WO2023062109A1 - Oral formulations comprising nicotine salt - Google Patents

Abstract

An oral formulation comprising nicotine salt dissolved in an oil phase, which is provided in an air-tight containment.

Description

ORAL FORMULATIONS COMPRISING NICOTINE SALT

FIELD OF THE INVENTION

The present invention relates to an oral formulation comprising nicotine salt dissolved in an oil phase, which oral formulation is provided in an air-tight containment, as well as consumer products and pharmaceutical preparations comprising said oral formulation, and methods of producing the same.

BACKGROUND OF THE INVENTION

Presently marketed nicotine products, such as the transdermal nicotine patch and the nicotine chewing gum, are not entirely satisfactory in that they do not provide the consumer with the nicotine "buzz" which is commonly associated with smoking a cigarette. This is because both the patch and the gum are slowly acting controlled release systems where only low nicotine plasma levels are obtained.

The nicotine patch, when placed on the skin, will give a steady release of nicotine over 24 hours and should be changed daily. With the patch in place, it takes 3 to 4 hours to attain significant blood levels of nicotine. The continuous dosing provided by patches can disrupt the usual day/night variation in nicotine intake provided by smoking and can result in a total dose of nicotine per 24 hours exceeding the normal smoking dose. Moreover, it seems that if nicotine is given both night and day compared to only daytime, sleep disturbances and nightmares can result. Another potential side effect of the patch is skin irritation.

The nicotine chewing gum is a slow-release preparation where the rate of release of nicotine will depend on the rate of chewing. It takes 20 to 30 min of vigorous chewing to release 95% of the nicotine content of the gum. Without chewing or if the gum is accidently swallowed negligible amounts of nicotine are released. The gum contains 2 or 4 mg of nicotine. A typical smoker needs about 15 pieces of gum a day. The gum has an unpleasant taste and may be irritating to the mouth and throat. Potential side effects are heartburn and hiccups. Tired and aching jaws may be experienced from intensive chewing and users rarely maintain blood nicotine concentrations above one third of their levels from smoking. Furthermore, the chewing gum is contraindicated in individuals with gastritis or active peptic ulcer disease and presents difficulties for those wearing dentures. "Snus" or snuff is a tobacco mixture from which the consumer forms a portion and places it under the lip. Alternatively, the tobacco mixture is already pre-portioned into pouches which are placed under the lip. The use of "snus" normally results in nicotine blood levels with a rather high steady state nicotine blood concentration, but they do not provide the peak levels obtained from smoking. The reason for this is that nicotine is released too slowly from the "snus" product. Further, "snus" normally deliver only a fraction of the available nicotine to the user. After 30 minutes use, for a number of "snus" products, the delivery of nicotine is often less than 50%, for some products less than 25% of the available amount of nicotine.

Nicotine is generally in either base form or in salt form. Nicotine base is readily absorbed through mucosal membranes. Unfortunately, nicotine base is highly unstable and is difficult to contain using conventional packaging materials. Nicotine salts, on the other hand, are generally stable but they are not readily absorbed through mucosal membranes.

In the prior art, this problem was addressed by addition of a pH adjusting agent. US9402810B2, for example, discloses a pouch comprising a powdered composition containing nicotine salt and a pH adjusting agent, such as sodium carbonate, to increase the uptake of nicotine through the oral mucosa into the blood stream.

However, despite addition of a pH adjusting agent, blood nicotine levels are not always satisfactory, and the consumer gets a burning sensation on the mucosa when the pH adjusting agent and the nicotine salt start to dissolve.

In W02019110076A1 , the problem of poor absorption was addressed by increasing the concentration of nicotine in the oral formulation. However, higher nicotine concentrations take longer to dissolve and also result in an enhanced burning sensation, which limits the amount of nicotine that can be used in an oral formulation.

US2011200670A1 discloses soft gelatin pastilles for nicotine replacement therapy.

Perfetti (1983) discloses the structural study of nicotine salts.

Pisinger et al. (2021) disclose novel tobacco and nicotine delivery products and types of devices.

Therefore, there is a need for improved means of fast and efficient nicotine delivery to consumers, without the side effect of an unpleasant burning sensation. SUMMARY OF THE INVENTION

It is the objective of the present invention to provide an oral formulation for fast and effective absorption of nicotine through the oral mucosa, which formulation does not have the side effect of an unpleasant burning sensation.

The objective is solved by the subject of the claims and as further described herein.

Surprisingly, it was found that nicotine salt can be dissolved in an oil phase, such as e.g., MCT oil, and that such liquid formulation of nicotine salts and oil is absorbed through the oral mucosa in such a fast and efficient way that it provides the consumer with the nicotine "buzz" which is commonly associated with smoking a cigarette, without causing a burning sensation in the mucosa of the mouth where the product is applied.

According to the invention there is provided an oral formulation comprising nicotine salt dissolved in an oil phase, which is provided in an air-tight containment.

Specifically, said nicotine salt is a mono-protonated salt. Specifically, said nicotine salt is produced by mixing unprotonated free-base nicotine with a higher organic acid e.g., with at least two, three, or four or more carbon atoms, to form such monoprotonated nicotine salt.

Specifically, said higher organic acid is a carboxylic acid, such as aromatic carboxylic acids, saturated aliphatic acids or unsaturated aliphatic acids. Preferably, said higher organic acid is selected from the group consisting of benzoic acid, salicylic acid, pyruvic acid, malic acid, levulinic acid, citric acid, aspartic acid and oleic acid.

Specifically, said nicotine salt is selected from the group consisting of nicotine benzoate, nicotine salicylate, nicotine pyruvate, nicotine malate, nicotine levulinate, nicotine citrate, nicotine aspartate, and nicotine oleate.

Specifically, said oil phase is an edible oil phase, specifically comprising an edible oil. Specifically, said oil phase comprises a non-toxic biocompatible oil, which includes, but is not limited to mono-, di- and triglycerides, fatty acids and their esters. Specifically, said oil phase is a vegetable oil. Specifically, said vegetable oil is a medium-chain triglyceride (MCT), specifically triglycerides of caprylic and capric acid, or mixtures of triglycerides such as coconut oil, olive oil, sunflower oil, corn oil, groundnut oil, grape seed oil, or wheat germ oil.

Specifically, the oral formulation described herein comprises oil phase in an amount of 60 to 95%, preferably 70 to 90% by weight of the total weight of the formulation. According to a specific embodiment, the oral formulation described herein further comprises nicotine as nicotine free base.

Advantageously, by providing the oral formulation in an air tight containment, the nicotine free base is protected from degradation through oxidation.

Specifically, the oral formulation described herein comprises nicotine, specifically nicotine salt, at a concentration of at least 0.01 % and up to 15 % by weight of the total weight of the oral formulation, preferably between 0.1 % and 10 % w/w, more preferably between 0.1 -1.5% w/w. Specifically, the oral formulation described herein comprises nicotine, specifically nicotine salt, at a concentration of at least 0.1 % and less than 15.0, 14.5, 14.0, 13.5, 13.0, 12.5, 12.0, 11.5, 11.0, 10.5, 10.0, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1 .5 or 1 .0 % by weight of the total weight of the oral formulation.

Specifically, the oral formulation described herein is characterized by a predefined nicotine release pattern.

Specifically, the predefined release pattern is a fast release pattern as further described herein. Specifically, the oral formulation described herein is designed for the content of nicotine to dissolve in the oral saliva within a short period, preferably a period of less than 240 seconds, more preferably less than 120 or 90 seconds, upon oral administration, and wherein at least 40% by weight of the nicotine is absorbed through the oral mucosa. Preferably, at least 50, 55, 60, 65, 70, 75, or 80 % by weight of the nicotine is absorbed through the oral mucosa within a period of less than 240 seconds, preferably less than 120 seconds, even more preferably less than 90 seconds.

A specific advantage of the formulation described herein is that the nicotine is directly absorbed into the mucosa, since it is dissolved in the oil phase. It is not necessary for the nicotine to be dissolved in the user’s saliva first, as it is necessary e.g. in a powdered product, where the nicotine is present in the product in an undissolved state and only dissolves upon contact with an aqueous phase, such as a subject’s saliva.

Specifically, an advantage of the oral formulation described herein is that a high relative nicotine absorption of more than 40, 50, 60, 70, 80 or 90 % by weight is obtained. This facilitates consumer satisfaction and/or an effective craving relief, without burning in the oral cavity and/or throat.

Specifically, the predefined release pattern is a phased release pattern. For example, the oral formulation may comprise fibers into which part or all of the nicotine is absorbed and from which it is released in a phased pattern e.g., half of the nicotine is released within 30 seconds and the other half is released within another 30 seconds.

The amount of nicotine content is generally given in amount per dosage unless otherwise specified. If the dosage is in the form of a tablet, the amount will refer to the complete tablet. If the dosage is referred to a mouth spray the amount will refer to the weight of the referred substance in the instructed dose e.g., the amount of substance referred to in relation to a single spray or e.g., the amount of substance in the instructed number of sprays related to the instructed timing. If the dosage is referred to a pouch or sachet, the amount will refer to the complete pouch or sachet.

According to an embodiment of the invention, said amount of nicotine, specifically nicotine salt, content is at least 0.1 mg per dosage. Specifically, said content of nicotine, specifically nicotine salt, is between 0.1 mg and 20.0 mg per dosage, preferably between 0.1 mg and 10.0 mg, even more preferably between 0.5 mg and 8.0 mg, such as between 0.5 mg and 4.0 mg.

Specifically, said content of nicotine, specifically nicotine salt, is at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3,

2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3,

4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0 mg per dosage. Preferably, said content of nicotine, specifically nicotine salt, is no more than 10.0, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5 or 3.0 mg per dosage.

Specifically, the oral formulation described herein has a pH of 7.0 to 9.5, preferably 7.0 or 7.5 to 9.0, even more preferably 8.0 to 9.0, in an aqueous phase upon partitioning. Preferably, the oral formulation described herein has a pH of about 8.2, 8.3,

8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3, 9.4 or 9.5, in an aqueous phase upon partitioning.

The oral formulation described herein is provided in an oxygen free environment. In particular embodiments, the oral formulation described herein is hermetically sealed to exclude oxygen, e.g., by formulation of the composition into an air-tight containment, specifically an air-tight capsule.

Specifically, the oral formulation provided herein is formulated to remain stable over a relatively long period of time. For example, the formulations provided herein are stored at room temperature, and remain stable for more than 1 day, 1 week, 1 month and in certain embodiments up to more than 1 year. For example, the oral formulation described herein can be prepared in an airtight capsule for oral administration, such as Capsugel from Pfizer, Inc. The oxygen-free environment may also be provided for example with a hermetically-sealed blister pack, or an air-tight container for a spray formulation.

In a specific aspect, the invention provides a package e.g., a blister pack, comprising an air-tight compartment containing one dose unit of the oral formulation described herein, e.g. a blister.

In a specific embodiment, the air-tight containment is wholly receivable in the oral cavity.

Specifically, the air-tight containment wholly receivable in the oral cavity is a gel matrix encapsulating the oral formulation described herein. Specifically, said gel matrix is configured to be air-tight and to at least partially dissolve upon contact with an aqueous phase, such as saliva, within less than 30 seconds, preferably less than 20 seconds, and even more preferably less than 10 seconds, so as to release the oral formulation.

Specifically, said gel matrix comprises or consists of a solid gel-forming material, specifically selected from the group consisting of gelatin, agar, carrageenan, alginate, pectins, gellan gum, arabic gum, ghatti gum, pullulan gum, mannan gum or modified starch, alone or as a mixture thereof, or in combination with gelatin. Specifically, said solid gel-forming material forms a shell.

Specifically, the amount of said gel-forming material present in the shell is 1.5 to 95% w/w, preferably 20% to 75% w/w, and even more preferably 30% to 50, 60, 70, 80, or 90 % w/w of the total dry weight of the shell.

Specifically, the shell further comprises any one or more of preservatives, sweeteners, fillers or plasticizers.

Specifically, the oral formulation described herein is provided in the form of a liquid, emulsion or gel.

Specifically, the air-tight containment which is a gel matrix, is in the form of a seamless capsule. Specifically, said seamless capsule encapsulates the oral formulation described herein, which preferably is provided in the form of a liquid, emulsion or gel.

In a further specific embodiment, the air-tight containment is not wholly receivable in the oral cavity or not intended for use in the oral cavity. Specifically, the air-tight containment not wholly receivable in the oral cavity is a solid containment, such as a mouth spray, or a containment from which the oral formulation can be removed prior to use, such as a blister pack.

Specifically, the air-tight containment not intended for use in the oral cavity is a containment from which the oral formulation can be removed prior to use, such as a wrapper.

Specifically, the oral formulation is provided in the form of a spray, a film, a tablet or a lozenge.

Specifically, the oral formulation described herein may be provided as a lozenge, tablet, liquid, or an oral film, which is individually packaged in air-tight containers, e.g. a sealed wrapper or a blister of a blister pack.

In one embodiment, the oral nicotine formulation described herein is provided in an orally disintegrating tablet or a lozenge, which is provided in an air-tight wrapper or a blister. Specifically, the said orally disintegrating tablet is a sublingual orally disintegrating tablet.

In one embodiment, the oral nicotine formulation described herein is a liquid mouth spray formulation, which is provided in an air-tight mouth spray containment.

In one embodiment, the oral nicotine formulation described herein is a liquid formulation, and the liquid formulation is provided as a pillow soaked in the liquid formulation, which is provided in an air-tight wrapper or a blister.

Further provided herein is an air-tight seamless capsule, comprising a filling which is an oral formulation comprising nicotine salt dissolved in an oil phase, such as the oral formulation described herein, preferably encapsulated in a gel matrix.

Specifically, the filling is provided in the form of a liquid.

Specifically, said gel matrix is configured to at least partially dissolve upon contact with an aqueous solution, specifically upon contact with saliva. Specifically, said gel matrix is configured to dissolve within a certain amount of time, such as for example within 5 to 10 seconds, or within less than 30 or 20 seconds.

Specifically, said gel matrix comprises a solid gel-forming material, specifically a hydrocolloid, selected from the group consisting of gelatin, agar, carrageenan, alginate, pectins, gellan gum, arabic gum, ghatti gum, pullulan gum, mannan gum and modified starch, alone or as a mixture thereof. Specifically, the gel matrix consists of gelatin, agar, carrageenan, alginate, pectins, gellan gum, arabic gum, ghatti gum, pullulan gum, mannan gum or modified starch. Specifically, the air-tight seamless capsule described herein has a size of 0.5- 10.0 mm. Preferably, the outer diameter of the capsule is in the range of 2 to 8 mm, preferably 3 to 5 mm, more preferably 3.4 to 4.8, and even more preferably 3.5 to 4.5 mm.

Specifically, the shell thickness of the capsule is 5-80 microns, preferably 10-40 microns, more preferably 15-35 microns. Specifically, the shell thickness of the capsule is about 30 microns.

The capsules described herein may be produced according to the protocol as published by Bhupendra (Prajapati, Bhupendra (2008)), or as published in the European patent application No. EP1310229A1 , or in the US patent No. US8820331 B2.

In a specific embodiment, the capsules described herein are contained in a carrier, such as a pouch or sachet, which is preferably water insoluble, and prevents the capsules from leaving the carrier. The carrier is permeable to aqueous liquids such as saliva. This means that in operation, saliva present in the oral cavity can penetrate through the carrier and transport the dissolved substances out through the carrier into the oral cavity. Once in the oral cavity, the nicotine can be absorbed through the mucosal membrane.

Thus, further provided herein is a water-permeable carrier comprising at least one capsule as described herein. Preferably, said carrier is a sachet or pouch.

Specifically, said carrier comprises or consists of a wrapping, preferably comprising any one or more of or consisting of cellulose, paper, non-woven and woven fabric made of cotton, viscose, rayon, and/or silk.

Specifically, the wrapping of the carrier described herein comprises fibers, such as cellulose fibers or fibrous paper, which are configured to absorb at least part of the capsule’s filling.

In some embodiments, the carrier described herein comprises capsules with a phased release pattern, wherein some capsules burst sooner than others. In a specific embodiment, a portion of the capsules, e.g. 10, 20 30, 40 or 50% of the capsules in the carrier, dissolves, at least partially, within about 5-10 seconds so as to release the encapsulated formulation, and a second or further portion of the capsules, e.g. 10, 20, 30, 40, or 50% of the capsules in the carrier, dissolves, at least partially, after 30 seconds or later, e.g. after 1 or 2 minutes or even later e.g. within about 2-10 minutes.

In a specific embodiment of the carrier described herein, the carrier comprises, in addition to the capsules containing the oral nicotine salt formulation described herein, capsules which do not contain nicotine. Specifically, such capsules contain a flavor formulation.

In another specific embodiment, the carrier is water-soluble and dissolves upon contact with an aqueous solution, such as e.g. saliva, thereby releasing its content, such as capsules comprising the oral nicotine formulation described herein.

In a specific example, the water-soluble carrier is configured to dissolve more slowly than at least some or all of the capsules it is filled with.

For example, the water-soluble carrier may comprise capsules comprising the oral formulation described herein and capsules comprising an oily flavor formulation, which are configured to dissolve more slowly than the nicotine capsules. In this specific example, the carrier may be configured to absorb at least part of the nicotine formulation released from the nicotine capsules and to dissolve more slowly than the capsules comprising the nicotine formulation, so that the nicotine formulation is retained and can be absorbed through the mucosa of the subject in the vicinity of where the carrier was placed in the oral cavity. Specifically, the flavor capsules may be configured to dissolve more slowly than the nicotine capsules and the carrier, so that the flavor formulation is easily distributed through the oral cavity.

In a specific embodiment of the carrier described herein, the carrier further comprises an amount of an insoluble composition. Specifically, the carrier further comprises tobacco material or tobacco fibers.

An advantage of the above embodiment may be that a residue is left even after use of a pouch comprising the formulation. This may lead to a pleasant perception for users of the sachet or pouch, e.g. due to similarity with tobacco containing products.

The oral formulation described herein may further be used to prepare a nicotine consumer product or a pharmaceutical preparation.

Provided herein is a consumer product comprising the oral formulation, capsule and/or the carrier described herein.

Also provided herein is a pharmaceutical preparation comprising the oral formulation, the capsule and/or the carrier described herein.

Specifically, the pharmaceutical preparation described herein is for medical use, preferably in the treatment of a subject by buccal, transmucosal or peroral administration. Specifically, the pharmaceutical preparation described herein is for use in the treatment of nicotine addiction, and is specifically used in nicotine replacement therapy to alleviate withdrawal symptoms. In a further specific aspect, the invention relates to a method to produce the oral formulation described herein, comprising the steps of providing the components used in the formulation, specifically the nicotine salt and oil, and mixing the components.

Specifically, said method comprises the steps of: i. providing nicotine and an acid; ii. mixing the nicotine and the acid under continuous stirring, preferably for 10-30 minutes, to produce nicotine salt; and iii. adding oil to the mixture of ii., and stirring the mixture, preferably for another 10-30 minutes.

Specifically, the nicotine is provided in step i. of the method described herein as nicotine free base.

Specifically, the acid is a higher organic acid, preferably a carboxylic acid, preferably selected from the group consisting of benzoic acid, oleic acid, salicylic acid, pyruvic acid, malic acid, levulinic acid, citric acid and aspartic acid.

In a specific embodiment, the nicotine-acid mixture is heated to a temperature of about 50-60°C, preferably about 55°C. Specifically, the heated nicotine-acid mixture is stirred for about 15-25 minutes, preferably about 20 minutes.

FIGURES

Fig. 1 Schematic representation of different types of air-tight capsules (1) encapsulating the oral formulation described herein as a (2) liquid, emulsion or gel.

Fig. 2 Schematic representation of carriers comprising the capsules described herein.

A) One air-tight gel matrix capsule comprising the oral nicotine formulation described herein (1) contained in a water-insoluble but permeable to liquids carrier (2), such as a pouch or sachet.

B) Several air-tight gel matrix capsules comprising the oral nicotine formulation described herein (1) contained in a water-insoluble but permeable to liquids carrier (2), such as a pouch or sachet.

C) Carrier (2) comprising capsules, comprising the oral nicotine formulation described herein, with phased release patterns, wherein a group of capsules (1) bursts earlier than a second group (3). D) A water-insoluble but permeable to liquids carrier (2) comprising capsules with the oral nicotine formulation described herein (1) and capsules which do not contain nicotine, but contain oil and/or flavor (3).

E) A water-insoluble but permeable to liquids carrier (2) comprising capsules of different sizes to provide a phased release pattern (1 , 3, 4). Some capsules comprise the oral nicotine formulation described herein (1 , 3) and some capsules do not contain nicotine, but contain oil and/or flavor (4).

Fig. 3 Ex vivo experiments showing the percentage of nicotine released for the present invention - sphere sachet and a commercial nicotine pouch.

DETAILED DESCRIPTION

Unless indicated or defined otherwise, all terms used herein have their usual meaning in the art, which will be clear to the skilled person.

Specific terms as used throughout the specification have the following meaning.

The terms “comprise”, “contain”, “have” and “include” as used herein can be used synonymously and shall be understood as an open definition, allowing further members or parts or elements. “Consisting” is considered as a closest definition without further elements of the consisting definition feature. Thus “comprising” is broader and contains the “consisting” definition.

The term “about” as used herein refers to the same value or a value differing by +/-10% or +/-5% of the given value. The term “about” as used for °C temperature typically refers to +/- 1 °C.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

As used herein and in the claims, the singular form, for example “a”, “an” and “the” includes the plural, unless the context clearly dictates otherwise.

As used herein, the term “%” and “percent” refers to percent by weight, unless otherwise is stated. As used herein, the term “subject” or “consumer” or “user” or “individual” or “patient” shall refer to a warm-blooded mammalian, particularly a human being.

As used herein, the term “nicotine” refers to nicotine in any form, specifically nicotine free base and nicotine salts. When referring to nicotine amounts, the amounts refer to the amount of pure nicotine. Thus, when measuring the concentration of nicotine added as nicotine salt, it is the mass of the equivalent amount of pure nicotine, not the mass of the salt, that is relevant. Nicotine may be obtained as an extract from tobacco as is well known in the art. Nicotine also covers nicotine not obtained from tobacco, often referred to as synthetic nicotine. Both, nicotine extract from tobacco and synthetic nicotine, are commercially available.

Nicotine is an alkaloid molecule containing dibasic nitrogen. This can occur in different states of protonation. For example, if protonation is not present, nicotine is unprotonated and means "free base”. If one nitrogen is protonated, the nicotine will be "mono-protonated".

As used herein the term “nicotine free base”, synonymously used with “free-base nicotine”, refers to non-protonated form of nicotine, and therefore does not include nicotine salts. Nicotine free base includes both free-base nicotine extracted from tobacco as well as synthetically manufactured free-base nicotine. Nicotine free base is not provided in the form of tobacco or powdered tobacco or tobacco fibers. Typically, free- base nicotine is provided as a liquid.

As used herein, the term “nicotine salt” refers to nicotine in ionized form bonded electrostatically to a counterion. Nicotine salt can be formed by addition of an appropriate acid, preferably an organic acid, to free-base nicotine.

In a specific embodiment, the nicotine salt of the oral formulation described herein is a higher organic salt, formed using an organic acid.

The presence of nicotine salt in the oral formulation and in the products described herein can be readily determined by a person skilled in the art using standard methods for the detection of an anion. Such standard methods may for example be acidimetryalkalimetry titration methods or spectrophotometric methods.

The presence of nicotine salt in the oral formulation described herein may also be determined by measuring the amount of nicotine in the water and in the oil phase upon partitioning. The amount of nicotine in the water phase may be measured by High- Performance Liquid Chromatography (HPLC) and the amount of nicotine in the oil phase may be determined by non-aqueous titration. Nicotine salt has a higher tendency to partition into the water phase than nicotine free base. Thus, in an oil solution comprising nicotine salt, the amount of nicotine detected in the water phase upon partitioning will be significantly higher than of an oil solution comprising only nicotine free base. Specifically, at least 70% of the nicotine salt in the oral formulation described herein is found in the water upon partitioning.

Specifically, this higher tendency of nicotine salt to partition into the water phase advantageously facilitates the absorption of the nicotine through the mucous membrane and into the blood stream.

The term "organic acid " as used herein means an organic compound having an acidic property (e.g., according to the definition of Bronsted-Lowry, or the definition of Lewis). Common organic acids are carboxylic acids, and their acidity is associated with their carboxyl group -COOH. The dicarboxylic acid has a dicarboxylic acid group. The tricarboxylic acid has three carboxyl functional groups -COOH. The relative acidity of the organic material is measured by its pKa value and those skilled in the art know how to calculate the acidity of an organic acid based on a given pKa value. The term "keto acid" as used herein means an organic compound containing a carboxylic acid group and a ketone group. Typical types of keto acids are alpha-keto acids such as pyruvic acid or oxaloacetic acid with a keto group adjacent to the carboxylic acid, or 2-oxo acid; Betaketo acids such as acetoacetic acid having a ketone group at the second carbon from the carboxylic acid, or 3-oxo acid; Gamma -keto acid such as levulinic acid having a ketone group at the third carbon from the carboxylic acid, or 4-oxo acid.

Examples of suitable organic acids are carboxylic acids, e.g. with at least two, three, or four or more carbon atoms, such as aromatic carboxylic acids, saturated aliphatic acids or unsaturated aliphatic acids, such as benzoic acid, oleic acid, salicylic acid, pyruvic acid, malic acid, levulinic acid, citric acid and aspartic acid. Nicotine salts are formed by the addition of an appropriate acid to nicotine. In some formulations provided herein, the stoichiometric ratio of nicotine to acid (nicotine: acid) is 1 : 1 , 1 : 2, 1 : 3, 1 : 4, 2: 3, 2: 5, 4, 3: 5, 3: 7, 3: 8, 3:10, 3:11 , 4: 5, 4: 7, 4: 9, 4:10, 4:11 , 4:13, 4:14, 4: 15, 5: 6, 5: 7, 5: 8, 5: 9, 5:11 , 5:12, 5:13, 5:14, 5:16, 5:17, 5:18, or 5 : 19. In some formulations provided herein, the stoichiometric ratio of nicotine to acid is 1 : 1 , 1 : 2, 1 : 3, or 1 : 4 (nicotine: acid).

The nicotine of the nicotine salt formulations provided herein is a naturally occurring nicotine (e.g., an extract of a nicotine species such as tobacco), or a synthetic nicotine. In some embodiments, the nicotine is (-) - nicotine, (+) - nicotine, or a mixture thereof. In some embodiments, the nicotine is used in a relatively pure form (e.g., greater than about 80%, 85%, 90%, 95%, or 99% purity). In some embodiments, the nicotine for the nicotine salt formulations provided herein is "colourless transparent" in appearance to minimize or avoid formation of tar residues during subsequent salt formation steps.

As used herein, the term "tobacco" is meant to refer to a part, e.g., leaves, flowers, and stems, of a member of the genus Nicotiana. Exemplary species of tobacco include N. rustica, N. tabacum, N. tomentosiformis, and N. sylvestris. Suitable tobacco fibers can include tobacco fibers formed from fermented and unfermented tobaccos, dark aircured, dark fire-cured, burley, flue cured, and cigar filler or wrapper, as well as the products from the whole leaf stemming operation. For example, tobacco can be conditioned by heating, sweating and/or pasteurizing steps as described in U.S. Publication Nos. 2004/0118422 or 2005/0178398. Fermenting typically is characterized by high initial moisture content, heat generation, and a 10 to 20% loss of dry weight. Cured, or cured and fermented tobacco can be further processed (e.g., cut, expanded, blended, milled or comminuted) prior to incorporation into the water-permeable carrier described herein.

The term "tobacco material" is used herein for tobacco leaves or parts of leaves, e.g. lamina and stem, wherein the leaves and parts of leaves are finely divided, such as ground, cut, shredded or threshed, and the parts of leaves are blended.

A suitable carrier for the nicotine salts described herein is an edible oil, wherein the nicotine salt is soluble at ambient conditions such that the nicotine salt does not form a solid precipitate.

The oil phase in the oral formulation provided herein can contain any non-toxic biocompatible oil, which includes, but is not limited to mono-, di- and triglycerides, fatty acids and their esters. The fatty acids and esters (used as such or where they form part of a glyceride) can be short chain, medium chain or long chain. As used herein, medium chain represents a hydrocarbon chain of Cs to C12 and short chain is a hydrocarbon chain of less than C8 and long chain means a hydrocarbon chain of more than C12.

As used herein, "biocompatible” substance, refers to a substance which when administered to a subject, such as a human, does not produce undesired or toxic effects.

The oil suitable for use in the oral formulation described herein includes any oil obtained from a natural or synthetic source that is suitable for consumption by a subject, specifically a human, and in which the nicotine is sufficiently soluble. Oils suitable for administration to subjects, including humans, are known. Any such oil can be used. The oil can be of vegetable or animal origin. The oil phase also can be synthetic or semisynthetic oils that are nontoxic to a subject.

Preferably, the oil suitable for use in the oral formulation described herein has a viscosity of 20 - 40 mPa s, preferably 30 mPa s, at a temperature of about 20°C.

In certain embodiments, the oils are short, medium or long chain triglycerides. In certain embodiments, the oils are medium chain triglycerides (MCTs). In certain embodiments, the MCT is tricaprylic triglyceride ester.

Exemplary sources for oils contemplated herein include, but are not limited to All Spice, Almond, Anise, Apple, Apricot, Avocado, Basil, Bayberry, Benzoin, Bergamot, Borage Seed, Cajeput, Calendula, Canola, Carnation, Carrot seed, Cassia bark, Castor, Cayenne, Cedarwood, Chamomile, Cinnamon, Citronella, Conjugated Linolenic Acid, Clary sage, Clove bud. Coconut, Cod Liver, Corn, Cranberry, Cypress, Evening Primros, Eucalyptus, Evergreen, Fir, Fish 18:12, Flax Seed, Frangipani, Frankincense, Freesia, Gardenia, Ginger, Grape Seed, Grapefruit, Heather, Honeysuckle, Hyacinth. Jasmine, Jojoba, Juniper berry. Lavender, Lecithin, Lemon, Lemon balm, Lemon, verbena, Lemongrass, Lilac, Lily of the valley, Lime, Magnolia, MCT, Menthol, Mulberry, Musk. Myrrh Oat, Olive, Orange, Oregano, Palm, Patchouli, Peach, Pennyroyal, Peppermint, Petitgrain, Pine, Pumpkin Seed, Rice Bran, Rose, Rosemary, Rosewood, Safflower, Sage, Salmon, Sandalwood, Sesame, Shark Liver, Soy Bean, Spearmint, Squalene, Strawberry, Sunflower, Tangerine, Tea tree, Thuja (Cedar leaf), Thyme, Tuna, Vanilla, Vitamin E, Wheat Germ, Wintergreen and Yiang yiang.

The oil is present in an amount sufficient to dissolve the nicotine salts in the oral formulation described herein. For example, in some embodiments, the oil is present at a concentration of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% and more by weight. Preferably, the oral formulation described herein comprises oil at a concentration of at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99% by weight of the total formulation. Thus, in certain embodiments, the oil is present at about 50% by weight up to about 90% or 95% by weight of the total weight of the oral formulation.

The formulations described herein vary in concentration. In some formulations, dilute concentrations of the nicotine salt in the carrier are used. In some formulations, lower dilution concentrations of the nicotine salt in the carrier are used. In some formulations, the concentration of nicotine in the nicotine salt formulation is from about 0.01 % (w/w) to about 15% (w/w). In some formulations, the concentration of nicotine in the nicotine salt formulation is from about 0.1 % (w/w) to about 10% (w/w). In some formulations, the concentration of nicotine in the nicotine salt formulation is from about 0.5% (w/w) to about 5% (w/w). In some embodiments, the concentration of nicotine in the nicotine salt formulation is from about 1 % (w/w) to about 10% (w/w).

The oral nicotine salt formulations described herein can be formed by adding a suitable acid to nicotine, stirring the mixture at ambient temperature or at high temperature, and then diluting the mixture with an oil as described herein. In some embodiments, the appropriate acid is completely dissolved by nicotine before dilution. The appropriate acid may not be completely dissolved by nicotine before dilution. The addition of the appropriate acid to the nicotine to form the mixture can be carried out at a temperature between 50-60°C, preferably at about 55°C. The addition of the appropriate acid to the nicotine to form the mixture can be carried out at room temperature. The mixture can be cooled to ambient temperature prior to dilution. Dilution can also be carried out at elevated temperatures.

As used herein, the term “release of nicotine” refers to the nicotine being made bioavailable, i.e. available for absorption over the mucous membrane in the oral cavity. While solid or powdered formulations comprising nicotine salt, require dissolution of the nicotine salt to be bioavailable, the nicotine of the oral formulation described herein, comprising nicotine salt dissolved in an oil phase, is readily absorbed into the body without dissolution. This provides the significant advantage that the nicotine can be absorbed more quickly, as dissolution of the nicotine in the saliva prior to absorption is not necessary for the nicotine dissolved in the oil to be absorbed.

Absorption of nicotine from the oral cavity, i.e. transmucosal uptake, to the systemic circulation is dependent on the pH of the formulations upon partitioning in an aqueous phase, such as the saliva inside and close to the product in use. Nicotine will predominantly be absorbed through the mucosa in the nonprotonated form. Therefore, it is preferable to have a pH which provides a high fraction of the nonprotonated nicotine. The pKa of nicotine is about 7.8 which means, for example, that at a pH of about 8.8 approximately 90% of the nicotine is in the nonprotonated form. Theoretically, the higher the local pH, the higher the fraction of nonprotonated nicotine. However, a too high pH will be irritating for the oral mucosa. Therefore, taking the above-mentioned aspects into account, a practical upper limit of the pH may be for example about pH 10. Thus, it is preferred that the oral formulation described herein, comprising nicotine salt dissolved in an oil phase, has a pH of 7.0 to 9.5, preferably 7.5 to 9.0, in an aqueous phase upon partitioning.

Thereby the nicotine salt in the powder is in a physical and chemical stable form until the product is used by a consumer and comes into contact with saliva. For example, saliva present in the oral cavity penetrates through the pouch or sachet, to the nicotine salt, and thereafter transport the substances out into the oral cavity. A reaction between the nicotine salt and the saliva results in the formation of unprotonated nicotine which can penetrate the oral mucosa and become absorbed.

As used herein, the term “peak saliva pH” refers to the peak value of the pH in saliva of the oral cavity. It should be understood that the peak saliva pH is considered to be achieved whenever the criterion is fulfilled. For example, if a peak saliva pH is at least 7.5, this peak saliva pH is achieved whenever the pH exceeds 7.5. Peak saliva pH is measured in vivo and is measured as follows:

At least 6 individuals chewed on a gum base free of buffer for 1 minute, after which the initial pH in a sample from the saliva from each of the individuals is measured with a suitable pH-electrode system, e.g. a stainless steel electrode PHW77-SS. Only individuals having, after chewing on a gum base free of buffer for one minute, an initial pH in the saliva inside the range from 6.7 and 7.3 are selected. These individuals thereby qualify as average individuals.

One dosage of the formulation is administered sublingually to at least six individuals. Hereafter, the saliva pH from each of the six individuals is measured at specified time intervals. Thus, each pH-value is the arithmetic mean of six measurements performed on saliva-samples from six individuals.

For liquid formulations, the peak saliva concentration of nicotine is measured after 1 unit dose of the liquid formulation is dispensed to the oral cavity. For tableted formulations, the peak saliva concentration of nicotine is measured after 1 tablet is dispensed to the oral cavity.

The pH of the formulation in an aqueous phase upon partitioning can for example be determined as follows:

In a separatory funnel, the oral formulation described herein and saline water (distilled water containing NaCI) are mixed in a 1 :5 proportion. After shaking, the phases are allowed to separate and are collected in separate beakers. A blank is done utilizing the same procedure with the pure oil. The pH of the water phase is then determined utilizing a freshly calibrated pH meter. The experiment is repeated in replicates of 3, to give a mean pH value.

In certain embodiments, the oral formulation described herein provides fast onset nicotine craving relief. As used herein, the term “fast onset nicotine craving relief’ refers to relief of nicotine craving, for which the onset is relatively fast, i.e. only a relatively short period of time after oral administering. In embodiments of the invention, the fast onset refers to a period after oral administration of the oral formulation described herein until craving relief is experienced being no more than 240 or 180 seconds, preferably such as no more than 120 seconds, such as no more than 60 seconds.

The oral formulation described herein is provided in an oxygen free environment. In particular embodiments, the oral formulation described herein is hermetically sealed to exclude oxygen. For example, the oral formulation described herein can be prepared in an airtight capsule for oral administration. The oxygen-free environment may also be provided for example with a hermetically-sealed blister pack, or an air-tight container for a spray formulation.

The term "air-tight" or "oxygen-impermeable" as used herein refers to a material that provides a barrier for oxygen, such that the oxygen transmission rate for the unformed material is preferably lower than 5 cm³/m² per day measured according to DIN 53380 at a pressure of 1 bar, a temperature of 23°C, and relative humidity of 35%. Preferably, the oxygen transmission rate is lower than 3 cm³/m² per day, more preferably lower than 2 cm³/m² per day, even more preferably about or less than 1 cm³/m² per day.

According to a specific example, the oral formulation described herein is in the form of a lozenge, a solid or semi-solid candy, a tablet, an orally disintegrating tablet, a troche, or an oral film strip and the air-tight containment is a blister pack. Preferably, each unit dosage, e.g. a single lozenge or tablet, is contained in a separate blister of the blister pack.

In another specific example, the oral formulation is provided in the form of a spray formulation and the air-tight containment is a mouth spray.

In yet another specific example, the oral formulation described herein is provided in an encapsulated form, e.g. in an air-tight seamless capsule or soft gel capsule.

As used herein, the term “capsule” means a delivery system of a substance, for example the oral formulation described herein or a flavor formulation, which is enclosed into a shell. Seamless capsules comprise a gel matrix as the shell, which is typically made of a water-soluble polymer such as gelatin, agar or carrageenan but also alginate, pectins, gellan gum, arabic gum, ghatti gum, pullulan gum, mannan gum and modified starch, alone or mixtures thereof. Seamless capsules encapsulating the oral formulation described herein may for example be produced using the Seamless softgel machine of Joysun Pharma or by co-extrusion as described in EP Patent Application No. EP1310229.

The capsules used to encapsulate the oral formulation described herein are water-soluble and may comprise a single layer or multiple layers. The outer layer can be enteric coated. Seamless and soft gel capsules offer rapid and consistent absorption, specifically of hydrophobic drugs. A capsule is a unitary package e.g., formed with gelatine outer layers, which contain the oral nicotine formulation described herein in solution, suspension, emulsion, gel or paste form. A capsule may have several shapes and sizes, dependent on the design. When dissolved, crushed or chewed, the capsule releases its filling immediately for absorption through the oral mucosa into the blood stream. The shell thickness is controllable and can be made accurately uniform. The shell thickness can be reduced to as little as 30 microns or less (in the case of a 3 mm diameter capsule).

Use of a multi-layered capsule structure, allows to add further functions to the capsule shell e.g., sustained releasing/releasing/adsorbing of target ingredients, light proofness and defined air tightness.

Specifically, the capsule described herein is configured to at least partially dissolve upon contact with an aqueous solution, specifically upon contact with saliva. Specifically, the capsule described herein is configured to dissolve within a certain amount of time, such as for example within 5 to 10 seconds, or within less than 30 or 20 seconds.

The seamless capsules described herein preferably have a size of 0.5-10.0 mm. Preferably, the outer diameter of the capsule is in the range of 2 to 8 mm, preferably 3 to 5 mm, more preferably 3.4 to 4.8, and even more preferably 3.5 to 4.5 mm. The shell thickness of the capsule can for example be 5-50 microns, preferably 10-40 microns, more preferably 15-35 microns.

The capsules described herein may be produced according to the protocol as published by Bhupendra (Prajapati, Bhupendra (2008)), or as published in the European patent application No. EP1310229A1 , or in the US patent No. US8820331 B2. As used herein, the term “carrier” shall refer to a containment, such as for example a pouch, pillow or sachet, which comprises the oral formulation described herein, preferably encapsulated in a gel matrix, which is for example a seamless capsule. In a specific embodiment, the capsules described herein are filled into a carrier, and are maintained in the carrier by a sealing. An ideal carrier material shall have the following characteristics: it shall be chemically and physically stable, be pharmaceutically acceptable, be easy to fill and seal and it shall provide a semi-permeable membrane layer which prevents the capsules from leaving the bag but permits saliva and components from the capsules in the carrier, such as nicotine dissolved in oil, to pass through said carrier. Thus, the “water-permeable carrier” described herein is configured to allow aqueous liquids, and preferably also oil solutions, to pass through the carrier material.

The carrier material may be water-insoluble or at least partially water-soluble. The carrier material may also consist of water-soluble material.

The carrier wrapping may be of any suitable material e.g., woven or non-woven fabric (e.g. cotton, fleece etc.), heat sealable non-woven cellulose or other polymeric material such as synthetic, semi-synthetic or natural polymeric material. An example of suitable material is paper made of pulp and a small amount of wet strength agent.

Specifically, the wrapping of the carrier described herein comprises fibers, such as cellulose fibers or fibrous paper, which are configured to absorb at least part of the capsule’s filling. This provides the advantage that the nicotine oil formulation is not distributed in the entire mouth cavity but remains concentrated in one spot and can efficiently be absorbed by the oral mucosa.

The carrier is placed in the oral cavity by the user. Saliva enters into the pouch, and nicotine and other components are transported with the saliva out of the pouch into the oral cavity where the nicotine is absorbed into the oral mucosa.

The carrier may comprise from 20 to 1000 mg of the oral formulation described herein encapsulated in air-tight seamless capsules, such as 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 or 950 mg.

As used herein the terms “pouch” and “sachet” are intended to mean a container typically formed by a web of a fibrous material enclosing a cavity. The container may be designed for administration of compounds such as nicotine in the oral cavity. In any case, it is adapted for oral use, it is non-toxic and not water-soluble. The fibrous material may e.g., form a woven or non-woven web or fabric. The container may for example be sealed by bonding two corresponding pieces of web or fabric to each other along their edges to form a cavity for the composition. In order to release the nicotine and optionally the flavor and further ingredients to be released, the pouch or sachet is permeable to water and oil so as to allow saliva from the oral cavity to penetrate the pouch or sachet and enter the cavity, where the saliva can come into contact with the encapsulated nicotine and/or flavor, the capsules dissolve at least partially thereby releasing the nicotine and/or flavor, whereby the nicotine and/or flavor are released from the oral pouch or sachet.

The products described herein may comprises further ingredients, such as fillers which may comprise flavors and/or sweeteners. Specifically, the products described herein further comprise pharmaceutically acceptable ingredients.

As used herein, "pharmaceutically acceptable" means that the ingredients which the term describes are suitable for use in contact with tissues, specifically the oral mucosa, without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.

Pharmaceutically acceptable carriers and excipients generally include any and all suitable solvents, fillers, coatings, and the like that are physiologically compatible the composition provided herein. As described herein, the formulation provided herein is applied to the oral mucosa of a subject. Pharmaceutical carriers and excipients suitable for facilitating such means of administration are well-known in the art.

Fillers with a secondary function may give the products described herein improved properties when it comes to the experience and/or the effects of the oral formulation described herein on the consumer. The type of components and the amount of the different components in the formulation or in the final product may vary depending on the desired properties of the final product, for example to obtain an attractive taste. Typically, the final product may comprise one or more fillers having a function as sweetener or flavor. For example, the carrier described herein may directly comprise a filler, or may in addition to the capsules comprising the oral nicotine formulation described herein comprise capsules comprising such filler. In addition, or alternatively, the carrier may comprise capsules comprising both the oral nicotine formulation described herein and capsules without nicotine.

Examples of sweeteners include mono- di- tri- and polysaccharides, polyols such as mannitol, maltitol and xylitol, natural and synthetic sweeteners such as sucrose, glucose, dextrose, maltose, fructose, saccharin, aspartame, acesulfame, sucralose, saccharin and cyclamates, and mixtures thereof.

Examples of flavors include bergamot, eucalyptus, orange, mandarin, citrus, lemon, peppermint, mint, menthol, liquorice, Wintergreen, tobacco, coffee, vanilla, lime, apple, peach and mixtures thereof.

Additional pharmaceutically acceptable carriers and excipients are well-known in the art and described in, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES.

The term "emulsifier" as used herein refers to a pharmaceutically acceptable surfactant that is suitable for oral application. Examples of emulsifiers include naturally occurring phospholipids extracted from egg yolk or soybean (e.g., L-oc- lecithin, soybean (or other sources)), synthetic phosphatidyl cholines or purified phosphatidyl cholines from vegetable origin.

According to a specific embodiment, pharmaceutically acceptable carriers, excipients and other additives can generally be included in the formulation described herein in quantities of 1 to 70 % (w/w), preferably 5 to 60 % (w/w), more preferably 5 to 50 % (w/w), in each case based on the total weight of formulation.

A preparation described herein is specifically administered at an effective amount, in particular a therapeutically effective amount, meaning a quantity or activity sufficient to effect beneficial or desired results, including clinical results, when administered to a subject, e.g. a patient suffering from a nicotine addiction. As such, an effective amount or synonymous quantity thereof depends upon the context in which it is being applied. An effective amount is intended to mean that amount of a compound that is sufficient to treat, prevent or inhibit a disease or disorder, specifically, nicotine addiction.

As used herein, the term “orally disintegrating tablet” refers to a tablet for oral administering which disintegrates in the oral cavity relatively fast from the administering, such as within less than 3 minutes, preferably even less than 1 minute, from oral administering. Orally disintegrating tablets may be intended for use as a sublingual tablet for positioning under the tongue, as a buccal tablet, as a tablet for melting on the tongue, or for other types of oral administering. Typically, orally disintegrating tablets refers to tablets that are completely soluble in saliva.

As used herein the term “liquid mouth spray formulation” refers to a mouth spray for application of drug orally, e.g. either sublingually or buccal. The mouth spray formulation is provided as a liquid, but may comprise gelling agents for forming a gel during/after administering to the oral cavity. Liquid mouth spray formulation may also be referred to as fast acting mouth spray.

As used herein, the term “mouth spray” refers to a pump-type or squeeze-type container having a spray nozzle and contains a liquid spray formulation to be sprayed into the mouth. The mouth spray is configured to provide an oxygen-free environment for the spray formulation to be stored in.

The term “peroral administration” as used herein refers to a topical route of administration by which products, such as the oral formulation and pharmaceutical preparations and consumer products comprising said oral formulation described herein, held or applied in the mouth diffuse through the oral mucosa and enter directly into the bloodstream.

The term "buccal administration", synonymous with “buccal delivery”, as used herein refers to a topical route of administration by which products, such as the oral formulation and pharmaceutical preparations and consumer products comprising said oral formulation described herein, held or applied in the buccal area (in the cheek) diffuse through the oral mucosa and enter directly into the bloodstream.

The term "sublingual administration" as used herein refers to a topical route of administration by which products, such as the oral formulation and pharmaceutical preparations and consumer products comprising said oral formulation described herein, held or applied under the tongue diffuse through the oral mucosa and enter directly into the bloodstream.

The following items are particular embodiments described herein.

1 . An oral formulation comprising nicotine salt dissolved in an oil phase, which is provided in an air-tight containment.

2. The oral formulation of item 1 , wherein said nicotine salt is a monoprotonated salt.

3. The oral formulation of item 2, wherein said nicotine salt is selected from nicotine benzoate, nicotine salicylate, nicotine pyruvate, nicotine malate, nicotine levulinate, nicotine citrate, nicotine aspartate, and nicotine oleate.

4. The oral formulation of any one of items 1 to 3, wherein said oil phase comprises vegetable oil, preferably medium-chain triglyceride (MCT) oil.

5. The oral formulation of any one of items 1 to 4, further comprising nicotine free base. 6. The oral formulation of any one of items 1 to 5, comprising nicotine at a concentration of at least 0.1 % and up to 10% by weight of the total weight of the oral formulation, preferably between 0.1-1.5%.

7. The oral formulation of any one of items 1 to 6, wherein the formulation has a pH of 7.0 to 9.5, preferably 8.0 to 9.5, in an aqueous phase upon partitioning.

8. The oral formulation of any one of items 1 to 7, which is characterized by a predefined nicotine release pattern upon contact with.

9. The oral formulation of any one of items 1 to 8, wherein the air-tight containment is wholly receivable in the oral cavity.

10. The oral formulation of item 9, wherein the oral formulation is provided in the form of a liquid.

11. The oral formulation of item 10, wherein the air-tight containment is a gel matrix.

12. The oral formulation of item 11 , wherein said gel matrix comprises a solid gel-forming material selected from the group consisting of gelatin, agar, carrageenan, alginate, pectins, gellan gum, arabic gum, ghatti gum, pullulan gum, mannan gum and modified starch, alone or as a mixture thereof.

13. The oral formulation of any one of items 9 to 12, wherein the air-tight containment is in the form of a seamless capsule.

14. The oral formulation of any one of items 1 to 8, wherein the oral formulation is provided in the form of a spray, a film, a tablet or a lozenge.

15. An air-tight seamless capsule, comprising a filling which is an oral formulation comprising nicotine salt dissolved in an oil phase, preferably encapsulated in a gel matrix.

16. The capsule of item 15, wherein the capsule has a size of 0.5-10 mm, preferably 3.0-5.5 mm.

17. A capsule according to items 15 or 16, wherein the filling is provided in the form of a liquid.

18. A water-permeable carrier comprising at least one capsule of any one of items 15 to 17, preferably wherein the carrier is a sachet, pouch, or pillow.

19. The carrier of item 18, which comprises or consists of a wrapping, preferably comprising any one or more of cellulose, paper, non-woven and woven fabric made of cotton, viscose, rayon, and/or silk. 20. The carrier of item 19, wherein the wrapping comprises fibers configured to absorb at least part of the capsule’s filling.

21. The carrier of any one of items 18 to 20, further comprising tobacco material or tobacco fibers.

22. A nicotine consumer product comprising the oral formulation of any one of items 1 to 14, or the capsule of any one of items 15 to 17, or the carrier of any one of items 18 to 21.

23. A pharmaceutical preparation comprising the oral formulation of any one of items 1 to 14, or the capsule of any one of items 15 or 17, or the carrier of any one of items 18 to 21.

24. The pharmaceutical preparation of item 23, for medical use, preferably in the treatment of a subject by buccal, transmucosal or peroral administration.

25. Use of an oral formulation of any one of items 1 to 14, to prepare a nicotine consumer product of item 22, or a pharmaceutical preparation of item 23.

26. A method of preparing the oral formulation of any one of items 1 to 14, comprising the steps: i. providing nicotine and an acid; ii. mixing the nicotine and the acid under continuous stirring to produce nicotine salt; and iii. adding oil to the mixture of ii., and stirring the mixture.

The examples described herein are illustrative of the present invention and are not intended to be limitations thereon. Many modifications and variations may be made to the techniques described and illustrated herein without departing from the spirit and scope of the invention. Accordingly, it should be understood that the examples are illustrative only and are not limiting upon the scope of the invention.

EXAMPLES

Example 1: Preparation of Nicotine Salt Solutions in Oil

The nicotine salt solutions in oil are prepared according to the following protocol.

Medium Chain Triglycerides (MCT) oil is used as the solvent in the preparation of Nicotine salt solutions, which are prepared utilizing standard laboratory techniques as described below. The nicotine USP/EP grade is commercially available nicotine free base.

Solution A1 : (Nicotine) For the preparation of 100 g of a solution with a final 1 .5% (w/w) concentration of nicotine free-base equivalent, 1 .5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 98.5 g MCT oil, the whole mixture is stirred at room temperature for 20 minutes. A visually homogeneous solution is obtained.

Solution B1 : (1 :0.99 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 1.12 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 97.38 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B2: (1 :0.95 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 1.07 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 97.43 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B3: (1 :0.8 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.90 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 97.60 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B4: (1 :0.75 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.85 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 97.65 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B5: (1 :0.5 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.56 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 97.94 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B6: (1 :0.33 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.38 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 98.12 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B7: (1 :0.25 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.28 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 98.22 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B8: (1 :0.2 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.23 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 98.27 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution B9: (1 :0.1 Nicotine / Benzoic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.11 g benzoic acid. Under continuous stirring, the mixture is warmed-up to 55°C for 20 minutes in an oil bath. A yellow oily mixture is obtained and the flask is removed from the heating bath. To the same flask, 98.39 g of MCT oil is then added and the whole mixture is stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C1 : (1 :0.99 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 2.59 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 95.91 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C2: (1 :0.95 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 2.48 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 96.02 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C3: (1 :0.8 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 2.09 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 96.41 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C4: (1 :0.75 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 1.96 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 96.54 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C5: (1 :0.5 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 1.31 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 97.19 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C6: (1 :0.33 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.87 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 97.63 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C7: (1 :0.25 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.65 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 97.85 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C8: (1 :0.2 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.52 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 97.98 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution C9: (1 :0.1 Nicotine / Oleic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.26 g oleic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 98.24 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution D1 : (1 :0.5 Nicotine / Levulinic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.54 g levulinic acid. The mixture is stirred at room temperature for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 97.96 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Solution E1 : (1 :0.5 Nicotine / Salicylic acid) For the preparation of 100 g of a solution with a final 1.5% (w/w) concentration of nicotine free-base equivalent, 1.5 g of nicotine is added to a flask equipped with a magnetic stirrer, followed by 0.64 g salicylic acid. The mixture is stirred at 55°C for 20 minutes. A light-yellow oily mixture is obtained. To the same flask, 97.86 g of MCT oil is then added and the whole mixture is again stirred at room temperature for further 20 minutes. A visually homogeneous solution is obtained.

Example 2: Production of a Seamless Soft Gelatine Capsule encapsulating a Formulation of Nicotine Salt and Oil of Example 1

The capsules (Fig. 1) were prepared by co-extrusion as described in EP Patent Application No. EP1310229 and have the following composition, according to tables 1 and 2 below.

Content of the capsules is shown in table 2, makeup of the capsule itself is shown in table 1.

Table 1. Capsules A0B1-0413-101

Table 2. Capsules A0B1-0413-101

Capsules outer diameter: 4134 +/- 52 pm

Capsules weight: 35.44 +/- 1 .56 mg

Example 3: Analysis of the Product

1. Determination of the nicotine content a. Direct analysis of the oil.

The content (in %) of nicotine free base in the oil can be directly analyzed utilizing the non-aqueous titration method for nicotine. The enhancement of acid or base strengths made possible by change of solvent can be used to extend the range of possible acid-base titrations (see Quantitative Chemical Analysis 6^th ed., D.C. Harris, pp. 245-246). A number of alkaloids and alkaloid derivatives have been identified in tobacco. The principal alkaloids are nicotine and nornicotine, nicotine forming 90%, nornicotine 8 or 9%, and other alkaloids 1 or 2% of the total alkaloid content. The structure of nicotine and its base dissociation constants are shown below:

In glacial acetic acid solvent (HOAc), both nitrogens are sufficiently basic that they may be titrated with HCIO4, as shown in Equation 3-5:

Although the titration really determines total alkaloid content, it is customary to report it as percent nicotine, the major factor. Nonaqueous Titration Protocol:

The presence of H2O in nonaqueous titration causes erratic results. All equipment should be free from H2O. Rinse all glassware with acetone; air-dry pipets and burets (Note 1 ).

Prepare approximately 0.05 N HCIO4 by adding 1 mL of concentrated HCIO4 to 250 mL of glacial acetic acid. The solution is standardized with potassium hydrogen phthalate (KHP) by the following procedure:

Transfer about 1 g of KHP to a weighting bottle, and dry for 1 to 2 hr at 110°C. Weigh out 0.2-g samples (±0.1 mg), and transfer to 125-mL Erlenmeyer flasks. Add 50 mL of glacial acetic acid, and heat carefully until the sample dissolves. Cool, add 4 drops of crystal violet indicator (Note 2), and titrate to the bright-blue endpoint (Notes 3, 4). Caculate the normality of the HCIO4 solution.

Obtain a nicotine oil sample (Formulations of Example 1 ), and weigh out 3-g samples. Pipet 100 mL of a 90% toluene-10% chloroform mixture into the flask, stopper tightly, and shake vigorously for 20 min. Pour off most of the organic solution through a fluted filter paper into a dry 125-mL Erlenmeyer flask. Add 2 g of anhydrous magnesium sulfate to the organic layer to dry it. Swirl the flask gently, stopper it, and let sit for at least 15 min. Pour the organic liquid through a fluted filter paper into a dry 250-mL Erlenmeyer flask.

Pipet a 25-mL sample of this organic solution into a dry 125-mL Erlenmeyer flask. Add a spin bar and 4 drops of crystal violet indicator solution. Titrate with 0.05 N perchloric acid in glacial acetic acid solution. Stir slowly while titrating. The volume required will be small, around 3 mL; so titrate cautiously. The endpoint color change is dark blue to forest green to yellow green to yellow. This occurs within 3 or 4 drops; so titrate very slowly, and stop at the first green.

When carrying out the calculations, it is important not to forget that only 25 mL of the organic phase was titrated and that n = 2 for nicotine. Report the percentage of nicotine in the formulation.

Notes

1. Caution: The solutions used in these titrations are toxic. Glacial acetic acid is very corrosive; perchloric acid is a strong oxidant and can cause spontaneous combustion or explosion of organic material. Wear nitrile gloves when working with these solutions and perform all titrations in a fume hood. 2. Preparation of crystal violet indicator: Dissolve 0.2 g of crystal violet in 100 mL of glacial acetic acid.

3. Volumes in this experiment will be fairly small, and a 25-mL buret, if available, is useful.

4. Only a few drops make a difference in the color transition of violet blue to bright blue to green to yellow. Be careful to stop at the bright blue.

The oil can also be directly analyzed utilizing a 907 Titrando (sold by metrohm) and following the protocol as published by metrohm (Titration Application Note T-175, Version 3- 06-2021AW TI CH1-1234-112016, published online under: https://www.metrohm.com/en/applications/AN-T-175) b. Analysis of nicotine dissolved in water

The nicotine content of the water phase of an oil-water partition experiment is determined by HPLC analysis following the protocol published by Alhusban and Ata (2021), or following the protocol published by Gholap et al. (2018).

2. Determination of the pH

In a separatory funnel, nicotine oil solution and saline water (distilled water containing 0.9%w/w NaCI) were mixed in a 1 :5 proportion. After shaking 5 times for 20 seconds at a 2-minute interval, the phases were allowed to separate and collected in separate beakers. A blank was done utilizing the same procedure with the pure MCT oil.

The pH of the water phase was determined utilizing a freshly calibrated pH meter.

Examples of pH measurements derived from the partition experiment of the following nicotine-containing oil solutions of Example 1 :

Blank (just MCT oil): pH = 6.66

Solution A1 (nicotine free base in oil): pH = 9.49

Solution B5 (nicotine salt in oil): pH = 8.21

Solution B6 (nicotine salt in oil): pH = 8.55

3. Determining nicotine salt in an oil solution

Upon partition, the amount of nicotine in the water and in the oil can be measured and the following results are found for solutions A1 (nicotine free base in oil) and B1 (nicotine benzoate in oil) from Example 1. Water phase can be measured by HPLC and oil phase by non-aqueous titration.

It can be shown that the nicotine present in the nicotine benzoate oil solution has a much higher tendency to partition into the water phase, Table 3, facilitating the absorption of the nicotine through the mucous membrane and into the blood stream.

Table 3: Determination of the partition of nicotine between the water and oil phases, 5:1 water/oil by weight

Example 4: Production of sachets filled with the spheres (gelatine capsules) of Example 3

The spheres of Example 3 were filled into a sachet using a pouch filling machine. Each sachet contains at least 1 sphere (target fill weight 30-1000 mg of oral formulation per sachet). The sachet is made of long fiber paper. The filled pouches were stored in plastic containers.

Example 5: Absorption of nicotine through the oral mucosa ex vivo

Ex vivo experiments were done to measure the amount of active ingredient which is available to a subject during a period of consumption of the product.

Method:

The subjects place the product under the upper lip. To ensure the same procedure for all the participants, the product is not allowed to be moved inside the buccal cavity and it is removed at different time points. The product is then removed, placed in a container with 10 g distilled water and shaken 5 times for 20 seconds at a 2- minute interval, this water fraction is then analyzed for the nicotine content.

Results:

The percentage of released nicotine from the product of the present invention (0.5 mg Sphere Sachets containing nicotine salt in oil; see Example 1 - solution B5) is compared to the nicotine release of a commercial product (3 mg Pouches containing dry solid nicotine salt, from on!, Helix Sweden AB, SE). The percentage nicotine is given as an average of 3 tests and is related to the average amount of nicotine in unused products for the same batch). Results are shown in Figure 3.

Example 6: User rating of nicotine craving relief

Users were given the product of the present invention (0.5 mg Sphere Sachets containing nicotine salt in oil; see Example 1 - solution B5) or a commercial product (3 mg Pouches containing dry solid nicotine salt, from on!, Helix Sweden AB, SE) and asked to rate the nicotine craving relief experienced, both the onset of craving relief as well as the duration. It was observed that for the present invention, the craving relief has a much faster onset and a longer duration for a much smaller nicotine amount, Table 4.

Table 4: Nicotine craving relief user rating.

REFERENCES

Alhusban and Ata, Simple HPLC method for rapid quantification of nicotine content in e-cigarettes liquids, Acta Chromatographica (2021), 33(3), 302-307.

Gholap et al., A Standardized Approach to Quantitative Analysis of Nicotine in e- Liquids Based on peak Purity Critera Using High-Performance Liquid Chromatography, Journal of Analytical Methods in Chemistry (2018), Article ID 1720375.

Prajapati, Bhupendra (2008), Seamless soft gelatine capsule manufacturing method.

Perfetti, Structural Study of Nicotine Salts, Beitrage zur Tabakforschung International (1983), 12(2), 43-54.

Pisinger et al., E-cigarettes, heated tobacco and other novel nicotine-containing products: a help to smokers or a public health threat? (2021), ERS Monograph Supporting Tobacco Cessation, 34-35.

Claims

1 . An oral formulation comprising nicotine salt dissolved in an oil phase, which is provided in an air-tight containment.

2. The oral formulation of claim 1 , wherein said nicotine salt is a monoprotonated salt, preferably wherein said nicotine salt is selected from nicotine benzoate, nicotine salicylate, nicotine levulinate, and nicotine oleate.

3. The oral formulation of claim 1 or 2, wherein said oil phase comprises vegetable oil, preferably medium-chain triglyceride (MCT) oil.

4. The oral formulation of any one of claims 1 to 3, further comprising nicotine free base.

5. The oral formulation of any one of claims 1 to 4, comprising nicotine at a concentration of at least 0.1 % and up to 10% by weight of the total weight of the oral formulation, preferably between 0.1-1.5%.

6. The oral formulation of any one of claims 1 to 5, wherein the formulation has a pH of 7.0 to 9.5, preferably 8.0 to 9.5, in an aqueous phase upon partitioning.

7. The oral formulation of claim 1 to 6, wherein the air-tight containment is a gel matrix, preferably wherein said gel matrix comprises a solid gel-forming material selected from the group consisting of gelatin, agar, carrageenan, alginate, pectins, gellan gum, arabic gum, ghatti gum, pullulan gum, mannan gum and modified starch, alone or as a mixture thereof.

8. The oral formulation of any one of claims 1 to 7, wherein the oral formulation is provided in the form of a spray, a film, a tablet or a lozenge.

9. An air-tight seamless capsule, comprising a filling which is an oral formulation comprising nicotine salt dissolved in an oil phase, preferably encapsulated in a gel matrix.

10. A capsule according to claim 9, wherein the filling is provided in the form of a liquid.

11. A water-permeable carrier comprising at least one capsule of claim 9 or 10, preferably wherein the carrier is a sachet, pouch, or pillow.

12. The carrier of claim 11 , which comprises or consists of a wrapping, preferably comprising any one or more of cellulose, paper, non-woven and woven fabric made of cotton, viscose, rayon, and/or silk.

13. The carrier of claims 11 or 12, further comprising tobacco material or tobacco fibers.

14. A nicotine consumer product comprising the oral formulation of any one of claims 1 to 8, or the capsule of claim 9 or 10, or the carrier of any one of claims 11 to 13.

15. A method of preparing the oral formulation of any one of claims 1 to 8, comprising the steps: i. providing nicotine and an acid; ii. mixing the nicotine and the acid under continuous stirring to produce nicotine salt; and iii. adding oil to the mixture of ii., and stirring the mixture.