Composition comprising nicotine, corresponding method and use

Abstract

The invention relates to a composition comprising or consisting of nicotine and water. The invention also relates to a method of preparing an article comprising the step of contacting nicotine and water to give a corresponding composition. The invention further relates to the use of a corresponding composition to stabilize nicotine. Moreover, the invention relates to the use of a corresponding composition as an intermediate product in the manufacture of an article.

Description

[0001] Composition comprising nicotine, corresponding method and use

[0002] Description

[0003] The present invention relates to a composition comprising or consisting of nicotine and water. The invention also relates to a method of preparing an article comprising the step of contacting nicotine and water to give a corresponding composition. The invention further relates to the use of a corresponding composition to stabilize nicotine. Moreover, the invention relates to the use of a corresponding composition as an intermediate product in the manufacture of an article.

[0004] Background

[0005] Nicotine is a component of numerous tobacco products, many of which are related to det- rimental health issues. Various methods and systems have been developed for providing nicotine without the presence of tobacco plant tissue. Common ways to provide tobacco- free nicotine include transdermal patches, lozenges, nicotine chewing gums, creams, tablets, nasal sprays, and electric cigarettes.

[0006] Nicotine, or 3-(1 -methyl-2-pyrrolidinyl) pyridine, is a tertiary amine with the following struc- ture (I):

[0007] Under ambient conditions, nicotine is an oily, volatile, hygroscopic, colourless liquid that is sensitive to light and air. Upon exposure to air, it readily oxidizes, resulting in the formation of a number of oxidation products, such as myosmine, cotinine, and nicotine N-oxides. These oxidation products not only affect smell and taste of the nicotine containing article, but also affect the colour, turning it into a light to dark brown depending on the degree of oxidation.

[0008] Although removal of these impurities is possible, e.g. via rectification, this results in loss of material. Additionally, purification requires significant efforts in terms of time and resources to remove the oxidation products.

[0009] Preventing the oxidation of nicotine by now requires significant technological effort, and e.g. utilization of expensive inert gases, special packaging and potentially cold storage. This greatly increases the cost of handling and storing nicotine.

[0010] In an effort to reduce potential processing and stability issues associated with the nicotine compound, a number of nicotine complexes have been developed. For example, one method includes the preparation of a complex of nicotine and an ion exchange resin. A well-known complex that is currently used in commercially available consumer products, e.g. nicotine chewing gums, is nicotine polacrilex, which is a complex of nicotine and the cation exchange resin AMBERLITE ® IPR-64 (EP 2198865 A1).

[0011] However, for the preparation of nicotine containing products nicotine polacrilex cannot always be directly used. In many cases, at least one further step is necessary to release the nicotine from the complex in order to produce the final product, like for example nicotine containing beverages or nicotine containing liquids for use in electronic cigarettes.

[0012] WO 2022219310 A1 (an equivalent of US 2024 / 188620 A1) discloses the use of calcium silicate as a support for nicotine suitable both for compositions for oral administration and for use in an inhalation device. Again, not all nicotine-containing products can be easily prepared from the supported nicotine.

[0013] CN 108254233 A discloses a kind of nicotine solution standard substances and its preparation method and application. The solvent in the standard substance is isopropanol or water, and the concentration of the nicotine solution is 5.00-9.80 mg / mL. According to the document, good stability is achieved under specific storage conditions, i.e. when the solution is stored in dark containers at -18°C.

[0014] WO 2022216320 A1 discloses liquid mixtures including triglyceride and liquid nicotine, and oral nicotine products including the liquid mixtures. The document teaches that antioxidants are necessary to stabilize nicotine. The antioxidant may include scorbyl palmitate, butylated hydroxytoluene (BHT), ascorbic acid, sodium ascorbate, monosterol citrate, tocopherols, propyl gallate, tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), Vitamin E, and any combination or derivative thereof.

[0015] Similarly, WO 2016 / 071705 teaches a nicotine solution comprising a carrier; one or more acids, wherein at least benzoic acid, levulinic acid or a mixture thereof is present as preservatives; and water in an amount of 1 to 50 wt.% based on the solution. The solution is intended for use in an electronic vaporizer. It was found that with solutions containing benzoic acid and / or levulinic acid less production of degradation products compared to many other acids was observed upon heating and vaporizing the solution.

[0016] WO 2017117575 A1 discloses a composition suitable for use in nicotine replacement therapy products which includes a nicotine product that includes a synthetic nicotine that is substantially free of one or more contaminants and / or impurities normally associated with tobacco-derived nicotine. The composition may comprise about 0.001 wt.% to about 25 wt.% of the nicotine product based on the total weight of the nicotine replacement composition, and one or more pharmaceutically acceptable excipients, additives and / or carriers (e.g., solvents). The solvent may be water in an amount of about 50 wt.% to about 99.99 wt.%, or water may be present in an amount of about 0.1 to about 10 wt.%, based on the total weight of the composition. According to the invention, fats and oils can be included in the nicotine replacement composition to improve its stability.

[0017] In US 20200383372 A1 , a nicotine pouch composition is disclosed, the pouch composition comprising free-base nicotine and having a water content of at least 15% by weight of said pouch composition. In WO 1991009731 A1 water is described as a degradation agent, which has to be avoided by a suitable barrier around the nicotine.

[0018] The importance of the pH of (aqueous extracts of) tobacco products for the stability of the nicotine in the tobacco products is expressed in GB1495941 A and GB2234663 A.

[0019] None of the water containing nicotine products without any stabilizing excipient have been examined for stability at room temperature.

[0020] Now it has surprisingly been found that the degradation of nicotine can be reduced by water, if it is employed in a certain amount with respect to the nicotine.

[0021] Figure 1 shows the amounts of cotinine, myosmine and nicotine N-oxides in a sample of neat nicotine over time if no water is present.

[0022] Figure 2 shows the amounts of cotinine, myosmine and nicotine N-oxides over time in a sample according to the invention comprising nicotine and 16.5 wt.% water.

[0023] Figure 3 shows the amounts of cotinine, myosmine and nicotine N-oxides over time in a sample not according to the invention comprising nicotine and 9.2 wt.% water.

[0024] Figure 4 shows the amount of nicotine over time for samples comprising nicotine and different amounts of water.

[0025] The present invention

[0026] The present invention relates, in its categories, to a composition comprising or consisting of water and nicotine, a method for preparing an article comprising the composition, the use of the composition for stabilizing nicotine and the use of the composition in the manufacture of an article. Variants, aspects or properties that are described in connection with one of these categories or described as preferred are each correspondingly or analogously applicable to the respective other categories, and vice versa.

[0027] Unless stated otherwise, preferred aspects or variants of the invention and their various categories can be combined with other aspects or variants of the invention and their various categories, especially with other preferred aspects or variants. The combination of respectively preferred aspects or variants with one another again results in preferred aspects or variants of the invention.

[0028] Detailed description

[0029] According to a first aspect the invention relates to a composition comprising or consisting of water and nicotine, wherein the respective concentrations are:

[0030] 10 to 60 wt.% water, and

[0031] 40 to 90 wt.% nicotine, based on the total weight of the composition.

[0032] Surprisingly, a composition according to the present invention, when stored with contact to air, i.e. when exposed to air, retains a higher amount of nicotine (e.g. determined by HPLC and UV-absorption), develops lower amounts of degradation (i.e., oxidation) products of nicotine (e.g. determined by HPLC and UV-absorption) and shows less undesired coloration. This may also be referred to as “stabilisation” or “stability” when used in the context of nicotine and its storage in contact with air.

[0033] Preferably, the nicotine in the composition according to the present invention (or in the composition according to the present invention which is described herein as being preferred) is present in liquid form, and preferably the water is dissolved in the nicotine-con- taining phase. Preferably, the composition according to the present invention (or a composition according to the present invention which is described herein as being preferred) is a liquid composition, preferably a liquid solution. Preferably, at 25 °C the composition according to the present invention is a homogenous (liquid) solution.

[0034] Preferably the composition of the invention comprises or consists of water and nicotine, wherein the respective concentrations are:

[0035] 10.0 to 60.0 wt.% water, and 40.0 to 90.0 wt.% nicotine, more preferably 10.00 to 60.00 wt.% water, and 40.00 to 90.00 wt.% nicotine, based on the total weight of the composition.

[0036] If the composition of the invention comprises water and nicotine, wherein the respective concentrations are:

[0037] 10 to 60 wt.% water, and

[0038] 40 to 90 wt.% nicotine, based on the total weight of the composition, the total concentration of water and nicotine is at least 50 wt.% (10 wt.% water plus 40 wt.% nicotine). Thus, other components / additives in a total concentration of at most 50 wt.% can be present.

[0039] All percentages defined in the context of the definition of compositions of the present invention are based on the total weight of the composition (which constitutes 100 wt.%), throughout the present description and claims, if not indicated otherwise.

[0040] Preferred compositions of the present invention are discussed herein below. If not stated otherwise, preferred features of such preferred compositions can be combined and corresponding compositions having combined preferred features are particularly preferred.

[0041] All aspects discussed in the context of preferred compositions of the present invention also apply to the methods and the uses of the present invention, mutatis mutandis.

[0042] Preferably, the total amount of water and nicotine in the composition of the present invention is above 90.00 wt.%, more preferably above 95.00 wt.%, even more preferably above 99.00 wt.%, still even more preferably 99.50 wt.%, most preferably above 99.90 wt.%.

[0043] The high content of water and nicotine and therefore the low content of other components and / or additives leads to lower required efforts for removing substances that are undesired in a nicotine containing product that is to be prepared from the composition of the present invention. When work-up is not considered, for the sake of the discussion, lower amounts of further components or additives in the composition of the present invention lead to lower amounts of such further components or additives in a final product prepared from the composition of the present invention. These lower amounts will less likely influence or even distort the taste, smell and / or the physiological properties of the products.

[0044] The composition of the present invention surprisingly does not need the presence of any of the stabilizing agents or additives typically used in the industry in order to preserve or stabilize substances that are sensitive to oxidization. Preferably, the composition of the present invention does not comprise any of those stabilizing agents or additives.

[0045] In more detail:

[0046] Preferably, the composition according to the present invention does not comprise any substance selected from the group consisting of ascorbic acid, sodium ascorbate, ascorbyl palmitate, natural tocopherols, synthetic tocopherols, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, and monosterol citrate. Thus, specifically the composition according to the present invention does preferably not comprise any substance selected from the group as listed in accordance with the International Numbering System (INS) for Food Additives: Ascorbic acid (INS300), sodium ascorbate (INS301), ascorbyl palmitate (INS304), natural tocopherols / Vitamin E (INS306), synthetic tocopherols (INS307 to INS309), propyl gallate (INS310), tertiary butylhydroquinone, TBHQ, (INS319), butylated hydroxyanisole, BHA, (INS320), butylated hydroxytoluene, BHT, (INS321), and monosterol citrate.

[0047] The International Numbering System for Food Additives (INS) is a harmonized naming system for food additives as an alternative to the use of the specific name. The numbers are listed by the World Health Organization and the Food and Agriculture Organization of the United Nations as part of the Codex Alimentarius with the reference CXG 36-1989, which was adopted in 1989, revised in 2008 and amended in 2018, 2019, 2021 , 2023. Wherever the present text refers to the INS, it refers to the amended version of 2023.

[0048] More preferably, the composition according to the present invention does not comprise any substance selected from the group consisting of the Numbers 300 to 321 of the International Numbering System for Food Additives, and monosterol citrate. The numbers 300 to 321 are a section of the list of INS numbers that relates to compounds with an antioxidant purpose. Even more preferably the composition does not contain any substance selected from the group consisting of the Numbers 300 to 324 of the International Numbering System for Food Additives, and monosterol citrate. This (extended) section of the list contains further known antioxidants.

[0049] Still even more preferably the composition does not contain any substance selected from the group consisting of the Numbers 300 to 340 of the International Numbering System for Food Additives, and monosterol citrate. This (further extended) section of the list contains further known antioxidants, such as phosphates which are approved additives in the EU.

[0050] Most preferably the composition does not contain any substance selected from the group consisting of Numbers 300 to 399 of the International Numbering System for Food Additives, and monosterol citrate. Within the EU classification, the corresponding numbers E300 to E399 make up the group of “antioxidants, acidity regulators”.

[0051] Preferably, the composition according to the present invention does not comprise any substance selected from the group consisting of benzoic acid and levulinic acid.

[0052] More preferably the composition does not contain any substance selected from the group consisting of the Numbers 200 to 220 of the International Numbering System for Food Additives, and levulinic acid. The numbers 200 to 220 are a section of the list of INS numbers that relates to compounds with solely a preservative purpose.

[0053] Even more preferably the composition does not contain any substance selected from the group consisting of the Numbers 200 to 290 of the International Numbering System for Food Additives, and levulinic acid. This (extended) section of the list contains further known preservatives, and additives that serve more than one purpose, but including preservation.

[0054] Preferably, benzoic acid and levulinic acid and more preferably benzoic acid, levulinic acid and other acids are not used in a process of preparing a composition of the present invention, are not present in the composition of the present invention itself, and are not used in a process of preparing an article of the present invention (see below for details). The composition of the present invention preferably does not comprise a nicotine salt.

[0055] Preferably, in a composition according to the present invention the total amount of substances selected from the group consisting of radical scavengers and sacrificial reductants is below 2 wt.%, preferably below 1 wt.%, more preferably below 0.5 wt. %, most preferably below 0.2 wt.%, especially below 0.1 wt.%, based on the total amount of the composition.

[0056] More preferably the composition does not comprise any substance selected from the group consisting of radical scavengers and sacrificial reductants.

[0057] Radical scavengers and / or sacrificial reductants are the common substances to prevent oxidation of a compound, including auto-oxidation, i.e. the gradual degradation of organic compounds in air at ambient temperatures.

[0058] The composition having low amounts of radical scavengers and sacrificial reductants or even none, in many situations reduces the amount of required work-up of the composition in order to prepare a specific product.

[0059] In many cases a composition according to the present invention comprises one, two or more compounds selected from the group consisting of myosmine, cotinine, and nicotine N-oxide. These compounds are typical minor components in nicotine containing compositions, and as such they are widely accepted by consumers.

[0060] In such a composition of the present invention preferably the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 1.0 area %, preferably below 0.45 area %, more preferably below 0.25 area %, even more preferably below 0.15 area %, most preferably below 0.05 area %, based on the total amount of alkaloids, determined by HPLC and UV-absorption. If not stated otherwise, determination of the amount of nicotine and other alkaloids by HPLC and UV-absorption (using a 254 nm UV absorption detector) is done according to the quality standards of the European Pharmacopoeia (Ph. Eur. 11thedition) and / orthe United States Pharmacopeia (USP-NF 2024, Issue 1). Specifics of the measuring method are described below.

[0061] Preferably, the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 1.0 area %, preferably below 0.45 area %, more preferably below 0.25 area %, even more preferably below 0.15 area %, most preferably below 0.05 area %, based on the total amount of nicotine, myosmine, cotinine, and nicotine N-oxide, determined by HPLC and UV-absorption.

[0062] Myosmine, cotinine, and nicotine N-oxide are products frequently observed in the autoxi- dation of nicotine. They do not have the same pharmacological effect as nicotine. Cotinine for example only retains about 1 / 100 of the effect of nicotine. The autoxidation of nicotine therefore not only leads to a change in colour, taste and smell but also lowers the desired pharmacological effectiveness of a nicotine product.

[0063] Also preferably, the composition comprises nicotine and other alkaloids (e.g., myosmine, cotinine, nicotine N-oxide, nornicotine, anatabine, anabasine, and beta-nicotyrine), wherein the total amount of other alkaloids in the composition is below 1 .0 area %, preferably below 0.45 area %, more preferably below 0.25 area %, even more preferably below 0.15 area %, most preferably below 0.05 area %, based on the total amount of nicotine and other alkaloids, determined by HPLC and UV absorption (using a 254 nm UV absorption detector, see below for details).

[0064] Preferred is a composition according to the present invention which comprises below 0.1 area %, preferably below 0.05 area% of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0065] Also preferred is a composition according to the present invention comprising below 0.1 area %, preferably below 0.05 area% of nicotine N-oxide, based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0066] Alternatively preferred is a composition according to the present invention comprising below 0.1 area %, preferably below 0.05 area% of myosmine, based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0067] Also preferred is a composition according to the present invention comprising below 0.1 area %, preferably below 0.05 area% of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption, and below 0.1 area %, preferably below 0.05 area% of nicotine N-oxide, based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0068] Also preferred is a composition according to the present invention comprising below 0.1 area %, preferably below 0.05 area% of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption, and below 0.1 area %, preferably below 0.05 area% of myosmine, based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0069] Also preferred is a composition according to the present invention comprising below 0.1 area %, preferably below 0.05 area% of nicotine N-oxide based on the total amount of alkaloids, determined by HPLC and UV-absorption, and below 0.1 area %, preferably below 0.05 area% of myosmine, based on the total amount of nicotine, myosmine, cotinine, and nicotine N-oxide, determined by HPLC and UV- absorption.

[0070] Also preferred is a composition according to the present invention comprising below 0.1 area %, preferably below 0.05 area% of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption, and below 0.1 area %, preferably below 0.05 area% of nicotine N-oxide, based on the total amount of nicotine, myosmine, cotinine, and nicotine N-oxide, determined by HPLC and UV-absorption, and below 0.1 area %, preferably below 0.05 area% of myosmine, based on the total amount of nicotine, myosmine, cotinine, and nicotine N-oxide, determined by HPLC and UV- absorption.

[0071] The alkaloids myosmine, cotinine and nicotine N-oxide are oxidation and degradation products of nicotine which can change the taste, smell and coloration of nicotine and nicotine- containing products. Keeping the amounts of those alkaloids low reduces these unwanted changes and eliminates the need to rectify nicotine-comprising compositions after storing.

[0072] Preferred is a composition comprising or consisting of water and nicotine according to the present invention which has been found to be particularly beneficial, wherein the respective concentrations (of water and nicotine) are:

[0073] 10 to 60 wt.% water, and 40 to 90 wt.% nicotine, based on the total weight of the composition, and the total amount of water and nicotine is above 90.00 wt.% and wherein the composition comprises below 0.1 area % of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or below 0.1 area % of nicotine N-oxide, based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or below 0.1 area % of myosmine, based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or the composition comprises one, two or more compounds selected from the group consisting of myosmine, cotinine, and nicotine N-oxide, wherein the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 1.0 area % based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0074] Preferably the concentration of water in the composition of the present invention is 12 to 50 wt.%, preferably 15 to 45 wt.%, more preferably 20 to 42 wt.%, most preferably 30 to 40 wt.%, based on the total weight of the composition.

[0075] Also preferably, the respective concentrations of water and nicotine in the composition of the present invention are:

[0076] 12 to 50 wt.% water, and 50 to 88 wt.% nicotine, based on the total weight of the composition, more preferably

[0077] 15 to 45 wt.% water, and 55 to 85 wt.% nicotine, based on the total weight of the composition, even more preferably

[0078] 20 to 42 wt.% water, and 58 to 80 wt.% nicotine, based on the total weight of the composition most preferably 30 to 40 wt.% water, and 60 to 70 wt.% nicotine, based on the total weight of the composition.

[0079] More preferably, the concentration of water in the composition of the present invention is 12 to 50 wt.%, preferably 15 to 45 wt.%, more preferably 20 to 42 wt.%, most preferably 30 to 40 wt.%, based on the total weight of the composition, and the respective concentrations of water and nicotine are:

[0080] 12 to 50 wt.% water, and 50 to 88 wt.% nicotine, based on the total weight of the composition, preferably

[0081] 15 to 45 wt.% water, and 55 to 85 wt.% nicotine, based on the total weight of the composition, more preferably

[0082] 20 to 42 wt.% water, and 58 to 80 wt.% nicotine, based on the total weight of the composition most preferably

[0083] 30 to 40 wt.% water, and 60 to 70 wt.% nicotine, based on the total weight of the composition.

[0084] Preferably the water in the composition of the present invention is selected from the group consisting of

[0085] H2O, pharmaceutical grade water, distilled water, deionized water, demineralized water, tap water, and drinking water.

[0086] Drinking water can be specified according to the standards regulated by the U.S. Environmental Protection Agency National Primary Drinking Water Regulations (USP-NF 2024, Issue 1), by regulations of the European Union, Japan or the World Health Organization (WHO). Pharmaceutical grade water or active pharmaceutical ingredient (API) purified water is produced according to good manufacturing practices (GMP) as specified by the WHO, the European Union or the U.S Food and Drug Administration (FDA) and in the respective Pharmacopoeias.

[0087] Using purified water (distilled, deionized, demineralized, pharmaceutical grade) is particularly preferred and has the advantage of incorporating lower amounts of solvated inorganic ions or even organic and biologic impurities, which may not be fully known for other sources of water. From a cost perspective, it may be beneficial to select tap or drinking water, if the purity is less of a concern. The terms used for characterizing the preferred water for use in compositions of the present invention are terms used in the art. The terms identify and define water qualities, and insofar they overlap to a certain extent.

[0088] Most preferably, the water in the composition of the present invention is pharmaceutical grade water.

[0089] Particularly preferred is a composition of the present invention consisting of or comprising

[0090] 15 to 45 wt.% water, and 55 to 85 wt.% nicotine, based on the total weight of the composition, wherein the water is selected from the group consisting of H2O, pharmaceutical grade water, distilled water, deionized water, demineralized water , tap water and drinking water; the composition does not contain any substance selected from the group consisting of Numbers 300 to 399 of the International Numbering System for Food Additives, does not contain monosterol citrate, and does not contain any substance selected from the group consisting of radical scavengers and sacrificial reductants, and wherein the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 0.45 area %, preferably below 0.15 area % based on the total amount of alkaloids, determined by HPLC and UV-absorption.

[0091] Preferably, such a preferred composition maintains these criteria during storage at 25 °C in the presence of air at 1013 hPa for 1 week or more, 2 weeks or more, or more preferably 3 weeks or more.

[0092] The present invention also relates to a method of preparing an article, comprising the step of contacting nicotine and water to give a composition according to the present invention, as defined above and in the accompanying claims optionally comprising the additional step of using the composition as an intermediate product in the preparation of the article.

[0093] As stated above, the disclosure regarding preferred compositions of the present invention also applies to the method of the present invention, mutatis mutandis, and vice versa.

[0094] Preferably the article prepared in accordance with the preparation method of the present invention is selected from the group consisting of compositions of the present invention as described above and as defined in the claims, nicotine polacrilex, nicotine bitartrate, and articles comprising one or both of nicotine polacrilex and nicotine bitartrate, and articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article comprises nicotine, nicotine polacrilex and / or nicotine bitartrate.

[0095] By contacting nicotine and water the described compositions of the present invention can be prepared in an expedient manner. The obtained composition can be an intermediate product in a method of preparing other nicotine containing articles.

[0096] In particular, the composition of the present invention, as preferably prepared according to a method of the present invention, can be a suitable intermediate for preparing nicotine polacrilex, nicotine bitartrate, and articles comprising one or both of nicotine polacrilex and nicotine bitartrate.

[0097] The composition of the present invention, as preferably prepared according to a method of the present invention, is also a suitable intermediate for preparing articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article comprises nicotine, nicotine polacrilex and / or nicotine bitartrate.

[0098] The present invention also relates to the use of a composition according to the present invention, as defined above and / or in the accompanying claims, and preferably as prepared according to a method of the present invention, for stabilizing nicotine during storage in the presence of air or another oxygen containing gas. Stabilizing refers to reduced oxidation or other degradation of nicotine over time, compared to nicotine or to a nicotine composition not comprising any stabilizing agent or the like, under otherwise identical storage conditions. The degradation can be quantified by HPLC measurement of nicotine and the resulting alkaloids, or observed qualitatively by changes of colour, smell and / ortaste of the composition.

[0099] Preferably, the invention relates to the use of a composition comprising or consisting of water and nicotine, wherein the respective concentrations are:

[0100] 10 to 60 wt.% water, and

[0101] 40 to 90 wt.% nicotine, based on the total weight of the composition, wherein the total amount of water and nicotine is above 90.00 wt.%, for stabilizing nicotine during storage in the presence of air or another oxygen containing gas. Preferably, the duration of the storage in the use according to the present invention is 10 days or longer, more preferably 20 days or longer, even more preferably 50 days or longer, most preferably 200 days or longer.

[0102] Also preferably the temperature during storage is in the range of from 10 to 50 °C, more preferably in the range of from 18 to 30 °C.

[0103] Similarly preferably, the composition has direct contact to ambient air during storage.

[0104] In another preferred variant, the duration of the storage is 10 days or longer, preferably 20 days or longer, more preferably 50 days or longer, most preferably 200 days or longer and the temperature during storage is in the range of from 10 to 50 °C, preferably in the range of from 18 to 30 °C.

[0105] In another preferred variant, the duration of the storage is 10 days or longer, preferably 20 days or longer, more preferably 50 days or longer, most preferably 200 days or longer and the composition has direct contact to ambient air.

[0106] In another preferred variant, the temperature during storage is in the range of from 10 to 50 °C, preferably in the range of from 18 to 30 °C and the composition has direct contact to ambient air.

[0107] In still another preferred variant, the duration of the storage is 10 days or longer, preferably 20 days or longer, more preferably 50 days or longer, most preferably 200 days or longer and the temperature during storage is in the range of from 10 to 50 °C, preferably in the range of from 18 to 30 °C and the composition has direct contact to ambient air.

[0108] The invention also relates to the use of the composition of the present invention and / or prepared according to the present invention, as an intermediate product in the manufacture of an article selected from the group consisting of nicotine polacrilex, nicotine bitartrate, and articles comprising one or both of nicotine polacrilex and nicotine bitartrate, and nicotine-containing articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article com-prises nicotine, nicotine polacrilex and / or nicotine bitartrate.

[0109] In particular preferred is the use of a composition comprising or consisting of water and nicotine, wherein the respective concentrations are:

[0110] 10 to 60 wt.% water, and

[0111] 40 to 90 wt.% nicotine, based on the total weight of the composition, wherein the total amount of water and nicotine is above 90.00 wt.%, or of the composition of the present invention (as defined herein) and / or prepared according to the method (of preparing an article) of the present invention, as an intermediate product in the manufacture of an article selected from the group consisting of nicotine bitartrate, and articles comprising both of nicotine polacrilex and nicotine bitartrate, and nicotine-containing articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article comprises nicotine and / or nicotine bitartrate.

[0112] Also particularly preferred is the use of the composition according to the present invention (as defined herein) or prepared according to the method (of preparing an article) of the present invention, as an intermediate product in the manufacture of an article selected from the group consisting of nicotine polacrilex, nicotine bitartrate, and articles comprising one or both of nicotine polacrilex and nicotine bitartrate, and nicotine-containing articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article com-prises nicotine, nicotine polacrilex and / or nicotine bitartrate.

[0113] The present invention also relates to the use of water for stabilizing nicotine against oxidation. Herein, water is preferably used to prepare a composition according to the present invention (as discussed above and as defined in the claims). This composition provides for the stabilization. Examples

[0114] The determination of the respective amounts of nicotine, myosmine, cotinine, nicotine N- oxides and other alkaloid impurities is conducted based on the methods published in the monographs concerning nicotine by the European Pharmacopoeia (Ph. Eur. 11thedition) and the United States Pharmacopeia (USP-NF 2024, Issue 1), and meeting the quality criteria stated therein. Specifically, the compounds are separated at room temperature by liquid chromatography on a 4.6-mm x 15-cm column with 5-pm packaging of end-capped polar-embedded octadecylsilyl amorphous organosilica polymer. The starting eluent is 100 % 25 mM ammonium acetate buffer at a pH value of 9.8 to 10, with an increasing amount of acetonitrile from 5 V / V % to 26 V / V % between 3 minutes and 28 minutes of elution and in a second step to 40 V / V % between 28 and 32 minutes. A flow rate of 1.0 mL / min is used for an injection volume of 20 pL of nominally 0.3 to 0.8 mg / mL nicotine dissolved in deionized water. After eluting, nicotine and other alkaloids are detected using a 254 nm UV absorption detector and attributed according to their known elution times. In the examples, quantification is done by considering the areas of the respective peaks in the chromatogram relative to the total area of the alkaloid peaks (including the peaks for nicotine, myosmine, cotinine, and nicotine N-oxides as well as the peaks of other alkaloids) in the chromatogram. For quantitative determination, compounds that are detectable using a 254 nm UV absorption detector are considered to be alkaloids.

[0115] 19.84 g of pure, rectified nicotine (>99.6 area % nicotine by HPLC) is placed in a flask, blanketed with air, and stirred at room temperature. The colour of the initially colourless and clear sample turns brownish after one day under these conditions. After three weeks, HPLC analysis shows a mixture with 93.72 area % nicotine, 1.5 area % myosmine, 1 .56 area % cotinine and 0.95 area % nicotine N-oxides (cis and trans). Balance are other minor and unknown alkaloid impurities. Figure 1 shows the amounts of cotinine, myosmine and nicotine N-oxides in a sample of neat nicotine over time if no water is present.

[0116] 20.01 g of pure, rectified nicotine (>99.99 area % nicotine) is charged to a flask, and 3.95 g water is added, resulting in a water / nicotine mixture of ca. 16.5 wt.% water and 83.5 wt.% nicotine based on the total weight of the composition (waternicotine 1 :5 wt / wt). The content is blanketed with air and stirred at room temperature. After three weeks, HPLC analysis shows a mixture with 99.99 area % nicotine, 0.01 area % myosmine and no detectable other impurities. The sample remains a clear and colourless mixture. Figure 2 shows the amounts of cotinine, myosmine and nicotine N-oxides over time in a sample according to the invention comprising nicotine and 16.5 wt.% water.

[0117] 18.3 g of pure, rectified nicotine (>99.96 area% nicotine) is charged to a flask, and 1.85 g water is added, resulting in a water / nicotine mixture of ca. 9.2 wt.% water and 90.8 wt.% nicotine based on the total weight of the composition (waternicotine ca. 1 :10 wt / wt). The content is blanketed with air and stirred at room temperature. After two weeks, HPLC analysis shows a mixture with 98.42 area % nicotine, 0.3 area % myosmine, 0.38 area % cotinine and 0.32 area % nicotine N-oxides (cis and trans). Balance are other, unknown alkaloid impurities. The initially clear and colourless sample turns pale yellow in that time. Figure 3 shows the amounts of cotinine, myosmine and nicotine N-oxides over time in a sample not according to the invention comprising nicotine and 9.2 wt.% water.

[0118] Pure, rectified nicotine (>99.94 area% nicotine) is charged to a flask, and water is added, resulting in a water / nicotine mixture of ca. 4.8 wt.% water and 95.2 wt.% nicotine based on the total weight of the composition (waternicotine ca. 1 :20 wt / wt). The content is blanketed with air and stirred at room temperature. After two weeks, HPLC analysis shows a mixture with 92.48 area % nicotine, 1 .62 area % myosmine, 1 .75 area % cotinine and 1 .77 area % nicotine N-oxides (including cis and trans). Balance are other, unknown alkaloid impurities.

[0119] Example 5

[0120] Pure, rectified nicotine (100 area% nicotine) is charged to a flask, and water is added, resulting in a water / nicotine mixture of ca. 30 wt.% water and 70 wt.% nicotine based on the total weight of the composition. The content is blanketed with air and stirred at room temperature. After three weeks, HPLC analysis shows no sign of impurities and 100 area % nicotine. Pure, rectified nicotine (100 area% nicotine) is charged to a flask, and water is added, resulting in a water / nicotine mixture of ca. 40 wt.% water and 60 wt.% nicotine based on the total weight of the composition. The content is blanketed with air and stirred at room temperature. After three weeks, HPLC analysis shows no sign of impurities and 100 area % nicotine.

[0121] Example 7

[0122] Pure, rectified nicotine (100 area% nicotine) is charged to a flask, and water is added, resulting in a water / nicotine mixture of ca. 60 wt.% water and 40 wt.% nicotine. The content is blanketed with air and stirred at room temperature. After three weeks, HPLC analysis shows no sign of impurities and 100 area % nicotine.

[0123] Figure 4 shows the amount of nicotine over time for samples comprising nicotine and different amounts of water.

[0124] Assessment of results:

[0125] It has surprisingly been found that the compositions according to the invention are remarkably stable against the decomposition of nicotine. The experiments have shown that over at least three weeks compositions comprising 16.5 to 60 wt.% water do not suffer from any significant decomposition of nicotine to other alkaloids or other compounds detectable by absorption of 254 nm radiation.

[0126] Compositions according to the invention correspondingly do not have to be stored under inert atmosphere, therefore suitable storage conditions are simpler and cheaper to fulfil.

[0127] This stabilization of nicotine is achieved without the addition of further antioxidants or preservatives which would have to be removed before using the composition in the manufacture of a nicotine product or which could alter the taste, smell or colour of the product. Furthermore, the composition of the present invention preferably has a pH value of 11 or more. The nicotine in such cases is free nicotine, whereas in other forms of storage nicotine may be present as a salt which is less suitable. Free nicotine can directly be used in the preparation of many nicotine products, i.e. nicotine bitartrate.

Claims

Claims1 . Composition comprising or consisting of water and nicotine, wherein the respective concentrations are:10 to 60 wt.% water, and40 to 90 wt.% nicotine, based on the total weight of the composition, wherein the total amount of water and nicotine is above 90.00 wt.% and wherein the composition comprises below 0.1 area % of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or below 0.1 area % of nicotine N-oxide, based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or below 0.1 area % of myosmine, based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or the composition comprises one, two or more compounds selected from the group consisting of myosmine, cotinine, and nicotine N-oxide, wherein the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 1.0 area % based on the total amount of alkaloids, determined by HPLC and UV-absorption.

2. Composition according to claim 1 , wherein the total amount of water and nicotine is above 95.00 wt.%, preferably above 99.00 wt.%, more preferably 99.50 wt.%, most preferably above 99.90 wt.%.

3. Composition according to claim 1 or 2, wherein the composition does not comprise any substance selected from the group consisting of ascorbic acid, sodium ascorbate, ascorbyl palmitate, natural tocopherols, synthetic tocopherols, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, and monosterol citrate, wherein the composition preferably does not comprise any substance selected from the group consisting of the Numbers 300 to 321 of the International Numbering System for Food Additives, and monosterol citrate,wherein the composition more preferably does not contain any substance selected from the group consisting of the Numbers 300 to 324 of the International Numbering System for Food Additives, and monosterol citrate, wherein the composition even more preferably does not contain any substance selected from the group consisting of the Numbers 300 to 340 of the International Numbering System for Food Additives, and monosterol citrate, and wherein the composition most preferably does not contain any substance selected from the group consisting of Numbers 300 to 399 of the International Numbering System for Food Additives, and monosterol citrate.

4. Composition according to any of the preceding claims, wherein the total amount of substances selected from the group consisting of radical scavengers and sacrificial reductants is below 2 wt.%, preferably below 1 wt.%, more preferably below 0.5 wt. %, most preferably below 0.2 wt.%, especially below 0.1 wt.%, based on the total amount of the composition, wherein the composition preferably does not comprise any substance selected from the group consisting of radical scavengers and sacrificial reductants.

5. Composition according to any of the preceding claims, comprising one, two or more compounds selected from the group consisting of myosmine, cotinine, and nicotine N-ox- ide, wherein the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 0.45 area %, preferably below 0.25 area %, more preferably below 0.15 area %, most preferably below 0.05 area %, based on the total amount of alkaloids, determined by HPLC and UV-absorption, wherein preferably the total amount of myosmine, cotinine, and nicotine N-oxide in the composition is below 1 .0 area %, preferably below 0.45 area %, more preferably below 0.25 area %, even more preferably below 0.15 area %, most preferably below 0.05 area %, based on the total amount of nicotine, myosmine, cotinine, and nicotine N-oxide, determined by HPLC and UV-absorption.

6. Composition according to any of the preceding claims, wherein the composition comprises below 0.05 area% of cotinine based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / orbelow 0.05 area% of nicotine N-oxide, based on the total amount of alkaloids, determined by HPLC and UV-absorption, and / or below 0.05 area% of myosmine, based on the total amount of alkaloids, determined by HPLC and UV-absorption.

7. Composition according to any of the preceding claims, wherein the concentration of water is:12 to 50 wt.%, preferably 15 to 45 wt.%, more preferably 20 to 42 wt.%, most preferably 30 to 40 wt.%, based on the total weight of the composition, and / or the respective concentrations of water and nicotine are:12 to 50 wt.% water, and 50 to 88 wt.% nicotine, based on the total weight of the composition, preferably15 to 45 wt.% water, and 55 to 85 wt.% nicotine, based on the total weight of the composition, more preferably20 to 42 wt.% water, and 58 to 80 wt.% nicotine, based on the total weight of the composition most preferably30 to 40 wt.% water, and 60 to 70 wt.% nicotine, based on the total weight of the composition.

8. Composition according to any of the preceding claims, wherein the nicotine in the composition is present in liquid form, preferably wherein the water is dissolved in the nico- tine-containing phase.

9. Composition according to any of the preceding claims, wherein the composition is a liquid composition, preferably a liquid solution, more preferably wherein, at 25 °C, the composition is a homogenous solution.

10. Composition according to any of the preceding claims, wherein the water is selected from the group consisting ofH2O, pharmaceutical grade water, distilled water,deionized water, demineralized water, tap water, and drinking water, preferably wherein the water is pharmaceutical grade water.11 . Method of preparing an article, comprising the step of contacting nicotine and water to give a composition according to any of claims 1 to10, optionally comprising the additional step of using the composition as an intermediate product in the preparation of the article.

12. Method according to claim 11 , wherein the article is selected from the group consisting of compositions according to any of claims 1 to 10, nicotine polacrilex, nicotine bitartrate, and articles comprising one or both of nicotine polacrilex and nicotine bitartrate, and articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article comprises nicotine, nicotine polacrilex and / or nicotine bitartrate.

13. Use of a composition comprising or consisting of water and nicotine, wherein the respective concentrations are:10 to 60 wt.% water, and40 to 90 wt.% nicotine, based on the total weight of the composition, wherein the total amount of water and nicotine is above 90.00 wt.%, or a composition according to any of claims 1 to 10, or prepared according to claim 11 or 12, for stabilizing nicotine during storage in the presence of air or another oxygen containing gas.

14. Use according to claim 13, wherein the duration of the storage is 10 days or longer, preferably 20 days or longer, more preferably 50 days or longer, most preferably 200 days or longer and / or the temperature during storage is in the range of from 10 to 50 °C, preferably in the range of from 18 to 30 °C and / or during storage, the composition has direct contact to ambient air.

15. Use of a composition comprising or consisting of water and nicotine, wherein the respective concentrations are:10 to 60 wt.% water, and40 to 90 wt.% nicotine, based on the total weight of the composition, wherein the total amount of water and nicotine is above 90.00 wt.%, or of the composition according to any of claims 1 to 10, or prepared according to claim 11 or 12, as an intermediate product in the manufacture of an article selected from the group consisting of nicotine bitartrate, and articles comprising both of nicotine polacrilex and nicotine bitartrate, and nicotine-containing articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article com-prises nicotine and / or nicotine bitartrate.

16. Use of the composition according to any of claims 1 to 10, or prepared according to claim 11 or 12, as an intermediate product in the manufacture of an article selected from the group consisting of nicotine polacrilex, nicotine bitartrate, and articles comprising one or both of nicotine polacrilex and nicotine bitartrate, and nicotine-containing articles selected from patches, lozenges, chewing gums, creams, tablets, nasal sprays, and electric cigarettes, wherein the article com-prises nicotine, nicotine polacrilex and / or nicotine bitartrate.

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