A nicotine source

Abstract

The present invention relates to a nicotine source comprising: a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material; wherein the molar ratio of organic acid to nicotine is from 0.6 or more.

Description

[0001] A NICOTINE SOURCE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a nicotine source, a process of production thereof, a composition comprising the nicotine source, and a nicotine oral delivery product containing said composition.

[0004] BACKGROUND

[0005] Nicotine oral delivery products are known as replacements for smoking articles such as cigarettes. These nicotine oral delivery products provide an alternative, reduced risk, means of administering nicotine to a user.

[0006] Nicotine oral delivery products may comprise a composition enclosed within a pouch. They are typically placed between the upper or lower gum and lip or cheek of a user and are retained in this position for a period of time during which saliva passes into the interior of the pouch and dissolved components including nicotine- containing components diffuse therefrom into a user’s mouth.

[0007] Existing nicotine sources for nicotine oral delivery products may comprise a liquid substance containing nicotine, or a solid support material on which nicotine is carried, for example, an ion exchange resin. To facilitate nicotine release, the nicotine sources must be used in combination with various additional additives, for example, bases such as sodium bicarbonate. The use of sodium bicarbonate can result in an unpleasant taste for the user, as well as potentially affect their blood pressure due to a high intake of sodium salt.

[0008] For existing nicotine sources comprising solid support material on which nicotine is carried, the nicotine is typically unstable with respect to oxidative degradation. To counter this effect, it is therefore necessary to include a large amount of the nicotine source in nicotine oral delivery products. Additionally, stabilisers such as glycerol, carbon dioxide and ethanol, are required to improve the nicotine stability of the nicotine oral delivery products. Such stabilisers typically result in an unpleasant taste for the user. Problems also exist with known nicotine sources for nicotine oral delivery products due to the difficulty in controlling nicotine release rate. Ingesting a large quantity of nicotine in a short period of time can affect a user's physical condition. On the other hand, a nicotine release rate that is too slow is not satisfactory for a user.

[0009] There is therefore a desire to provide a nicotine source for use in nicotine oral delivery products that has high nicotine stability and is capable of effectively delivering nicotine to a user with controlled release of nicotine over a longer period of time.

[0010] SUMMARY OF THE INVENTION

[0011] According to an aspect of the present invention, there is provided a nicotine source comprising: a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material; wherein the molar ratio of organic acid to nicotine is from 0.6 or more.

[0012] According to another aspect of the present invention, there is provided a composition comprising a nicotine source, the nicotine source comprising: a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material; wherein the molar ratio of organic acid to nicotine is from 0.6 or more.

[0013] According to a further aspect of the present invention, there is provided a nicotine oral delivery product containing a composition enclosed in a water insoluble pouch, wherein said pouch is permeable for saliva and dissolved components of the composition, and the composition comprises a nicotine source, the nicotine source comprising: a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material; wherein the molar ratio of organic acid to nicotine is from 0.6 or more.

[0014] According to a further aspect of the present invention, there is provided a process for the production of a nicotine source comprising a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material, the process comprising: (a) combining nicotine and an organic acid with water and / or an organic solvent;

[0015] (b) combining the product of step (a) with an inorganic carrier material; and

[0016] (c) removing the water and / or organic solvent to form the nicotine source, wherein the molar ratio of organic acid to nicotine in step (a) is 0.6 or more.

[0017] According to a further aspect of the present invention, there is provided a nicotine source comprising a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material, wherein the nicotine source is obtainable by a process comprising:

[0018] (a) combining nicotine and an organic acid with water and / or an organic solvent;

[0019] (b) combining the product of step (a) with an inorganic carrier material; and

[0020] (c) removing the water and / or organic solvent to form the nicotine source, wherein the molar ratio of organic acid to nicotine in step (a) is 0.6 or more.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 compares the elution rate (release rate) of nicotine sources according to the present invention to the elution rate of two comparative nicotine sources outside of the scope of the present invention.

[0023] FIG. 2 compares the % supported nicotine of a nicotine source according to the present invention to the % supported nicotine of a comparative nicotine source outside of the scope of the present invention.

[0024] FIG. 3, 4a & 4b compare the elution rate (release rate) of nicotine sources according to the present invention to the elution rate of two comparative nicotine sources outside of the scope of the present invention. FIG. 5 compares the elution rate (release rate) of a composition of the present invention to the elution rate (release rate) of a comparative composition outside of the scope of the present invention.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] It has been surprisingly and advantageously found that the nicotine source of the present invention demonstrates high nicotine stability, and effectively delivers nicotine to a user with controlled release of nicotine over an extended period of time. The nicotine source of the present invention also has a pleasant taste and mouth-feel, and the use of disagreeable additive salts, such as sodium bicarbonate, can be avoided.

[0027] As used herein, a’ nicotine-organic acid salt’ refers to a nicotine salt formed from the nicotine and organic acid described herein. As used herein, ‘free-base nicotine’ refers to unprotonated nicotine (C10H14N2). Protonated nicotine’ refers to mono-protonated or di-protonated nicotine (protonated at the nicotine pyridine nitrogen and / or nicotine pyrrolidine nitrogen). The term ‘electrically neutral form’ as used herein with reference to the organic acid is meant the form of the organic acid having no net electrical charge (not deprotonated).

[0028] It has been surprisingly and advantageously found that the advantageous effects realised by the nicotine source of the present invention result from the molar ratio of organic acid to nicotine in the nicotine source being of 0.6 or more. The effective delivery of nicotine to a user with controlled release of nicotine over an extended period of time can thus be achieved. Such a molar ratio improves the immobility of nicotine (whether in the form of nicotine-organic acid salt or nicotine) on the inorganic carrier material, as discussed in more detail below. A nicotine source having increased nicotine stability is therefore provided. The nicotine source of the present invention enables nicotine to be released to the user over a longer period of time than existing nicotine sources. Furthermore, no additives such as sodium carbonate or sodium bicarbonate are required to facilitate and / or modify the release of the nicotine, removing the negative effects that such components may have on users. Preferably, for the nicotine source of the present invention, the molar ratio of organic acid to nicotine is from 0.6 to 3.5, or from 0.6 to 3.0, such as from 0.6 to 2.5, such as from 0.6 to 2.0, or from 0.6 to 1.5. Preferably, the molar ratio of organic acid to nicotine is from 0.6 to 0.9, such as from 0.6 to 0.8. More preferably, the molar ratio of organic acid to nicotine is from 0.6 to 0.7. Such molar ratios advantageously increase the effective delivery of nicotine to a user with controlled release of nicotine over an extended period of time. Such molar ratios improve the immobility of nicotine (whether in the form of nicotine-organic acid salt or nicotine) on the inorganic carrier material, as discussed in more detail below. A nicotine source having increased nicotine stability is therefore provided.

[0029] Preferably, for the nicotine source of the present invention, the molar ratio of organic acid to nicotine is from 0.60 to 1.10, such as from 0.61 to 1.00, such as from 0.62 to 0.90, such as from 0.62 to 0.80, or from 0.65 to 0.70. Such molar ratios advantageously increase the effective delivery of nicotine to a user with controlled release of nicotine over an extended period of time. Such molar ratios improve the immobility of nicotine (whether in the form of nicotine-organic acid salt or nicotine) on the inorganic carrier material, as discussed in more detail below. A nicotine source having increased nicotine stability is therefore provided.

[0030] By ‘molar ratio’ as defined herein in relation to the nicotine source of the present invention is meant the ratio of the moles of organic acid to moles of nicotine in the nicotine source. This can be defined by: moles of organic acid moles of nicotine

[0031] The moles of organic acid includes all organic acid present in the nicotine source whether in the form of nicotine-organic acid salt or organic acid, and whether carried on the inorganic carrier material or otherwise, as described herein. The moles of nicotine includes all nicotine present in the nicotine source whether in the form of nicotine-organic acid salt or nicotine, and whether carried on the inorganic carrier material otherwise, as described herein. The molar ratio of organic acid to nicotine of the nicotine source is the same as the ratio of the moles of organic acid to the moles of nicotine reacted together in the production of the nicotine source. When calculating the moles of the organic acid and moles of nicotine (moles = mass (g) / molar mass (g / mol)), the molar mass (g / mol) of the organic acid (electrically neutral form, e.g. 192.12 g / mol for citric acid) and free- base nicotine (C10H14N2, 162.24 g / mol) is respectively used, irrespective of the form in which the components are present in the nicotine source.

[0032] For the nicotine source of the present invention, as described herein, the nicotine source may be formed from nicotine, organic acid, and inorganic carrier material. As noted herein, in the formation of the nicotine source, nicotine and organic acid are used in a molar ratio of organic acid to nicotine of from 0.6 or more. The resulting nicotine source thus comprises organic acid and nicotine in a molar ratio of organic acid to nicotine of from 0.6 or more. It will be appreciated that, as described herein, in the resulting nicotine source, this nicotine and organic acid may be present in the resulting nicotine source as nicotine-organic acid salt and / or nicotine, and nicotine-organic acid salt and / or organic acid, respectively. This nicotine and organic acid may be carried on the inorganic carrier material in the resulting nicotine source as nicotine-organic acid salt, and optionally nicotine and / or organic acid.

[0033] It has further been surprisingly and advantageously found that for the nicotine source of the present invention, when the molar ratio of organic acid to nicotine is 0.6 or more, the % supported nicotine is 90% or more. Preferably, 95% or more.

[0034] By ‘% supported nicotine’ is meant the amount of nicotine carried on the inorganic carrier material of the nicotine source of the present invention (whether in the form of nicotine-organic acid salt or nicotine). The higher the value of the % supported nicotine, the more advantageous. If the % supported nicotine is high, a lower amount of nicotine source is required for the composition of the present invention to achieve the same results. This leads to a lower production costs. The % supported nicotine may be calculated using the following formula: where (A) is the amount of nicotine used in step (a) in the production of the nicotine source according to the present invention, and (B) is the amount of nicotine (whether in the form of nicotine or nicotine-organic acid salt) not carried on the inorganic carrier material, measured using LC-DAD (liquid chromatography with diode array detection) (1260 Infinity n LC / MSD from Agilent).

[0035] It has further been surprisingly and advantageously found that the nicotine source of the present invention has high nicotine stability. By this, is meant that the nicotine of the nicotine source of the present invention (whether in the form of nicotine-organic acid salt or nicotine) has a lower risk of decomposition, for example by oxidation of the nicotine (nicotine reduction). In particular, the nicotine source of the present invention has high nicotine stability upon exposure to heat, i.e. high heat stability.

[0036] In particular, the present inventors have demonstrated that the nicotine source of the present invention has increased nicotine stability with respect to existing nicotine sources, in particular upon exposure to heat. Without being bound by theory, the present inventors consider this may be related to the interaction of the nicotine, organic acid and inorganic carrier material within the nicotine source. Without being bound by theory, the present inventors consider that nicotine interacts with both the organic acid and the inorganic carrier material. The nicotine of the nicotine source (whether in the form of nicotine-organic acid salt or nicotine) therefore has increased immobility on the inorganic carrier material, and the nicotine source of the present invention is stable with respect to nicotine decomposition over an extended period of time.

[0037] For the nicotine source of the present invention, nicotine-organic acid salt, and optionally nicotine, is carried on the inorganic carrier material. The nicotine on the inorganic carrier material may be in the form of free-base nicotine and / or protonated nicotine. For the nicotine source of the present invention, nicotine is therefore carried on the inorganic carrier material as a constituent of the nicotineorganic acid salt, and optionally carried on the inorganic carrier material in the form of free-base nicotine, and / or protonated nicotine. In a nicotine-organic acid salt, the nicotine may be protonated at (at least) the pyrrolidine nitrogen in the nicotine-organic acid salt. In a nicotine-organic acid salt, the nicotine may be present as its conjugate acid.

[0038] Without being bound by theory, the inventors consider that the nicotine-organic acid salt, and optional nicotine, may interact with the inorganic carrier material via the nicotine pyridine nitrogen and / or nicotine pyrrolidine nitrogen of the nicotine constituent of the nicotine-organic acid salt or the nicotine pyridine nitrogen and / or nicotine pyrrolidine nitrogen of the nicotine. The nicotine-organic acid salt, and optional nicotine, may be protonated at the pyridine nitrogen and / or pyrrolidine nitrogen of the nicotine constituent of the nicotine-organic acid salt or the pyridine nitrogen and / or pyrrolidine nitrogen of the nicotine.

[0039] The nicotine-organic acid salt, and optional nicotine, carried on the inorganic carrier may be adsorbed (chemisorption and / or physisorption) on the inorganic carrier material. The nicotine-organic acid salt, and optional nicotine, carried on the inorganic carrier may be carried on the inorganic carrier material by hydrogenbonding.

[0040] The nicotine source of the present invention may further comprise nicotine-organic acid salt and / or nicotine other than the nicotine-organic acid salt, and optional nicotine, carried on the inorganic carrier material. As for the nicotine-organic acid salt, and optional nicotine, carried on the inorganic carrier material, this nicotineorganic acid salt and / or nicotine may be in the form of free-base nicotine, and / or protonated nicotine, and / or a constituent of the nicotine-organic acid salt.

[0041] For the nicotine source of the present invention, the nicotine (whether of the nicotine-organic acid salt or nicotine) may be derived from tobacco or may be synthetic nicotine. Tobacco includes any part, e.g. leaves, flowers or stems, of any member of the genus Nicotiana, and reconstituted material thereof. Preferably, the nicotine of the nicotine source of the present invention is (S)- nicotine.

[0042] The nicotine source according to the present invention does not comprise an ion exchange resin. For example, the nicotine source of the present invention does not comprise a cation exchange resin, such as nicotine polacrilex.

[0043] The nicotine source of the present invention may comprise nicotine in any suitable amount. This includes all nicotine in the nicotine source, whether in the form of nicotine-organic acid salt or nicotine, and whether carried on the inorganic carrier material or otherwise, as described herein. The nicotine source may comprise 1 to 40 wt.% nicotine, preferably 5 to 30 wt.% nicotine, and more preferably 10 to 25 wt.% nicotine. The nicotine source of the present invention may comprise 20 wt.% or less of nicotine, such as 18 wt.% or less, or 16 wt.% or less, of nicotine. Advantageously, this lower amount of nicotine suppresses localisation of the nicotine source within the composition. Additionally, this lower amount of nicotine enhances the degree of freedom in product design when manufacturing products with low nicotine content.

[0044] Organic acid may be present in the nicotine source of the present invention in the form of the nicotine-organic acid salt and / or organic acid. The organic acid may be present in the nicotine source of the present invention in the form of organic acid (electrically neutral form), and / or deprotonated organic acid, and / or as a constituent of the nicotine-organic acid salt. In a nicotine-organic acid salt, the organic acid may be deprotonated, for example at a carboxyl (-COOH) group. In a nicotine-organic acid salt, the organic acid may be present as its conjugate base.

[0045] For the nicotine source of the present invention, organic acid is carried on the inorganic carrier material in the form of the nicotine-organic acid salt. Organic acid may also be carried on the inorganic carrier material in the form of organic acid (electrically neutral form), and / or deprotonated organic acid. Accordingly, the organic acid is carried on the inorganic carrier material as a constituent of the nicotine-organic acid salt, and optionally may be carried on the inorganic carrier material in the form of organic acid (electrically neutral form), and / or deprotonated organic acid. The organic acid is carried on the inorganic carrier material in the form of nicotine-organic acid salt and optionally as organic acid.

[0046] Without being bound by theory, the inventors consider that the nicotine-organic acid salt carried on the inorganic carrier material (and optional organic acid carried on the inorganic carrier material) may interact with the inorganic carrier material via the organic acid constituent of the nicotine-organic acid salt or the organic acid, for example, via a carboxyl (-COOH) group of the organic acid constituent of the nicotine-organic acid salt or the organic acid. This may be through, for example, deprotonation of the carboxyl group (to -COO’).

[0047] Accordingly, without being bound by theory, the inventors consider that the nicotine-organic acid salt may interact with the inorganic carrier material via: (a) the nicotine pyridine nitrogen and / or nicotine pyrrolidine nitrogen of the nicotine constituent of the nicotine-organic acid salt; and / or (b) the organic acid constituent of the nicotine-organic acid salt, for example, via a carboxyl (-COOH) group of the organic acid constituent of the nicotine-organic acid salt.

[0048] The nicotine-organic acid salt, and optional organic acid, may be carried on the inorganic carrier material by adsorption (chemisorption and / or physisorption) on the inorganic carrier material. The nicotine-organic acid salt, and optional organic acid, may be carried on the inorganic carrier material by hydrogen-bonding.

[0049] The nicotine source of the present invention may further comprise organic acid not carried on the inorganic carrier material. This organic acid may be in form of free-base organic acid (electrically neutral form), and / or deprotonated organic acid, and / or as a constituent of a nicotine-organic acid salt.

[0050] For the nicotine source of the present invention, the organic acid may be a carboxylic acid. As used herein, a carboxylic acid refers to an organic acid comprising at least one carboxyl (-COOH) group. Preferably, the organic acid is a hydroxy carboxylic acid. By ‘hydroxy carboxylic acid’ is meant a carboxylic acid also containing a hydroxy (-OH) group. The hydroxy group may be positioned one (a-hydroxy), two (p-hydroxy), or three (y-hydroxy) atoms away from the carboxyl group. Preferably, the organic acid is an a-hydroxy carboxylic acid.

[0051] For the nicotine source of the present invention, the organic acid may be selected from gluconic acid, citric acid, malic acid, formic acid, acetic acid, propionic acid, butyric acid (butanoic acid), 2-methylbutyric acid, 3-methylbuthric acid, valeric acid, benzoic acid, phenylacetic acid and pyruvic acid. Preferably, the organic acid is selected from citric acid, malic acid, benzoic acid, and butyric acid. More preferably, the organic acid is selected from citric acid, malic acid, and butyric acid. The organic acid may be selected from citric acid and butyric acid. More preferably, the organic acid is selected from malic acid and citric acid, such as citric acid. Advantageously, citric acid has high solubility in water and organic solvents. This advantageously enables manufacture of the nicotine source with less water and / or organic solvent, which may generally cause degradation of nicotine. Citric acid also has no aroma or flavour itself, which is advantageous in the formation of the nicotine source, composition, and nicotine oral delivery products of the present invention.

[0052] Preferably, the organic acid of the nicotine source is anhydrous. If citric acid is selected, the citric acid is preferably anhydrous citric acid.

[0053] Accordingly, the nicotine-organic acid salt carried on the inorganic carrier material in the nicotine source of the present invention may be selected from nicotine gluconate, nicotine citrate, nicotine dicitrate, nicotine hemicitrate, nicotine malate, nicotine formate, nicotine acetate, nicotine propionate, nicotine butyrate, nicotine 2-methylbutyrate, nicotine 3-methylbutyrate, nicotine valerate, nicotine benzoate, nicotine phenylacetate, and nicotine pyruvate. Preferably, the nicotine-organic acid salt is selected from nicotine citrate, nicotine malate, nicotine benzoate, and nicotine butyrate, such as nicotine citrate and nicotine malate. More preferably, the nicotine-organic acid salt is nicotine citrate.

[0054] The nicotine source may comprise a nicotine-organic acid salt selected from nicotine gluconate, nicotine citrate, nicotine dicitrate, nicotine hemicitrate, nicotine malate, nicotine formate, nicotine acetate, nicotine propionate, nicotine butyrate, nicotine 2-methylbutyrate, nicotine 3-methylbutyrate, nicotine valerate, nicotine benzoate, nicotine phenylacetate, and nicotine pyruvate. Preferably, selected from nicotine citrate, nicotine malate, nicotine benzoate, and nicotine butyrate, such as nicotine citrate and nicotine malate. More preferably, nicotine citrate.

[0055] For the nicotine source of the present invention, the organic acid may not be tartaric acid. The nicotine source according to the present invention may not comprise nicotine tartrate. The nicotine-organic acid salt carried on the inorganic carrier material may not be nicotine tartrate. For the nicotine source of the present invention, the organic acid may not be a fatty acid.

[0056] The nicotine source of the present invention may comprise organic acid in any suitable amount. This includes all organic acid in the nicotine source, whether in the form of nicotine-organic acid salt or organic acid, and whether carried on the inorganic carrier material or otherwise, as described herein. The nicotine source may comprise 5 to 55 wt.% organic acid, such as 10 to 50 wt.% organic acid. Preferably, the nicotine source comprises 15 to 45 wt.% organic acid. The nicotine source may comprise 5 to 14 wt.% organic acid, such as from 5 to 13 wt.% organic acid, or from 5 to 10 wt.% organic acid.

[0057] As discussed above, the nicotine source of the present invention may further comprise nicotine-organic acid salt and / or nicotine that is not carried on the inorganic carrier material. The nicotine source of the present invention may further comprise nicotine-organic acid salt and / or organic acid that is not carried on the inorganic carrier material. The nicotine source of the present invention may further comprise nicotine-organic acid salt and / or nicotine and / or organic acid that is not carried on the inorganic carrier material.

[0058] The nicotine source of the present invention may further comprise inorganic carrier material that does not carry nicotine or nicotine-organic acid salt. The nicotine source of the present invention may further comprise inorganic carrier that does not carry nicotine-organic acid salt or organic acid. The nicotine source of the present invention may further comprise inorganic carrier that does not carry nicotine-organic acid salt or nicotine or organic acid. The nicotine source of the present invention may comprise inorganic carrier material that does not carry any additional components.

[0059] For the nicotine source of the present invention, the organic acid and nicotine may be present in the nicotine source at a mass ratio of organic acid to nicotine of 0.5 or more, or 0.6 or more, such as 0.7 or more. The organic acid and nicotine may be present in the nicotine source at a mass ratio of organic acid to nicotine of 3.5 or less, or 3.0 or less, such as 2.5 or less, or 2.0 or less. Preferably, a mass ratio of from 0.5 to 3.5, or from 0.5 to 3.0, such as from 0.5 to 2.5, or from 0.6 to 2.0, or from 0.7 to 2.0, such as a mass ratio of from 0.7 to 1 .5, or from 0.7 to 1 .0.

[0060] By ‘mass ratio’ as defined herein in relation to the nicotine source of the present invention is meant the ratio of the mass (grams) of organic acid to mass (grams) of nicotine in the nicotine source. This can be defined by: mass of organic acid mass of nicotine

[0061] When calculating the mass of organic acid, the organic acid includes all organic acid present in the nicotine source whether in the form of nicotine-organic acid salt or organic acid, and whether carried on the inorganic carrier material or otherwise, as described herein. When calculating the mass of nicotine, the nicotine includes all nicotine present in the nicotine source whether in the form of nicotine-organic acid salt or nicotine, and whether carried on the inorganic carrier material or otherwise, as described herein. The mass ratio of organic acid to nicotine of the nicotine source is the same as the ratio of the mass of organic acid to the mass of nicotine reacted together in the production of the nicotine source.

[0062] For the nicotine source of the present invention, the inorganic carrier material is preferably porous. For the nicotine source according to the present invention, the inorganic carrier material is preferably amorphous. For the nicotine source of the present invention, the inorganic carrier material may be selected from silica (silicon dioxide), silicate salts, and silicate esters. Preferably, the inorganic carrier material is selected from silica and silicate salts. More preferably, the inorganic carrier material is silica. Advantageously, when the inorganic carrier material is silica, improved nicotine support and elution efficiency can be demonstrated.

[0063] For the nicotine source of the present invention, the inorganic carrier material is preferably not cellulose or derivatives thereof. Preferably, the nicotine source of the present invention does not comprise cellulose or derivatives thereof.

[0064] For the nicotine source of the present invention, the inorganic carrier material may have a D5o particle size of from 1 to 700 pm, such as from 50 to 600 pm, or from 100 to 500 pm. The inorganic carrier material may have a D5o particle size of from 200 to 700 pm, such as from 250 to 600 pm, or from 300 to 500 pm. Such D5o particle size enables the nicotine source to be retained in the nicotine oral delivery products of the present invention, whilst having a suitable texture. D5o particle size is the value of the particle size at a volume-based cumulative frequency 50% in a particle size distribution. This may be determined by laser diffraction particle size distribution, which can be performed using a device such as the Master Size 3000 from Malvern Panarital. The D5o particle size may be measured according to ASTM D6913.

[0065] The nicotine source of the present invention may comprise the inorganic carrier material in any suitable amount. This includes all the inorganic carrier material present in the nicotine source. The nicotine source may comprise 5 to 70 wt.% inorganic carrier material, such as 15 to 60 wt.%, or 30 to 50 wt.% inorganic carrier material.

[0066] The nicotine source of the present invention may have a neutral taste. By "neutral taste" is meant a taste that is pleasant to the user and allows any selected one or more flavour introduced into a composition of the present invention for use in a nicotine oral delivery product of the present invention to be the predominant taste associated with the nicotine oral delivery product. The inorganic carrier material of the nicotine source of the present invention contributes to the neutral taste of the nicotine source.

[0067] Preferably, the nicotine source of the present invention comprises nicotine citrate and / or nicotine carried on the inorganic carrier material. More preferably the nicotine source of the present invention comprises nicotine citrate and / or nicotine carried on silica.

[0068] The nicotine source of the present invention may be provided in the form of a powder. A ‘powder’ as used herein refers to fine particles of the component in question.

[0069] The nicotine source may have a D5o particle size of from 1 to 700 pm, such as from 50 to 600 pm, or from 100 to 500 pm. Such a D5o particle size enables the nicotine source to be retained in the nicotine oral delivery products of the present invention, whilst having a suitable texture. D5o particle size is the value of the particle size at a volume-based cumulative frequency 50% in a particle size distribution. This may be determined by laser diffraction particle size distribution, which can be performed using a device such as the Master Size 3000 from Malvern Panarital. The D5o particle size may be measured according to ASTM D6913.

[0070] According to a further aspect of the present invention, the nicotine source of the present invention may be formed by a process comprising:

[0071] (a) combining nicotine and an organic acid with water and / or an organic solvent;

[0072] (b) combining the product of step (a) with an inorganic carrier material; and

[0073] (c) removing the water and / or organic solvent to form the nicotine source, wherein the molar ratio of organic acid to nicotine in step (a) is 0.6 or more. The nicotine source, nicotine, organic acid, and inorganic carrier material may be as described above and herein for all aspects of the present invention. All optional and preferred features detailed herein for all other aspects of the present invention may be applied to this aspect as far as applicable thereto.

[0074] The ‘molar ratio’ of organic acid to nicotine in step (a) is the ratio of the moles of organic acid to the moles of nicotine reacted together in step (a). This can be defined by: moles of organic acid moles of nicotine

[0075] When calculating the moles (moles = mass (g) / molar mass (g / mol)) of the organic acid and moles of nicotine, the molar mass of the organic acid (electrically neutral form, e.g. 192.12 g / mol for citric acid) and free-base nicotine (C10H14N2, 162.24 g / mol ) is used.

[0076] In step (a), the molar ratio of organic acid to nicotine is preferably from 0.6 to 3.5, such as from 0.6 to 3.0, or from 0.6 to 2.5, or from 0.6 to 2.0, such as from 0.6 to 1 .5. Preferably, in step (a), the molar ratio of the organic acid to nicotine is from 0.6 to 1 .0, such as 0.6 to 0.9. More preferably, in step (a), the molar ratio of the organic acid to nicotine is from 0.6 to 0.7.

[0077] In step (a), the molar ratio of organic acid to nicotine may be from 0.60 to 1.10, such as from 0.61 to 1.00, such as from 0.62 to 0.90, such as from 0.62 to 0.80, or from 0.65 to 0.70.

[0078] In step (a), the mass ratio of the organic acid to nicotine may be 0.5 or more, such as 0.6 or more, or 0.7 or more. In step (a), the mass ratio of the organic acid to nicotine may be 3.5 or less, or 3.0 or less, such as 2.5 or less, or 2.0 or less. Preferably, in step (a), the mass ratio of organic acid to nicotine is from 0.5 to 3.5, such as from 0.5 to 3.0, or from 0.5 to 2.5, such as from 0.6 to 2.0, or from 0.7 to 2.0, such as from 0.7 to 1 .5, or from 0.7 to 1 .0. The ‘mass ratio’ of organic acid to nicotine is step (a) is the ratio of the mass (g) organic acid to mass (grams) of nicotine reacted together in step (a). This can be defined by: mass of organic acid mass of nicotine

[0079] In step (a), a nicotine-organic acid salt of the nicotine and organic acid may be formed.

[0080] In step (a), the nicotine and organic acid may be dissolved in the water and / or organic solvent.

[0081] In step (a), the nicotine and organic may react to form a nicotine-organic acid salt in the water and / or organic solvent.

[0082] In step (a), after combining the nicotine and organic acid with the water and / or organic solvent, a homogeneous solution or mixture may be formed. Accordingly, step (a) may comprise combining the nicotine and organic acid with water and / or organic solvent to form a homogeneous mixture or solution.

[0083] Step (a) may comprise mixing and / or stirring to combine the nicotine and organic acid with the water and / or organic solvent. Step (a) may comprise mixing and / or stirring.

[0084] Step (a) may be carried out at any suitable temperature. Step (a) may be carried out at a temperature of from 40 to 90°C or less, such as from 40 to 80°C. Step (a) may be carried out at ambient temperature.

[0085] In step (a), the ratio of the amount (g) of the organic acid to water and / or organic solvent may be from 1 :2 to 1 :6 (organic acid:water and / or organic solvent), such as 1 :3 to 1 :5, preferably 1 :4. Advantageously, such a ratio of organic acid to water and / or organic solvent enables the amount of nicotine (whether in the form of nicotine-organic acid or nicotine) carried on the inorganic carrier material in the resulting nicotine source to be increased. Such ratios are therefore preferable to utilising just enough water and / or organic solvent to dissolve the organic acid. In step (a), the nicotine and organic acid are preferably combined with water or an organic solvent.

[0086] In step (a), the water may be distilled water.

[0087] In step (a), the organic solvent may be selected from ethanol, hexane, heptane, and ethyl acetate, or combinations thereof. More preferably, the organic solvent may be selected from ethanol, hexane, and ethyl acetate, such as from ethanol and hexane, and preferably ethanol.

[0088] In step (a), the organic solvent may be non-polar.

[0089] It will be appreciated that the product of step (a) referred to in step (b) is the mixture or solution formed after the nicotine and organic acid have been combined with water and / or an organic solvent in step (a).

[0090] In step (b), mixing and / or stirring may be used to combine the inorganic carrier material. Step (b) may comprise mixing and / or stirring.

[0091] In step (b), additional water and / or additional organic solvent may be introduced. Preferably, in step (b), additional water and / or additional organic solvent is introduced. The additional water and / or additional organic solvent may be introduced after combining the product of step (a) with the inorganic carrier material. The additional organic solvent may be selected from ethanol, hexane, heptane, and ethyl acetate, or combinations thereof, such as selected from ethanol, hexane, and ethyl acetate, preferably from ethanol and hexane. The additional water and / or additional organic solvent of step (b) may be the same or different to the water and / organic solvent used in step (a). If organic solvent is used in step (a), and an additional organic solvent is used in step (b), the additional organic solvent used in step (b) may be the same or different to the organic solvent used in step (a). If organic solvent is used in step (a), and additional water and / or additional organic solvent is used in step (b), the additional water and / or additional organic solvent is preferably additional solvent. If water is used in step (a), and additional water and / or additional organic solvent is used in step (b), the additional water and / or additional organic solvent is preferably additional water. In step (b), any suitable amount of additional water and / or additional organic solvent may be added. The amount may be sufficient to enable stirring and / or mixing. The amount of additional water and / or additional organic solvent may be 12 times or more of the amount of inorganic carrier material used in step (b), for example, 10 times or more of the amount of inorganic carrier material used in step (b), such as 6 times or more, or 4 times or more of the amount of the inorganic carrier material. The amount of additional water and / or additional organic solvent may be 12 times the amount of inorganic carrier material used in step (b), such as 10 times the amount of inorganic carrier material used in step (b), or 6 times, or 4 times the amount of the inorganic carrier material. The upper limit of the amount of additional water and / or additional organic solvent in step (b) may be 15 times the amount of inorganic carrier material used in step (b), such as 14 times the amount of inorganic carrier material, or 12 times the amount of inorganic carrier material, such as 11 times, or 10 times the amount of inorganic carrier material. The amount of additional water and / or additional organic solvent used in step (b) may from 4 times to 15 times the amount of inorganic carrier material used in step (b), such as from 6 times to 14 times, or from 8 to 12 times, or from 9 to 11 times, such as 10 times the amount of inorganic carrier material used in step (b). It is preferable to use a smaller amount of additional water and / or additional organic solvent to prevent leakage of nicotine during production of the nicotine source of the present invention, and to reduce drying time in step (c).

[0092] If additional water and / or additional organic solvent is used, it will be appreciated that step (c) may include removing the additional water and / or additional organic solvent to form the nicotine source, such as removing the additional water and / or additional organic solvent by drying as described herein for the water and / or organic solvent.

[0093] In step (b), the inorganic carrier material is in the form of a powder.

[0094] In step (b), the inorganic carrier material may have a D5o particle size of from 1 to 700 pm, such as from 50 to 600 pm, or from 100 to 500 pm. In step (b), the inorganic carrier material may have a D5o particle size of from 200 to 700 pm, such as from 250 to 600 pm, or from 300 to 500 pm. Such D5o particle size enables the nicotine source to be retained in the nicotine oral delivery products of the present invention, whilst having a suitable texture. D5o particle size is the value of the particle size at a volume-based cumulative frequency 50% in a particle size distribution. This may be determined by laser diffraction particle size distribution, which can be performed using a device such as the Master Size 3000 from Malvern Panarital. The D5o particle size may be measured according to ASTM D6913.

[0095] Step (c) advantageously improves the immobility of nicotine on the inorganic carrier material, enhancing the nicotine stability of the nicotine source produced. Step (c) also advantageously increases the handleability of the nicotine source produced, helping to improve mixing efficiency when producing compositions of the present invention comprising said nicotine source. Additionally, reducing the water content in the nicotine source helps to minimise undesirable chemical or physical changes in other components of a composition of the present invention in which said nicotine source is utilised, prior to use.

[0096] Step (c) may comprise removal of water and / or organic solvent by drying. This may be the evaporation of water and / or organic solvent. The water and / or organic solvent may refer to the water and / or organic solvent of step (a) and where used, may also refer to the additional water and / or additional organic solvent of step (b).

[0097] In step (c), excess water and / or organic solvent may be removed. In step (c), some or all of the water and / or organic solvent may be removed. In step (c), some or all of the water and / or organic solvent may be removed such that the nicotine source formed has a solid form. In step (c), the water and / or organic solvent may be removed to obtain a nicotine source in solid form. Accordingly, in step (c), the nicotine source obtained is in solid form. In step (c), the nicotine source obtained may be in the form of a powder.

[0098] In step (c), the water and / or organic solvent may be removed by allowing the water and / or organic solvent to evaporate. Step (c) may comprise evaporation of some or all of the water and / or organic solvent. The nicotine source may be formed in step (c) by allowing the water and / or organic solvent to evaporate. Step (c) may comprise drying. The drying may be carried out under any suitable conditions. For example, at ambient temperature. By the term "ambient temperature" as used herein is meant a temperature of from 10 to 35 °C, typically 15 to 25 °C. Ambient temperature is encompassed by the broader definition of "ambient conditions", which refers to the normal range of conditions of the surrounding environment to which the solution and thus the nicotine source, is exposed, i.e. the range of temperatures, pressures and atmospheric conditions to which the mixture and thus the nicotine source is exposed during production, use, storage and otherwise. This includes solar radiation including electromagnetic radiation of X-rays, ultraviolet (UV) and infrared (IR) radiation. Typically, ambient conditions include a temperature of from 10 to 35 °C, a pressure of from 20 to 100 kPa, and the environment is typically an oxygen-containing atmosphere. Drying of the water and / or organic solvent may be carried out in a desiccator. Air flow may be increased to facilitate drying. Drying of the water and / or organic solvent may be carried out in drying chambers, as the product of step (b) is placed or passes therethrough. Drying of the water and / or organic solvent may be carried out by freeze drying. This low temperature dehydration process involves freezing and lowering pressure, removing ice by sublimation. Drying of the water and / or organic solvent may be carried out using any combination of these methods.

[0099] The drying in step (c) may take place by heating, for example, to a temperature of from 20 to 130 °C, such as from 30 to 100 °C, or from 35 to 100 °C, such as from 40 to 80 °C. Suitable heating methods include conventional heating method. For example, heating may be achieved through heating on a hot plate, or other suitable heating apparatus.

[0100] The drying in step (c) may take from 10 minutes to 96 hours, such as from 30 minutes to 72 hours, or from 45 minutes to 48 hours, or from 1 hour to 24 hours, or 2 hours to 12 hours. Preferably, the drying in step (c) takes 72 hours or less.

[0101] The nicotine source of the present invention may comprise less than 20% moisture content, such as less than 15% moisture content, or less than 10% moisture content. The moisture content is the water content of the nicotine source of the present invention. The moisture content may be measured using a heat-drying moisture meter (e.g. HB 43-S made by METTER TOLEDO). For measurement, the sample is injected into a predetermined container and heated to a temperature of 100°C. The measurement ends when there is a change of less than 1 mg in 60 seconds, and the moisture content is calculated from the weighed value before and after heating.

[0102] According to a further aspect of the present invention, there is provided a nicotine source comprising a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material, wherein the nicotine source is obtainable by a process comprising:

[0103] (a) combining nicotine and an organic acid with water and / or an organic solvent;

[0104] (b) combining the product of step (a) with an inorganic carrier material; and

[0105] (c) removing the water and / or organic solvent to form the nicotine source, wherein the molar ratio of the organic acid to nicotine in step (a) is 0.6 or more.

[0106] The nicotine source, nicotine, organic acid, inorganic carrier material, molar ratio, step (a), step (b), step (c), and organic solvent, are as described above and herein for all aspects of the present invention. All optional and preferred features detailed herein for all other aspects of the present invention may be applied to this aspect as far as applicable thereto. The nicotine source of this further aspect of the present invention may comprise organic acid and nicotine in a molar ratio of organic acid to nicotine of from 0.6 or more.

[0107] The composition of the present invention comprises the nicotine source of the present invention. All optional and preferred features detailed herein for all other aspects of the present invention may be applied to this aspect as far as applicable thereto. The composition may comprise one or more nicotine source of the present invention. The composition of the present invention may be in the form of a powder or granules. The composition may have a D5o particle size of from 1 to 700 pm, such as from 50 to 600 pm, or from 100 to 500 pm. Such a D5o particle size enables the composition to be retained in the nicotine oral delivery products of the present invention, whilst having a suitable texture. D5o particle size is the value of the particle size at a volume-based cumulative frequency 50% in a particle size distribution. This may be determined by laser diffraction particle size distribution, which can be performed using a device such as the Master Size 3000 from Malvern Panarital. The D5o particle size may be measured according to ASTM D6913.

[0108] The composition of the present invention may comprise the nicotine source of the present invention in any suitable amount. It will be appreciated that the amount of the nicotine source in the composition can be modified, for example, based on the requirement of the nicotine oral delivery product specification like texture, taste, and nicotine release speed. Preferably, the composition comprises 1 to 80 wt.% of the nicotine source, such as 4 to 60 wt.% of the nicotine source, or even 10 to 50 wt.% of the nicotine source.

[0109] The composition of the present invention may comprise 0.05 wt.% to 40 wt.%, such as 1 to 40 wt.%, or 5 to 30 wt.%, or even 10 to 25 wt.%, of nicotine (in the form of nicotine and / or nicotine-organic acid salt, as described herein).

[0110] The composition according to the present invention may further comprise one or more pH-adjusting agents. The term "pH adjusting agent" and like terms used herein refers to agents which adjust and regulate the pH of the composition to which they are added. Such agents may be acids and bases, including acidic and alkaline buffering agents. However, the term does not encompass substances that only affect pH by dilution.

[0111] Any pharmaceutically acceptable pH adjusting agent may be utilised in the composition of the present invention. Suitable examples of pH adjusting agents include, but are not limited to: carbonates including monocarbonates, bicarbonates and sesquicarbonates of alkaline metals or ammonium such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and magnesium carbonate; acetates of alkaline metals or ammonium; glycinates of alkaline metals or ammonium; gluconates of alkaline metals or ammonium, borates of alkaline metals or ammonium, glycerophosphates of alkaline metals or ammonium; citrates of alkaline metals or ammonium; phosphate systems including monohydrogenphosphate, dihydrogenphosphate and trihydrogenphosphate such as sodium dihydrogen phosphate; metal hydroxides such as sodium hydroxide and potassium hydroxide; and mixtures thereof. Preferably, the one or more pH adjusting agent is selected from sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. More preferably, the one or more pH-adjusting agent is sodium carbonate.

[0112] The absorption of nicotine over the mucous membrane in the oral cavity of a user is affected by local pH, i.e. the pH inside and in close proximity to the nicotine oral delivery product in the saliva of the user. Preferably, the one or more pH-adjusting agent provides a local pH of 6 or above, such as a pH of from 8 to 10, more preferably 9, when the composition is dissolved or dispersed in aqueous solution such as purified water.

[0113] The amount of pH-adjusting agent present in the composition affects local pH. The one or more pH-adjusting agent may be present in the composition of the present invention in any suitable amount. The composition may comprise from 1 to 10 wt%, such as from 2 to 8 wt% of the one or more pH adjusting agent.

[0114] The composition of the present invention may further comprise one or more fillers and / or gelling agents.

[0115] Suitable examples of fillers include but are not limited to: cellulose or derivatives thereof including microcrystalline cellulose (MCC), spherical cellulose and porous cellulose; di- or polysaccharides; sugar alcohols such as maltitol, xylitol, erythritol; inorganic materials such as amorphous silicate, calcium silicate, silica; polyurethane; natural fibres such as cellulose fibre, cellulose pulp; and mixtures thereof. It is noted that a filler may also have a secondary function as, for example, a sweetener.

[0116] The term "cellulose derivative" as used herein refers to cellulose which has been modified by virtue of the hydroxyl groups of the compound being partially or fully reacted with one or multiple reagents. Examples of suitable cellulose derivatives include cellulose ethers and cellulose esters. In the production of cellulose ethers, the hydroxyl groups of the cellulose are typically reacted with alkali such as sodium hydroxide, followed by one or more etherifying agents such as methyl chloride, ethyl chloride, ethylene oxide or propylene oxide. Cellulose esters are commonly derived from cellulose through the reaction of the hydroxyl groups with organic acids, anhydrides, or acid chlorides. The cellulose derivative may be provided in any form, including but not limited to: powder and granular forms.

[0117] Suitable cellulose ethers include, but are not limited to the following: alkyl cellulose ethers such as methylcellulose, ethylcellulose and ethyl methyl cellulose; hydroxyalkyl cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose and ethyl hydroxyethyl cellulose; and carboxymethyl cellulose ethers such as carboxymethylcellulose. When carboxymethylcellulose is used, the carboxymethylcellulose is preferably in its sodium salt form, sodium carboxymethylcellulose. Suitable cellulose esters include, but are not limited to the following: organic cellulose esters such as cellulose acetate, cellulose triacetate, cellulose propionate, cellulose acetate-propionate and cellulose acetate-butyrate; and inorganic cellulose esters such as nitrocellulose (cellulose nitrate) and cellulose sulfate.

[0118] Suitable examples of gelling agents include cellulose derivatives, and polysaccharides with carboxyl groups, such as carrageenan, pectin, arabia gum, xanthan gum, gellan gym, tragant gum, and alginic acid. Pectin, gellan gum, and alginic acid are preferred gelling agents, in particular pectin, such as LM (low methoxyl) pectin. One of these gelling agents may be used alone, or two or more may be combined in any type and proportion. A gelling agent may be accompanied by a gelling aid. Preferably, the gelling aid provides calcium ions. Suitable gelling aids include, but are not limited to halogenates (such as chlorides), citrates, carbonates, sulphates, and phosphates, of calcium. Calcium lactate, calcium carbonate, and calcium phosphate are preferred as gelling aids, in particular calcium lactate. Gelling aids other than those providing calcium ions include, for example, magnesium, silver, zinc, and those comprising metal ions such as copper, gold, and aluminium ions, and cationic polymers thereof, for example, halogenates (such as chlorides), citrates, carbonates, sulphates, phosphates, and cationic polymers, of these metal ions. One of these gelling aids may be used alone, or two or more combined in any type and proportion.

[0119] Preferably, the composition of the present invention is free of sugars, in light of the negative impact that they may have on a user’s teeth.

[0120] The one or more filler may be present in the composition of the present invention in any suitable amount. The composition may comprise from 10 to 80 wt%, such as from 20 to 70 wt%, or from 30 to 60 wt.% of the one or more filler.

[0121] It will be appreciated that if cellulose or derivatives thereof are utilised in the composition of the present invention, they are preferably separate to the nicotine source. They are preferably separate to the nicotine (whether in the form of nicotine and / or a nicotine-organic acid salt, as described herein). Nicotine (whether in the form of nicotine and / or nicotine-organic acid salt, as described herein) may not be carried on the cellulose or derivatives thereof in a composition of the present invention.

[0122] The composition of the present invention may further comprise one or more flavour. By "flavour" and like terms used herein is meant a substance used to influence aroma and / or taste of the composition, including but not limited to, essential oils, single flavour compounds, compounded flavourings and extracts. Examples of suitable flavours include essential oils, single flavour compounds, compounded flavourings and extracts of: bergamot, eucalyptus, orange, mandarin, citrus, lemon, peppermint, spearmint, mint, menthol, liquorice, Wintergreen, whiskey, rum, cherry, various berries, tobacco, coffee, vanilla, lime, apple, peach, carvone, limonene, and any combination thereof. Other suitable flavours include cooling agents such as those of the WS series such as WS-3, WS-5 and WS-11 or Coolact® 10, sensation agents such as capsaicin and camphor, or TRPV1 / A1 activating agents, and any combination thereof. Other suitable flavours include salts such as sodium chloride (NaCI), epithelial sodium channels (EnaC) activating agents, denatonium benzoate, columbin, amarogentin, quassin, absinthin, quinine hydrochloride, caffeine, coffee extract, quinine, quinine hydrochloride, denatonium benzoate, theobromine, cacao extract, limonin, naringin, hesperidin, sugar transfer vitamin P, tannin, tryptophan, phenylalanine, tyrosine, arginine, valine, leucine, isoleucine, proline, isoflavone, rutin, sagebrush extract, assembly extract, hop extract, humulone, isohumulone, citric acid, tartaric acid, malic acid, ascorbic acid, adipic acid, sodium citrate, glucono delta lactone, gluconic acid, succinic acid, monosodium succinate (crystal), anhydrous sodium acetate, DL -Tartaric acid, L-tartaric acid, DL-sodium tartrate, L-sodium tartrate, lactic acid, sodium lactate, glacial acetic acid, fumaric acid, monosodium fumarate, DL-malic acid, DL-sodium malate, phosphoric acid, or mixtures thereof.

[0123] The one or more flavours may be used to provide taste, such as saltiness, bitterness, sourness, or umami. For saltiness, suitable examples of the one or more flavours typically include salts such as sodium chloride (NaCI), and epithelial sodium channels (EnaC) activating agents. For bitterness, suitable examples of the one or more flavours typically include denatonium benzoate, columbin, amarogentin, quassin, absinthin, quinine hydrochloride, caffeine, coffee extract, quinine, quinine hydrochloride, denatonium benzoate, theobromine, cacao extract, limonin, naringin, hesperidin, sugar transfer vitamin P, tannin, tryptophan, phenylalanine, tyrosine, arginine, valine, leucine, isoleucine, proline, isoflavone, rutin, sagebrush extract, assembly extract, hop extract, humulone, isohumulone, or mixtures thereof. For sourness, suitable examples of the one or more flavours typically include citric acid, tartaric acid, malic acid, ascorbic acid, adipic acid, sodium citrate, glucono delta lactone, gluconic acid, succinic acid, monosodium succinate (crystal), anhydrous sodium acetate, DL -Tartaric acid, L-tartaric acid, DL-sodium tartrate, L-sodium tartrate, lactic acid, sodium lactate, glacial acetic acid, fumaric acid, monosodium fumarate, DL-malic acid, DL-sodium malate, phosphoric acid or mixtures thereof.

[0124] The one or more flavour may be present in the composition of the present invention in any suitable amount. The composition may comprise from 0.5 to 15 wt%, such as from 0.5 to 10 wt%, or even from 1 to 8 wt.% of the one or more flavour.

[0125] The composition of the present invention may further comprise one or more humectants. Humectants may also be known in the art as moisturisers or softeners and are present in the composition of the present invention to control and maintain appropriate moisture levels of the composition.

[0126] Suitable examples of humectants include, but are not limited to: glycerol, glycerine, polyol, propylene glycol, hexyleneglycol, butylene glycol, polydextrose, sorbitol, maltitol, xylitol, glyceryl triacetate, triethylene glycol and combinations thereof. Preferably, the one or more humectant is selected to be glycerol, propylene glycol, or a combination thereof. The amount of propylene glycol in the composition will be in accordance with associated safety regulations. More preferably, the one or more humectant is glycerol.

[0127] The one or more humectants may be present in the composition of the present invention in any suitable amount. The composition may comprise from 1 to 25 wt%, such as from 1 to 15 wt%, such as from 5 to 15 wt% of the one or more humectant.

[0128] The composition of the present invention may further comprise one or more sweetener to enhance the taste and sweetness of flavour provided. Suitable examples of sweetener include, but are not limited to: polyols such as xylitol, mannitol, and maltitol; mono-, di- and tri-polysaccharides; natural and synthetic sweeteners such as sucrose, glucose, dextrose, maltose, fructose, saccharin, aspartame, acesulfame including acesulfame K, sucralose, saccharin and cyclamate and mixtures thereof.

[0129] The one or more sweeteners may be present in the composition of the present invention in any suitable amount. The composition may comprise from 1 to 20 wt% of the one or more sweetener.

[0130] The composition of the present invention may be enclosed in a water insoluble pouch, i.e. completely contained within a water insoluble pouch. Accordingly, according to a further aspect of the present invention, a nicotine oral delivery product according to the present invention may be formed. All optional and preferred features detailed herein for all other aspects of the present invention may be applied to this aspect as far as applicable.

[0131] The nicotine oral delivery product of the present invention may comprise the composition of the present invention sealed within a water insoluble pouch. The water insoluble pouch may be formed from any suitable material. The water insoluble pouch may be formed from any suitable pharmaceutically acceptable material. The term "pharmaceutically acceptable" as used herein refers to nontoxic compounds or materials that are biocompatible and physiologically acceptable, and do not decrease the effectiveness of the biological activity of the active ingredient, i.e. nicotine. Such pharmaceutically acceptable materials for the water insoluble pouch will be well known in the art.

[0132] Examples of suitable materials from which the water insoluble pouch may be formed include but are not limited to: woven or non-woven fabrics such as cotton or fleece; and heat-sealable non-woven cellulose or other polymeric materials such as synthetic, semi-synthetic or natural polymeric agents. The water insoluble pouch may further comprise components, such as polymers, to bind the materials and facilitate sealing of the pouch. Preferably, the water insoluble pouch is formed from a non-woven material comprising viscose rayon fibres (i.e. regenerated cellulose) and an acrylic polymer that acts as a binder for the non-woven material and provides for heat-sealing of the pouch during manufacturing thereof.

[0133] The water insoluble pouch may be sealed to enclose and retain the composition of the present invention with the pouch. Preferably, the water insoluble pouch is heat-treated to seal the composition inside and form the nicotine oral delivery product of the present invention.

[0134] It will be appreciated that the material of the water insoluble pouch influences the mouth-feel of the nicotine oral delivery product for the user. It will further be appreciated that the water insoluble pouch: does not dissolve in saliva; is chemically and physically stable; is pharmaceutically acceptable; is insoluble in water i.e. incapable of being dissolved in water; is easily fillable with the composition of the present invention; and is easily sealable.

[0135] The water insoluble pouch may provide a semi-permeable membrane which prevents the composition of the present invention leaving the pouch, but when the product is in use and placed in a user’s mouth, is permeable to saliva and dissolved components of the composition including nicotine and flavour components such that they can diffuse therefrom into the user’s mouth.

[0136] In the context of the present invention, the nicotine released and / or supplied to the user by the nicotine source, composition, and nicotine oral delivery products of the present invention is in the form of free-base nicotine. The source of nicotine of the present invention provides nicotine in a form that can be solubilised by saliva entering the interior of the pouch of the nicotine oral delivery product of the present invention such that nicotine can diffuse therefrom in the saliva and pass into a user’s mouth.

[0137] The nicotine oral delivery product of the present invention is intended to be placed in the oral cavity of a user, such as by buccal placement (placing the product between the upper or lower gum and the lip or cheek). The nicotine oral delivery product may therefore be sized and configured to fit comfortably and discreetly in the user’s mouth in this manner. It may have an oblong shape, such as a rectangular shape.

[0138] The composition of the present invention may be enclosed in the water insoluble pouch to form the nicotine oral delivery product of the present invention in any suitable amount. Preferably 50 to 1 ,000 mg, such as 200 to 800 mg of the composition is enclosed in the water insoluble pouch. It will be appreciated that the amount of the composition enclosed in the water insoluble pouch is selected such that the nicotine oral delivery product remains of an appropriate size.

[0139] The total weight of the nicotine oral delivery product (both composition and water insoluble pouch) according to the present invention may be from 0.3 to 1.5 g, such as from 0.3 to 1 .2 g, or even from 0.4 to 1 .0 g.

[0140] The composition of the present invention may not contain water. Accordingly, microorganisms are prevented from growing, providing a longer shelf life for the nicotine oral delivery products of the present invention.

[0141] The nicotine oral delivery product of the present invention further has a pleasant taste to the user. The inorganic carrier material of the nicotine source contributes to the neutral taste of the nicotine oral delivery product, which is welcomed by a user, with any additional flavours or sweeteners in the composition of the nicotine oral delivery product of the present invention providing the predominant enjoyable taste to the user.

[0142] During use, the nicotine oral delivery product of the present invention is placed and retained for a period of time in the mouth of a user. This is commonly between the upper or lower gum of the user and the chin or cheek. Once saliva enters the interior of the pouch, it dissolves any components of the composition enclosed therein that are soluble in saliva. These solubilised components of the composition (including nicotine, and flavour components) diffuse from the pouch in the saliva and into the mouth of the user. Once released from the pouch, the nicotine is bioavailable, i.e. available for absorption over a mucous membrane in the oral cavity of the user. Accordingly, once released from the pouch, nicotine is absorbed over a mucous membrane of the oral cavity of a user into their blood so as to provide nicotine and satisfaction to the user.

[0143] It is noted that the nicotine oral delivery products of the present invention are intended for single use.

[0144] As used herein, the terms "mouth" and "oral cavity" are interchangeable.

[0145] According to a further aspect of the present invention, there is provided a method of making a nicotine oral delivery product containing a composition enclosed in a water insoluble pouch, wherein said pouch is permeable for saliva and dissolved components of the composition, the composition comprising a nicotine source, the nicotine source comprising: a nicotine-organic acid salt and / or nicotine carried on an inorganic carrier material; and organic acid and nicotine in a molar ratio of organic acid to nicotine of from 0.6 or more.

[0146] For this further aspect of the present invention, the nicotine oral delivery product, composition, water insoluble pouch, nicotine source, nicotine, organic acid, inorganic carrier material, and molar ratio are as described above and herein for all aspects of the present invention. All optional and preferred features detailed herein for all other aspects of the present invention may be applied to this aspect as far as applicable.

[0147] The method of making the nicotine oral delivery product according to the further aspect of the present invention may comprise the steps of admixing the components of the composition, filling the composition into the water insoluble pouch, and enclosing the composition in the water insoluble pouch such that the composition is completely contained within. Preferably, the water insoluble pouch is sealed by heat to enclose and retain the composition therein. Appropriate machines for the manufacture of the nicotine oral delivery products of the present invention will be well known in the art. All of the features contained herein may be combined with any of the above aspects and in any combination.

[0148] All references to chemical compounds herein are to be interpreted as covering the compounds per se, and also, where appropriate, derivatives, hydrates, solvates, complexes, isomers and tautomers thereof.

[0149] All references to "wt%" as used herein refer to the percentage by weight relative to the total weight of the nicotine source, composition, or nicotine oral delivery product of the present invention. For the nicotine source, this includes all components carried on, and not carried by, the inorganic carrier material, and in any form as described herein.

[0150] All references to " (g)" as used herein refer to the unit of grams.

[0151] For a better understanding of the present invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the following experimental data.

[0152] EXPERIMENTAL DATA

[0153] Example 1

[0154] Nicotine Sources A to F according to the present invention, and Comparative Nicotine Sources G and H were prepared as set out below.

[0155] Nicotine Source A

[0156] 0.40 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.32 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine of 0.68) in 1.28 g of ethanol (CAS No. 64-17-5 from FUJIFILM Wako Chemicals). The resulting mixture was combined with 2.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 20 g of ethanol for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0157] Nicotine Source B

[0158] 0.40 g of nicotine (CAS No. 54-11 -5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.4 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine of 0.85) in 1.60g of ethanol (CAS No. 64-17-5 from FUJIFILM Wako Chemicals). The resulting mixture was combined with 2.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 20 g of ethanol for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0159] Nicotine Source C

[0160] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.56 g of malic acid (CAS No. 6915-15-7 from FUJIFILM Wako Chemicals) (molar ratio malic acid to nicotine of 0.68) in 2.24 g of ethanol (CAS No. 64-17-5 from FUJIFILM Wako Chemicals). The resulting mixture was combined with 5.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 50 g of ethanol for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0161] Nicotine Source D

[0162] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.8 g of malic acid (CAS No. 6915-15-7 from FUJIFILM Wako Chemicals) (molar ratio malic acid to nicotine is 0.97) in 3.2 g of ethanol (CAS No. 64-17-5 from FUJIFILM Wako Chemicals). The resulting mixture was combined with 5.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 50 g of ethanol for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0163] Nicotine Source E

[0164] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 1.0 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 0.85) in 4.0 g of ethanol (CAS No. 64-17-5 from FUJIFILM Wako Chemicals). The resulting mixture was combined with 2.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 20 g of ethanol for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0165] Nicotine Source F

[0166] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 1.0 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 0.85) in 4.0 g of distilled water. The resulting mixture was combined with 2.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5O particle size of 320 pm). The mixture was stirred under 20 g of distilled water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0167] Comparative Nicotine Source G

[0168] Comparative Nicotine Source G was nicotine polacrilex (CAS No. 96055-45-7 from CONTRAF-NICOTEX-TOBACCO GMBH).

[0169] Comparative Nicotine Source H

[0170] 2.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 1.0 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals) (molar ratio citric acid to nicotine 0.42) in 4.0 g distilled water. The resulting mixture was combined with 5.0 g of calcium silicate (CAS No. 1344-95- 2 from Sigma-Aldrich - D5o particle size of around 7 to 10 pm). The mixture was stirred under 50 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0171] The elution rate (release rate) of nicotine from the Nicotine Sources A to F and Comparative Nicotine Sources G and H was measured based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012), and as set out below.

[0172] Step 1 : Make a pouch containing 0.3 g of the nicotine source;

[0173] Step 2: Deliver a constant flow of artificial saliva (4 ml / min) into the pouch using CE7 Smart (Sotax);

[0174] Step 3: Collect fraction liquids at 8 time points of 2, 5, 8, 10, 20, 30, 45,

[0175] 60 minutes; and

[0176] Step 4: Measure the amount of nicotine in each fraction using LC-DAD

[0177] (1260 Infinity n LC / MSD from Agilent).

[0178] In Step 1 , a water-impermeable non-woven fabric pouch was used. After putting the nicotine source into the pouch, the pouch was sealed by thermal bonding. The size of the pouch was 14 mm x 28 mm (rectangular).

[0179] In Step 2, the artificial saliva was prepared based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012). Briefly, the pH of 1 L of deionized (DI) water was first lowered to pH 2.5 by adding 2 mL of concentrated hydrochloric acid. The artificial saliva solution was then prepared by dissolving 0.68 g of potassium hydrogen phosphate anhydrous (K2HPO4- H2O), 0.33 g of sodium chloride (anhydrous), 0.15 g of calcium chloride dihydrate (CaCI 2H2O), 0.75 g potassium chloride (anhydrous), 0.53 g of potassium carbonate (anhydrous), and 0.17 g of magnesium chloride hexahydrate (MgCI'6H2O) in the acidified DI water. If needed, the pH solution was further adjusted to 6.8 ± 0.1 using small, incremental additions of 5 N sodium hydroxide with a disposable glass Pasteur pipette.

[0180] The results are shown in FIG. 1.

[0181] FIG. 1 demonstrates the controlled release of nicotine from Nicotine Sources A to F (labelled NS-A to NS-F) of the present invention versus Comparative Nicotine Sources G and H (labelled NS-G and NS-H).

[0182] Example 2

[0183] Samples I and J relating to nicotine sources according to the present invention and Comparative Samples K to N were prepared as follows, but using differing amounts of nicotine and citric acid. The amounts of nicotine and citric acid are shown in Table 1.

[0184] Samples (Nicotine Sources) I and J and Comparative Samples (Comparative Nicotine Sources) K to N

[0185] Nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) in 1.28 g of ethanol (CAS No. 64-17-5 from FUJIFILM Wako Chemicals). The resulting mixture was combined with 1.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 10 g of hexane for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. After the solid had completely settled in the bottle, 0.1 mL of the supernatant was taken, and the nicotine amount was measured using LC-DAD (liquid chromatography with diode array detection) (1260 Infinity n LC / MSD from Agilent).

[0186] Table 1

[0187] The % supported nicotine was calculated using the following formula:

[0188] % supported nicotine

[0189] (A) is the amount of nicotine shown in Table 1 . This is the amount of nicotine used in the production of the Samples and Comparative Samples.

[0190] (B) is the amount of nicotine measured from the supernatant. This is the amount of nicotine not carried on the silica.

[0191] The results are shown in FIG. 2.

[0192] FIG. 2 demonstrates how Samples I and J relating to nicotine sources of the present invention having a molar ratio of organic acid to nicotine of 0.6 or more achieve a greater % supported nicotine value than Comparative Samples K to N. For example, Comparative Sample K has a reduced % supported nicotine of 15% compared to Sample J, and nearly 20% compared to Sample I.

[0193] Example 3

[0194] Nicotine Source P of the present invention and Comparative Nicotine Source Q were prepared by the same methods as for Nicotine Source F and Comparative Nicotine Source H of Example 1 respectively.

[0195] TG-DTA analysis (thermogravimetry differential thermal analysis) was carried to determine the nicotine stability of Nicotine Source P and Comparative Nicotine Source Q using TG-DTA (Thermo plus EVO2 from Rigaku) based on the method of the reference (Hua et al., Thermochimica Acta, 656 (2017), 53-58), and as set out below.

[0196] Stepl : 5 mg sample is loaded into a Pt (platinum) crucible; and

[0197] Step 2: After setting the sample on Thermo plus EVO2 (Rigaku), it is heated from 35 °C to 500 °C in N2under 20 °C / min heating rate, and held for 5 min at 500 °C.

[0198] Results are shown in Table 2:

[0199] Table 2

[0200] The results shown in Table 2 demonstrate that the thermal decomposition of the Nicotine Source P is higher than Comparative Nicotine Source Q. It indicates that the nicotine (whether in the form of nicotine and / or nicotine-citric acid salt) of Nicotine Source P appears to be carried on the inorganic carrier material more strongly than for Comparative Nicotine Source Q. Such a result indicates that the stability of the nicotine (whether in the form of nicotine and / or nicotine-citric acid salt) carried on the inorganic carrier material of the nicotine sources of the present invention is higher than nicotine sources outside the scope of the present invention.

[0201] Example 4

[0202] Nicotine Sources R to T according to the present invention, and Comparative Nicotine Sources U and V were prepared as set out below.

[0203] Nicotine Source R

[0204] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.72 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 0.61) in 2.88 g of water. The resulting mixture was combined with 2.2 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 22 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0205] Nicotine Source S

[0206] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.96 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 0.81) in 3.84 g of water. The resulting mixture was combined with 2.0 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 20 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0207] Nicotine Source T

[0208] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 1.18 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 1.00) in 4.72 g of water. The resulting mixture was combined with 1.8 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 18 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0209] Comparative Nicotine Source U

[0210] Prepared in accordance with Comparative Nicotine Source G, described above in Example 1 .

[0211] Comparative Nicotine Source V

[0212] Prepared in accordance with Comparative Nicotine Source H, described above in Example 1 .

[0213] The elution rate (release rate) of nicotine from the Nicotine Sources R, S and T and Comparative Nicotine Sources U and V was measured based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012), and as set out below.

[0214] Step 1 : Make a pouch containing 0.3 g of the nicotine source;

[0215] Step 2: Deliver a constant flow of artificial saliva (4 ml / min) into the pouch using CE7 Smart (Sotax);

[0216] Step 3: Collect fraction liquids at 8 time points of 2, 5, 8, 10, 20, 30, 45,

[0217] 60 minutes; and

[0218] Step 4: Measure the amount of nicotine in each fraction using LC-DAD

[0219] (1260 Infinity n LC / MSD from Agilent).

[0220] In Step 1 , a water-impermeable non-woven fabric pouch was used. After putting the nicotine source into the pouch, the pouch was sealed by thermal bonding. The size of the pouch was 14 mm x 28 mm (rectangular). In Step 2, the artificial saliva was prepared based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012). Briefly, the pH of 1 L of deionized (DI) water was first lowered to pH 2.5 by adding 2 mL of concentrated hydrochloric acid. The artificial saliva solution was then prepared by dissolving 0.68 g of potassium hydrogen phosphate anhydrous (K2HPO4- H2O), 0.33 g of sodium chloride (anhydrous), 0.15 g of calcium chloride dihydrate (CaCI 2H2O), 0.75 g potassium chloride (anhydrous), 0.53 g of potassium carbonate (anhydrous), and 0.17 g of magnesium chloride hexahydrate (MgCI 6H2O) in the acidified DI water. If needed, the pH solution was further adjusted to 6.8 ± 0.1 using small, incremental additions of 5 N sodium hydroxide with a disposable glass Pasteur pipette.

[0221] The results are shown in FIG. 3.

[0222] FIG. 3 demonstrates the controlled release of nicotine from Nicotine Sources R, S and T (labelled NS-R, NS-S, and NS-T) of the present invention versus Comparative Nicotine Sources U and V (labelled NS-U and NS-V).

[0223] Example 5

[0224] Nicotine Sources A’ to F’ according to the present invention, and Comparative Nicotine Sources G’ and H’ were prepared as set out below.

[0225] Nicotine Source A

[0226] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.5 g of malic acid (CAS No. 6915-15-7 from FUJIFILM Wako Chemicals) (molar ratio malic acid to nicotine is 0.61) in 2.0 g of water. The resulting mixture was combined with 2.5 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 25 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0227] Nicotine Source B’ 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.66 g of malic acid (CAS No. 6915-15-7 from FUJIFILM Wako Chemicals) (molar ratio malic acid to nicotine is 0.80) in 2.64 g of water. The resulting mixture was combined with 2.3 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 23 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0228] Nicotine Source C

[0229] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.83 g of malic acid (CAS No. 6915-15-7 from FUJIFILM Wako Chemicals) (molar ratio malic acid to nicotine is 1.01) in 3.32 g of water. The resulting mixture was combined with 2.1 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 21 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0230] Nicotine Source D’

[0231] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.33 g of butyric acid (CAS No.107-92-6 from FUJIFILM Wako Chemicals) (molar ratio butyric acid to nicotine is 0.61) in 1.32 g of water. The resulting mixture was combined with 2.6 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 26 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 120 minutes under ambient conditions at 25 °C to a powder form.

[0232] Nicotine Source E’

[0233] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.43 g of butyric acid (CAS No.107-92-6 from FUJIFILM Wako Chemicals) (molar ratio butyric acid to nicotine is 0.79) in 1.72 g of water. The resulting mixture was combined with 2.5 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 25 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0234] Nicotine Source F’

[0235] 1.0 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.54 g of butyric acid (CAS No.107-92-6 from FUJIFILM Wako Chemicals) (molar ratio butyric acid to nicotine is 1.00) in 2.16 g of water. The resulting mixture was combined with 2.4 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5o particle size of 320 pm). The mixture was stirred under 24 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0236] Comparative Nicotine Source G’

[0237] Prepared in accordance with Comparative Nicotine Source G, described above in Example 1 .

[0238] Comparative Nicotine Source H’

[0239] Prepared in accordance with Comparative Nicotine Source H, described above in Example 1 .

[0240] The elution rate (release rate) of nicotine from the Nicotine Sources A to F’ and Comparative Nicotine Sources G’ and H’ was measured based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012), and as set out below.

[0241] Step 1 : Make a pouch containing 0.3 g of the nicotine source;

[0242] Step 2: Deliver a constant flow of artificial saliva (4 ml / min) into the pouch using CE7 Smart (Sotax);

[0243] Step 3: Collect fraction liquids at 8 time points of 2, 5, 8, 10, 20, 30, 45,

[0244] 60 minutes; and Step 4: Measure the amount of nicotine in each fraction using LC-DAD (1260 Infinity n LC / MSD from Agilent).

[0245] In Step 1 , a water-impermeable non-woven fabric pouch was used. After putting the nicotine source into the pouch, the pouch was sealed by thermal bonding. The size of the pouch was 14 mm x 28 mm (rectangular).

[0246] In Step 2, the artificial saliva was prepared based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012). Briefly, the pH of 1 L of deionized (DI) water was first lowered to pH 2.5 by adding 2 mL of concentrated hydrochloric acid. The artificial saliva solution was then prepared by dissolving 0.68 g of potassium hydrogen phosphate anhydrous (K2HPC>4- H2O), 0.33 g of sodium chloride (anhydrous), 0.15 g of calcium chloride dihydrate (CaCI 2H2O), 0.75 g potassium chloride (anhydrous), 0.53 g of potassium carbonate (anhydrous), and 0.17 g of magnesium chloride hexahydrate (MgCI 6H2O) in the acidified DI water. If needed, the pH solution was further adjusted to 6.8 ± 0.1 using small, incremental additions of 5 N sodium hydroxide with a disposable glass Pasteur pipette.

[0247] The results are shown in FIG. 4a & 4b.

[0248] FIG. 4a & 4b demonstrate the controlled release of nicotine from Nicotine Sources A to F’ (labelled NS-A to NS-F’) of the present invention versus Comparative Nicotine Sources G’ and H’ (labelled NS-G’ and NS-H’).

[0249] Example 6

[0250] Nicotine Source I’ according to the present invention, and Comparative Nicotine Source K’ were prepared as set out below.

[0251] Nicotine Source I’

[0252] 0.15 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.18 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 1.01 ) in 0.72 g of water. The resulting mixture was combined with 0.27 g of silica (CAS No. 112926-00-8 from Evonik industries AG, product name: SIPERNAT® 2200 - D5O particle size of 320 pm). The mixture was stirred under 2.7 g of water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0253] Comparative Nicotine Source K’

[0254] 0.15 g of nicotine (CAS No. 54-11-5 from CONTRAF-NICOTEX-TOBACCO GMBH) was mixed with 0.075 g of citric acid (CAS No. 77-92-9 from FUJIFILM Wako Chemicals - anhydrous citric acid) (molar ratio citric acid to nicotine is 0.42) in 0.3 g of water. The resulting mixture was combined with 0.38 g of silica (CAS No. 1344-95-2 from Sigma-Aldrich - D5o particle size of around 7 to 10 pm). The mixture was stirred under water for 60 minutes at a rotation speed of 250 rpm under ambient conditions at 25 °C. The mixture was dried for 12 hours under ambient conditions at 25 °C to a powder form.

[0255] Nicotine Source I’ and Comparative Nicotine Source K’ were formed into compositions of the present invention. To form the composition, the total amount of the Nicotine Source I’ or Comparative Nicotine Source K’ produced was mixed with the components shown in Table 3. The amounts of the components are shown in Table 3.

[0256] Table 3

[0257] The elution rate (release rate) of nicotine from the composition comprising Nicotine Source I’ or Comparative Nicotine Source K’ was measured based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012), and as set out below.

[0258] Step 1 : Make a pouch containing 0.3 g of the composition comprising the nicotine source;

[0259] Step 2: Deliver a constant flow of artificial saliva (4 ml / min) into the pouch using CE7 Smart (Sotax);

[0260] Step 3: Collect fraction liquids at 8 time points of 2, 5, 8, 10, 20, 30, 45,

[0261] 60 minutes; and

[0262] Step 4: Measure the amount of nicotine in each fraction using LC-DAD

[0263] (1260 Infinity n LC / MSD from Agilent).

[0264] In Step 1 , a water-impermeable non-woven fabric pouch was used. After putting the composition into the pouch, the pouch was sealed by thermal bonding. The size of the pouch was 14 mm x 28 mm (rectangular).

[0265] In Step 2, the artificial saliva was prepared based on the method of the reference (Miller et al., Journal of Chromatography B, 1141 (2020) 122012). Briefly, the pH of 1 L of deionized (DI) water was first lowered to pH 2.5 by adding 2 mL of concentrated hydrochloric acid. The artificial saliva solution was then prepared by dissolving 0.68 g of potassium hydrogen phosphate anhydrous (K2HPO4- H2O), 0.33 g of sodium chloride (anhydrous), 0.15 g of calcium chloride dihydrate (CaCI 2H2O), 0.75 g potassium chloride (anhydrous), 0.53 g of potassium carbonate (anhydrous), and 0.17 g of magnesium chloride hexahydrate (MgCI'6H2O) in the acidified DI water. If needed, the pH solution was further adjusted to 6.8 ± 0.1 using small, incremental additions of 5 N sodium hydroxide with a disposable glass Pasteur pipette.

[0266] The results are shown in FIG. 5.

[0267] FIG. 5 demonstrates the controlled release of nicotine from a composition comprising Nicotine Source I’ (labelled NS-I’) of the present invention versus Comparative Nicotine Source K’ (labelled NS-K’).

[0268] Embodiments

[0269] 1 . A nicotine source comprising: a nicotine-organic acid salt and / or nicotine carried on an inorganic carrier material; and organic acid and nicotine in a molar ratio of organic acid to nicotine of from 0.6 or more.

[0270] 2. A composition comprising the nicotine source according to embodiment 1 .

[0271] 3. A nicotine oral delivery product containing a composition according to embodiment 2 enclosed in a water insoluble pouch, wherein said pouch is permeable for saliva and dissolved components of the composition.

[0272] 4. A process for the production of a nicotine source comprising nicotine and organic acid adsorbed on the surface of an inorganic carrier material, the process comprising:

[0273] (a) combining nicotine and an organic acid with water and / or an organic solvent;

[0274] (b) combining the product of step (a) with an inorganic carrier material; and (c) removing the water and / or organic solvent to form the nicotine source, wherein the molar ratio of the organic acid to nicotine in step (a) is from 0.6 or more.

[0275] 5. The nicotine source, composition, nicotine oral delivery product, or process according to any of embodiments 1 to 4, wherein the molar ratio of the organic acid to nicotine is from 0.6 to 3.5, preferably from 0.6 to 3.0, more preferably from 0.6 to 2.5, more preferably from 0.6 to 2.0, more preferably from 0.6 to 1 .5, more preferably from 0.6 to 1 .0, more preferably from 0.6 to 0.9, more preferably from 0.6 to 0.8, and more preferably from 0.6 to 0.7.

[0276] 6. The process according to embodiment 4 or 5, wherein step (c) comprises drying.

[0277] 7. The nicotine source, composition, nicotine oral delivery product, or process according to any of embodiments 1 to 6, wherein the inorganic carrier material is selected from silica, silicate salts, and silicate esters, preferably wherein the inorganic carrier material is selected from, silica and silicate salts, more preferably wherein the inorganic carrier material is silica, and optionally wherein the inorganic carrier material is amorphous.

[0278] 8. The process according to any of embodiments 4 to 7, wherein the organic solvent is selected from ethanol, hexane, heptane, and ethyl acetate, or combinations thereof, more preferably selected from ethanol, hexane, and ethyl acetate, or combinations thereof, more preferably selected from ethanol and hexane, or combinations thereof, and more preferably ethanol.

[0279] 9. The nicotine source, composition, nicotine oral delivery product, or process according to any of embodiments 1 to 8, wherein the nicotine is derived from tobacco or is synthetic nicotine, preferably wherein the nicotine is (S) nicotine. 10. The nicotine source, composition, nicotine oral delivery product, or process according to any of embodiments 1 to 9, wherein the organic acid is a carboxylic acid, preferably wherein the organic acid is a hydroxy carboxylic acid, more preferably an a-hydroxy carboxylic acid.

[0280] 11 . The nicotine source, composition, nicotine oral delivery product, or process according to any of embodiments 1 to 10, wherein the organic acid is selected from gluconic acid, citric acid, malic acid, formic acid, acetic acid, propionic acid, butyric acid, 2-methylbutyric acid, 3-methylbuthric acid, valeric acid, benzoic acid, phenylacetic acid and pyruvic acid, preferably the organic acid is selected from citric acid, malic acid, benzoic acid, and butyric acid, more preferably the organic acid is selected from malic acid and citric acid, and more preferably is citric acid.

[0281] 12. The nicotine source, composition, nicotine oral delivery product, or process according to any of embodiments 1 to 11 , wherein the nicotine-organic acid salt is selected from nicotine gluconate, nicotine citrate, nicotine dicitrate, nicotine hemicitrate, nicotine malate, nicotine formate, nicotine acetate, nicotine propionate, nicotine butyrate, nicotine 2-methylbutyrate, nicotine 3-methylbutyrate, nicotine valerate, nicotine benzoate, nicotine phenylacetate, and nicotine pyruvate, preferably, the nicotine-organic acid salt is selected from nicotine citrate, nicotine malate, nicotine benzoate, and nicotine butyrate, more preferably from nicotine citrate and nicotine malate, and more preferably is nicotine citrate.

[0282] 13. A nicotine source comprising a nicotine-organic acid salt and / or nicotine carried on an inorganic carrier material, wherein the nicotine source is obtainable by the process according to any of embodiments 4 to 12.

Claims

CLAIMS1 . A nicotine source comprising: a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material; wherein the molar ratio of organic acid to nicotine is from 0.6 or more.

2. A composition comprising the nicotine source according to claim 1 .

3. A nicotine oral delivery product containing a composition according to claim 2 enclosed in a water insoluble pouch, wherein said pouch is permeable for saliva and dissolved components of the composition.

4. A process for the production of a nicotine source comprising nicotineorganic acid salt, and optionally nicotine, carried on an inorganic carrier material, the process comprising:(a) combining nicotine and an organic acid with water and / or an organic solvent;(b) combining the product of step (a) with an inorganic carrier material; and(c) removing the water and / or organic solvent to form the nicotine source, wherein the molar ratio of the organic acid to nicotine in step (a) is from 0.6 or more.

5. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 4, wherein the molar ratio of organic acid to nicotine is from 0.6 to 3.5, preferably from 0.6 to 3.0, more preferably from 0.6 to 2.5, more preferably from 0.6 to 2.0.

6. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 5, wherein the molar ratio of organic acid to nicotine is from 0.6 to 1 .5, preferably from 0.6 to 1 .0.

7. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 6, wherein the molar ratio of organic acid to nicotine is from 0.6 to 0.9, preferably from 0.6 to 0.8.

8. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 7, wherein the molar ratio of organic acid to nicotine is from 0.6 to 0.7.

9. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 8, wherein the molar ratio of the organic acid to nicotine is from 0.60 to 1.10.

10. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 9, wherein the molar ratio of the organic acid to nicotine is from 0.61 to 1.00, preferably from 0.62 to 0.90, more preferably from 0.62 to 0.80, and more preferably from 0.65 to 0.70.11 . The process according to any of claims 4 to 10, wherein step (c) comprises drying, preferably drying to attain a solid, such as in powder form, and optionally wherein the drying comprises heating to a temperature of from 20 to 130 °C, preferably from 30 to 100 °C, more preferably from 40 to 80 °C.

12. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 11 , wherein the inorganic carrier material is selected from silica, silicate salts, and silicate esters, preferably wherein the inorganic carrier material is selected from, silica and silicate salts, and optionally wherein the inorganic carrier material is amorphous.

13. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 12, wherein the inorganic carrier material is silica, and optionally wherein the inorganic carrier material is amorphous.

14. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 13, wherein the inorganic carrier material has a D5O particle size of from 1 to 700 pm, preferably from 50 to 600 pm, or from 100 to 500 pm.

15. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 14, wherein the inorganic carrier material has a D5O particle size of from 200 to 700 pm, such as from 250 to 600 pm, or from 300 to 500 pm.

16. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 15, wherein the nicotine source comprises less than 20% moisture content, preferably less than 15% moisture content, and more preferably less than 10% moisture content.

17. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 16, wherein the nicotine source comprises 20 wt.% or less of nicotine, preferably 18 wt.% or less, more preferably 16 wt.% or less.

18. The process according to any of claims 4 to 17, wherein in step (a), the nicotine and organic acid is combined with an organic solvent.

19. The process according to any of claims 4 to 18, wherein the organic solvent is selected from ethanol, hexane, heptane, and ethyl acetate, or combinations thereof, more preferably selected from ethanol, hexane, and ethyl acetate, or combinations thereof, more preferably selected from ethanol and hexane, or combinations thereof, and more preferably ethanol.

20. The process according to any of claims 4 to 17, wherein in step (a), the nicotine and organic acid is combined with water.

21. The process according to any of claims 4 to 20, wherein in step (b), additional water and / or additional organic solvent is introduced, preferably in an amount of 10 times or more of the amount of inorganic carrier material used in step (b), preferably 6 times or more, or 4 times or more of the amount of the inorganic carrier material.

22. The process according to any of claims 4 to 21 , wherein in step (a), the ratio of the amount of organic acid to water and / or organic solvent (organic acid: water and / or organic solvent) is from 1 :2 to 1 :6, preferably from 1 :3 to 1 :5, and more preferably 1 :4.

23. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 22, wherein the nicotine is derived from tobacco or is synthetic nicotine, preferably wherein the nicotine is (S) nicotine.

24. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 23, wherein the organic acid is a carboxylic acid, preferably wherein the organic acid is a hydroxy carboxylic acid, more preferably an a-hydroxy carboxylic acid.

25. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 24, wherein the organic acid is selected from gluconic acid, citric acid, malic acid, formic acid, acetic acid, propionic acid, butyric acid, 2-methylbutyric acid, 3-methylbuthric acid, valeric acid, benzoic acid, phenylacetic acid and pyruvic acid.

26. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 25, wherein the organic acid is selected from citric acid, malic acid, benzoic acid, and butyric acid, preferably the organic acid is selected from malic acid and citric acid, and more preferably is citric acid.

27. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 26, wherein the nicotine-organic acid salt isselected from nicotine gluconate, nicotine citrate, nicotine dicitrate, nicotine hemicitrate, nicotine malate, nicotine formate, nicotine acetate, nicotine propionate, nicotine butyrate, nicotine 2-methylbutyrate, nicotine 3- methylbutyrate, nicotine valerate, nicotine benzoate, nicotine phenylacetate, and nicotine pyruvate.

28. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 27, wherein the nicotine-organic acid salt is selected from nicotine citrate, nicotine malate, nicotine benzoate, and nicotine butyrate, preferably from nicotine citrate and nicotine malate, and more preferably is nicotine citrate.

29. The nicotine source, composition, nicotine oral delivery product, or process according to any of claims 1 to 28, wherein the nicotine source comprises 5 to 14 wt.% organic acid, preferably from 5 to 13 wt.% organic acid, or from 5 to 10 wt.% organic acid.

30. A nicotine source comprising a nicotine-organic acid salt, and optionally nicotine, carried on an inorganic carrier material, wherein the nicotine source is obtainable by the process according to any of claims 4 to 29.

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