 / 4 polyalcohol) · Bulking agents (no polyalcohols added, polysaccharides and / or humectants added) FIG. 3 shows that reducing the buffer content by a factor of two in the current pouch formulation recipe results in similar nicotine release at 30 minutes (black star with error bars, Example 2).

[0073] When the nicotine content is doubled in the current pouch formulation recipe (Table 2, Example 3), the nicotine release at 30 minutes is less compared to the nicotine release at 30 minutes for Examples 1, 2 and 4 (Table 2). However, a similar trend could be observed for the reference pouch products with higher nicotine amounts analyzed (Figure 1, filled triangles). For example, the analysis of the Reference 1B pouch containing 4 mg of NPR (Figure 1, right triangles) shows less nicotine release at 30 minutes compared to the Reference 1A pouch containing 2 mg of NPR (Figure 1, left triangles). A similar scenario is observed for the Reference 2 pouch product: the pouch containing 6 mg of nicotine salt (Figure 1, downward triangles) shows less nicotine release at 30 minutes than the pouch containing 3 mg of nicotine salt (Figure 1, upward triangles).

[0074] FIG. 3 shows that reducing the polyalcohol content by a factor of four in the current formulation recipe resulted in slightly less nicotine release at 30 minutes (solid five-pointed star with error bars, Example 4).

[0075] FIG. 3 shows that reducing the polyalcohol content to zero and adding a polysaccharide and a humectant such as sodium alginate results in similar nicotine release (open circles with error bars, Example 5).

[0076] Figure 3 also shows the batch-to-batch variability according to the present invention (Example 1). There is a relatively high batch-to-batch variability of nicotine at the 10 minute time point (filled circles, squares and diamonds with error bars).

[0077] The nicotine polacrilex-based pouch according to the present invention with reduced amounts of buffer (Example 3) has the same nicotine release at 30 minutes as the nicotine polacrilex-based pouch according to the present invention (Example 1). The nicotine polacrilex-based pouch according to the present invention with reduced amounts of buffer (Example 3) appears to have a similar nicotine release at 30 minutes as the reference pouch based on a nicotine salt, such as nicotine tartrate. The nicotine polacrilex-based pouch according to the present invention with reduced amounts of polyalcohol (Example 4) has a slightly lower nicotine release at 30 minutes as the nicotine polacrilex-based pouch according to the present invention (Example 1). The nicotine polacrilex-based pouch according to the present invention with reduced amounts of polyalcohol (Example 4) has a higher nicotine release as the reference pouch based on nicotine polacrilex.

[0078] The pH of the nicotine-containing aqueous phase from the test tubes for the pouch samples of Example 1 examined was also measured. The resulting pH values ​​are summarized in Table 4.

[0079] Table 4 shows that the pH of the nicotine polacrilex-based pouches according to the present invention is greater than pH 8.

[0080] The pH of the nicotine-containing aqueous phase from the test tubes was also measured for the pouch samples examined from Example 1 and Example 5. The resulting pH values ​​are summarized in Table 4B.

[0081] Table 4B shows that the pH of the nicotine polacrilex-based pouches according to the present invention is greater than pH8.

[0082] [Table 7]

[0083] [Table 8]

Claims

1. A pouch comprising a product for oral delivery of nicotine, comprising: The nicotine oral delivery product comprises a powder composition, The powder composition comprises: Nicotine source; at least one pH adjuster; and At least one bulking agent said pouch being permeable to saliva and to components of a powder composition dissolved in saliva, the weight proportions of said powder composition being 0.15-2% by weight of a nicotine source calculated as nicotine base, 2-15% by weight of a pH adjusting agent and 40-85% by weight of at least one bulking agent, and said product comprising microcrystalline cellulose in an amount of 30-70% by weight.

2. 10. The product of claim 1, wherein the nicotine source is stabilized in the form of a nicotine salt or bound to an ion exchange resin.

3. 3. The product of claim 2, wherein the ion exchange resin is a weak cation exchange resin.

4. A product according to claims 1 to 3, wherein the nicotine source is nicotine benzoate or nicotine maleate.

5. 5. The product of any one of claims 1 to 4, wherein the at least one pH adjusting agent is a buffer comprising carbonate, bicarbonate, borate, glycinate, ammonium, phosphate, hydroxide, Tris, or mixtures thereof.

6. The product of any one of claims 1 to 5, wherein the at least one bulking agent comprises a polyalcohol, a sweetener, a polysaccharide, a cellulose, a natural fiber, a flavor, or a mixture thereof.

7. The product described in any one of claims 1 to 6, wherein the microcrystalline cellulose is Avicel PH-200.

8. 7. The product of claim 6, wherein the sweetening agent is selected from the group consisting of mannitol, xylitol, maltitol, sucralose, acesulfame potassium, aspartame, steviol glycosides, or mixtures thereof.

9. 7. The product of claim 6, wherein the flavor is selected from the group consisting of menthol, cinnamon, mint, peppermint, spearmint, apple, cherry, melon, mango, peach, passion fruit, orange, blood orange, grapefruit, mandarin, tangerine, licorice, ginger, vanilla, wintergreen, lemon, lime, strawberry, raspberry, salmonberry, lingonberry, cranberry, blueberry, muscadine berry, seaweed, chocolate, coffee, mocha, or mixtures thereof.

10. 10. The product according to any one of claims 1 to 9, wherein the weight proportions of the powder composition are 0.5 to 2% by weight of a nicotine source, calculated as nicotine base, 4 to 15% by weight of a pH adjusting agent and 70 to 85% by weight of at least one bulking agent.

11. A product according to any one of claims 1 to 10, wherein the pouch has a nicotine release rate of 50-100% after 30 minutes.

12. The product of any one of claims 1 to 11, wherein the pouch is made from a nonwoven material.

13. A method for preparing a product according to any one of claims 1 to 12, comprising the steps of: a) providing said nicotine source, said at least one pH adjusting agent and said at least one bulking agent in powder form; b) mixing the powders provided in step a); c) sieving the powder mixture of step b) into a powder composition; and d) Filling the powder composition into a pouch. The method comprising:

14. Use of a product according to any one of claims 1 to 12 for the oral delivery of nicotine.

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