RU2825844C1 - Pressed nicotine lozenge - Google Patents

Abstract

FIELD: smoking accessories.

SUBSTANCE: group of inventions relates to a water-soluble pressed lozenge for nicotine cravings relief and a method for production thereof. Water-soluble pressed nicotine lozenge for oral administration comprises a first module and a second module, the first and second modules are connected by crimping, first and second modules are formed by a plurality of compacted particles, the first module is a resorption module containing at least one sugar alcohol in an amount of at least 50 wt.% of first module, and the second module is an FDT module containing at least one sugar alcohol in an amount of at least 50 wt.% of second module, and nicotine, where the second module contains a baking powder, where the second module contains nicotine in amount of 0.2 to 5 wt.% of second module, where the leavening agent contains a superdisintegrant, where the superdisintegrant includes cross-linked polymers, where the amount of superdisintegrant is from 1 to 14 wt.% of second module, where the first module does not contain nicotine and where the first module contains a flavouring agent. Method for production of water-soluble pressed nicotine lozenge for oral administration includes the following stages: providing a first powder composition and a second powder composition, where the first powder composition contains at least one sugar alcohol in an amount of at least 50 wt.% of first powder composition, second powder composition contains at least one sugar alcohol in an amount of at least 50 wt.% of a second powder composition, and nicotine; pressing the first powder composition and the second powder composition to produce a modular lozenge, combined by pressing with the FDT-module, where the second powder composition contains a baking powder, where the second powder composition contains nicotine in amount of 0.2 to 5 wt.% of second powder composition, where baking powder contains superdisintegrant, where the superdisintegrant includes cross-linked polymers, where the amount of superdisintegrant is from 1 to 14 wt.% of second module, where the first module does not contain nicotine and where the first module contains a flavouring agent. Water-soluble pressed nicotine lozenge for oral administration comprises a first module and a second module, the first and second modules are combined by pressing, first and second modules are formed by a plurality of compressed particles, the first module is a modular lozenge and the second module is an FDT module containing nicotine, where the second module contains a baking powder, where the second module contains nicotine in amount of 0.2 to 5 wt.% of second module, where baking powder contains superdisintegrant, where superdisintegrant includes cross-linked polymers, where the amount of superdisintegrant ranges from 1 to 14 wt.% of second module, where the first module does not contain nicotine and where the first module contains a flavouring agent.

EFFECT: above-described compositions effectively relieve craving for nicotine, mask burning sensation.

80 cl, 1 dwg, 13 tbl, 70 ex

Description

AREA OF TECHNOLOGY

The invention relates to a pressed nicotine lozenge and a method for producing a pressed nicotine lozenge.

PREREQUISITES FOR THE CREATION OF THE INVENTION

Various types of delivery devices have been used to deliver nicotine orally to users. These delivery devices include pouches, chewing gum, and lozenges. The general expectation of users is that relief from nicotine cravings is achieved at the right time, but that they still experience pleasure during the nicotine administration.

However, in the technical field, a major challenge is to determine what consumers actually want in terms of consumer experience. What is important in terms of the nicotine effect in terms of craving and what are the important parameters in terms of taste and the user of delivery vehicles and, even more importantly, what are the most acceptable compromises between the various chains of reactions and experiences during use of the delivery vehicle.

These trade-offs have been a constant problem for the industry for many years.

The present invention addresses issues and trade-offs, particularly those associated with user expectations of nicotine delivery systems compared to what a user may experience, for example, when smoking a cigarette.

ESSENCE OF THE INVENTION

The invention relates to a water-soluble pressed nicotine lozenge for oral use, comprising a first module and a second module,

the first and second modules are connected by compression,

wherein the first module is a resorption module containing at least one sugar alcohol and

the second module is an FDT module containing at least one sugar alcohol and nicotine.

In this context, a module is defined as a plurality of pressed particles. A typical implementation of such a lozenge may be, for example, a lozenge consisting of two modules, a first and a second module, where each module represents a layer of the lozenge. In other words, such an example may be a two-layer lozenge. Another number of modules may also be used within the scope of the invention.

It should be noted that a module is understood in this context as a module that enables and facilitates the intended effect, i.e., the effective delivery or administration of nicotine, while at the same time providing the intended masking. This imposes some structural constraints on modules in the sense that modules must be large enough to be able to deliver not only nicotine but also the desired masking compounds and at the right time.

Thus, the module in the present context, in a preferred embodiment, comprises a set of compressed particles weighing at least 10% of the mass of the lozenge. In other words, the module is not intended to designate individual particles as is commonly understood in the field of tabletting.

As for the first module, which is a lozenge, a lozenge is a well-known term for medicinal tablets designed to dissolve or disintegrate slowly in the mouth, usually to release an active ingredient. Lozenges with various active ingredients are known, such as nicotine lozenges and lozenges for the temporary cessation of, for example, coughing, lubrication and soothing of irritated throat tissue (usually due to a sore throat).

The second module is designed and presented as a module which is itself characterized by being an FDT, i.e. a module having the characteristics of a so-called lozenge. Lozenges usually exhibit rapid disintegration, usually less than 60 seconds after being placed in the mouth or even faster, for example, 30 seconds after being placed in the mouth.

The idea of combining two structurally different modules, one of which contains nicotine, allows the creation of a lozenge that delivers nicotine in which taste masking and pleasure are combined with an impressive effect for the user.

The second module is typically designed to disintegrate in less than 60 seconds when administered orally as a multi-module lozenge.

However, surprisingly, the desired effect is achieved by masking the first module, but at the same time maintaining the nicotine concentration in the FDT below a certain level. The desired effect may, for example, include relief of nicotine craving, taste and/or pleasure perceived by the user.

Lozenges are an ideal way to give the nicotine user a quick dose/shot of nicotine that produces a rapid effect. However, this quick relief from cravings does not fully cover the pleasure often associated with the desired pleasure for the nicotine user. In addition, unwanted side effects can occur if the nicotine load is too high, delivered too quickly.

Thus, a long-lasting feeling of pleasure can be achieved by combining the feeling of rapid craving relief with the feeling of the second phase in one lozenge.

The compression/fusion of two such different compositions into a single multi-modular lozenge may not necessarily be trivial, as the invention requires a specific design to achieve the desired effect.

The invention, among many advantages, benefits from intuitive and uncomplicated use of nicotine compared to prior art delivery systems.

The time for the consumer can be easily reduced to about 5 minutes, i.e. similar to smoking a cigarette. The bitter taste of nicotine can be reduced.

An additional advantage of the invention may be that unexpectedly effective craving relief is achieved. Thanks to the second module, which is an FDT module containing at least one sugar alcohol and nicotine, the lozenge according to the invention promotes a rapid effect of nicotine, but at the same time it has been shown that it provides a stable craving relief, which is very effective. The presence of a very effective craving relief may additionally provide a reduction in the required dose of nicotine in the tablet without compromising the final effect. A lower dose of nicotine may, in turn, lead to a reduction in production costs, since nicotine can be relatively expensive, and may also help users who want to reduce their nicotine intake.

In a preferred embodiment of the invention, the first module provides suitable long-term masking of nicotine, while the second module provides a very rapid release of nicotine at a concentration, preferably below a certain level, thereby ensuring that the initial burning sensation is masked in the best possible way.

The use of the FDT module in the lozenge used as a carrier for nicotine release further facilitates the manufacture of reliable tablets, providing a prolonged release of masking compounds while prolonging the induced salivation during use of the tablet.

In a preferred embodiment, the second module contains nicotine in an amount of less than 5% by weight of the second module, for example less than 3% by weight of the second module, for example less than 2% by weight of the second module.

In an embodiment of the invention, the second module contains nicotine in an amount of 0.2-5% by weight of the second module, for example, 0.3-3% by weight of the second module, for example, 0.5-2% by weight of the second module.

In an embodiment of the invention, the second module contains nicotine in an amount of at least 0.2% by weight of the second module, for example at least 0.3% by weight of the second module, for example at least 0.5% by weight of the second module.

In a preferred embodiment of the invention, the mass of the second modules is from 50 to 250 mg, such as from 75 to 150 mg.

In this context, the invention presents an attractive biphasic delivery of masking, even though the nicotine delivery is “single-phasic”.

In a preferred embodiment of the invention, the second module contains nicotine in an amount of no more than 5% by weight of the module and at least 0.2 mg nicotine by weight of the module.

In a preferred embodiment of the invention, the second module contains at least 0.2 mg nicotine.

In a preferred embodiment of the invention, the second module contains from 0.2 to 5.0 mg nicotine, such as from 0.5 to 4.0 mg nicotine, such as from 1.0 to 3.0 mg nicotine.

In a preferred embodiment of the invention, the lozenge contains nicotine in an amount of at least 0.5 mg, such as at least 1.0 mg, such as at least 2.0 mg.

In a preferred embodiment of the invention, the lozenge contains nicotine in an amount of from 0.5 to 8.0 mg, such as from 1.0 to 6.0 mg, such as from 2.0 to 4.0 mg.

In one embodiment, the nicotine of the second module is selected from the group consisting of a nicotine salt, nicotine free base, nicotine bound to an ion exchanger such as an ion exchange resin such as nicotine polacrilex resin, a nicotine inclusion complex, or nicotine in any non-covalent bond; nicotine bound to zeolites; nicotine bound to cellulose such as microcrystalline cellulose or starch microspheres, and mixtures thereof.

In a preferred embodiment of the invention, the second module comprises a nicotine salt.

In an embodiment of the invention, the nicotine of the second module is a nicotine salt.

In an embodiment of the invention, the nicotine salt is selected from nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine bitartrate, nicotine chloride (e.g. nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, nicotine gensitate, nicotine lactate, nicotine mucate, nicotine laurate, nicotine levulinate, nicotine malate, nicotine perchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate, nicotine succinate, nicotine zinc chloride, nicotine sulfate, nicotine tosylate and nicotine hydrates (e.g. nicotine zinc chloride monohydrate).

In a preferred embodiment of the invention, the second module comprises nicotine bitartrate.

In an embodiment of the invention, the nicotine of the second module is nicotine bitartrate.

In an embodiment of the invention, the nicotine is nicotine bitartrate.

In a preferred embodiment of the invention, the second module comprises nicotine free base.

In a preferred embodiment of the invention, the nicotine of the second module is free base nicotine.

Free base nicotine includes nicotine mixed with sugar alcohols, modified calcium carbonate, water-soluble fibers, ion exchange resin, and combinations thereof. Nicotine bound to modified calcium carbonate is described in International Patent Application WO 2010/121619, incorporated herein by reference.

In a preferred embodiment of the invention, the first module contains nicotine.

In one embodiment, the nicotine of the first module is selected from the group consisting of a nicotine salt, a free base nicotine, nicotine bound to an ion exchanger such as an ion exchange resin such as nicotine polacrilex resin, a nicotine inclusion complex or nicotine in any non-covalent bond; nicotine bound to zeolites; nicotine bound to cellulose such as microcrystalline cellulose or starch microspheres, and mixtures thereof.

In a preferred embodiment of the invention, the first module comprises nicotine bound to an ion exchange resin.

In an embodiment of the invention, the nicotine of the first module is nicotine bound to an ion exchange resin.

In a preferred embodiment, the first module comprises nicotine polacrilex resin (NPR).

In an embodiment, the nicotine of the first module is nicotine polacrilex resin (NPR).

In a preferred embodiment of the invention, nicotine in the first module is absorbed by the midmucosa more slowly than nicotine in the second module.

In a preferred embodiment of the invention, the first module comprises a nicotine salt.

In an embodiment of the invention, the nicotine of the first module is a nicotine salt.

In an embodiment of the invention, the nicotine salt is selected from nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine bitartrate, nicotine chloride (e.g. nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, nicotine gensitate, nicotine lactate, nicotine mucate, nicotine laurate, nicotine levulinate, nicotine malate, nicotine perchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate, nicotine succinate, nicotine zinc chloride, nicotine sulfate, nicotine tosylate and nicotine hydrates (e.g. nicotine zinc chloride monohydrate).

In a preferred embodiment of the invention, the first module comprises nicotine bitartrate.

In an embodiment of the invention, the nicotine of the first module is nicotine bitartrate.

In a preferred embodiment of the invention, the first module does not contain nicotine.

Thus, in the above embodiment, and when the lozenge consists of a first and a second module, the second module contains nicotine.

In an embodiment of the invention, nicotine is contained in the second module. Thus, the first module and any additional modules, if any, do not contain nicotine.

In an embodiment of the invention, the lozenge comprises a nicotine salt.

In an embodiment of the invention, the nicotine in the lozenge is a nicotine salt.

In a preferred embodiment of the invention, the lozenge comprises nicotine bitartrate.

In an embodiment of the invention, the nicotine in the lozenge is nicotine bitartrate.

In a preferred embodiment of the invention, the lozenge contains free nicotine base.

In a preferred embodiment of the invention, the nicotine in the lozenge is free base nicotine.

In a preferred embodiment of the invention, the second module comprises a disintegrant.

In a preferred embodiment of the invention, the second module contains a disintegrant in an amount of from 0.5% to 25% by weight of the second module.

Leavening agent in this context refers to compounds other than sugar alcohols.

In a preferred embodiment of the invention, the disintegrant is selected from starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate and starch derivatives), cellulose, microcrystalline cellulose, alginates, ion exchange resin and super disintegrants such as cross-linked cellulose (such as sodium carboxymethyl cellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural super disintegrants, low-substituted hydroxypropyl cellulose (L-HPC) and calcium silicate and combinations thereof.

In an embodiment of the invention, the disintegrant comprises cross-linked polyvinylpyrrolidone.

In an embodiment of the invention, the disintegrant is a cross-linked polyvinylpyrrolidone.

The advantage of using cross-linked polyvinylpyrrolidone, also known as crospovidone, as a disintegrant may be that it reduces the dependence of the disintegration time on the compression force, while providing a fairly short disintegration time. In addition, due to the greater independence from the compression force, there is less variation between the second modules of different lozenges due to differences in compression force.

In an embodiment of the invention, at least 50% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 50 micrometers.

This corresponds to the commercial grades Kollidon CL-F and CL-SF available from BASF.

In an embodiment of the invention, at least 25% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 15 micrometers.

This corresponds to the commercial grade Kollidon CL-SF available from BASF.

The advantage of the above embodiment of using cross-linked polyvinylpyrrolidone with a smaller particle size is that a shorter disintegration time is ensured, for example, due to the larger relative surface area of the disintegrant particles.

In a preferred embodiment of the invention, the leavening agent comprises starch.

In a preferred embodiment of the invention, the disintegrant comprises low-substituted hydroxypropyl cellulose (L-HPC).

In a preferred embodiment of the invention, the disintegrant comprises super disintegrants, wherein the amount of super disintegrant is from 2 to 13% by weight of the second module, for example from 5 to 12% by weight of the second module.

In a preferred embodiment of the invention, super disintegrants comprise cross-linked polymers.

In a preferred embodiment of the invention, the super disintegrants are selected from the group of croscarmellose sodium, crospovidone and sodium starch glycolate.

In a preferred embodiment of the invention, the disintegrant comprises cross-linked polyvinylpyrrolidone.

In a preferred embodiment of the invention, at least 50% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 50 micrometers.

In a preferred embodiment of the invention, at least 25% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 15 micrometers.

In a preferred embodiment of the invention, the second module comprises a leavening agent and a sugar alcohol.

In a preferred embodiment of the invention, the second module comprises

nicotine in an amount from 0.2 mg to 5 mg,

sugar alcohol in an amount from 40 mg to 250 mg and

baking powder in an amount from 5 mg to 50 mg.

In a preferred embodiment of the invention, the average particle size used to compress the first module is greater than the average particle size used to compress the second module.

In a preferred embodiment of the invention, the average particle size of the particles used to compress the second module is less than 350 micrometers, such as 250 micrometers, such as 150 micrometers.

In a preferred embodiment of the invention, the particles used to press the second module comprise particles with a particle size of at least 500 micrometers, such as at least 750 micrometers, such as at least 100 micrometers.

In an embodiment of the invention, the particles used to press the second module contain at least 10% by weight of particles with a particle size of at least 500 micrometers, such as at least 750 micrometers, such as at least 100 micrometers.

In a preferred embodiment of the invention, the first module comprises at least 50% by weight of the lozenge, such as at least 60% by weight of the lozenge.

In a preferred embodiment of the invention, the first module comprises from 50% to 90% by weight of the lozenge, such as from 50% to 90% by weight of the lozenge, such as from 60% to 90% by weight of the lozenge, such as from 70% to 90% by weight of the lozenge, such as from 70% to 80% by weight of the lozenge, such as from 80% to 90% by weight of the lozenge, such as from 65% to 75% by weight of the lozenge.

In a preferred embodiment of the invention, the second module comprises at least 10% by weight of the lozenge, such as at least 20% by weight of the lozenge.

In a preferred embodiment of the invention, the second module comprises from 10% to 50% by weight of the lozenge, for example from 20% to 40% by weight of the lozenge, for example from 10% to 30% by weight of the lozenge, for example from 20% to 30% by weight of the lozenge.

In a preferred embodiment of the invention, the second module has an open surface area comprising a maximum of 50% of the total open surface area of the lozenge, such as 40% of the total open surface area of the lozenge, such as 30% of the total open surface area of the lozenge, such as 20% of the total open surface area of the lozenge.

In a preferred embodiment of the invention, the maximum total volume of the lozenge is 0.7 cm3, such as 0.6 cm3, such as 0.5 cm3, such as 0.4 cm3, such as 0.3 cm3.

In a preferred embodiment of the invention, the maximum total mass of the lozenge is 1 gram, such as 0.9 grams, such as 0.75 grams, such as 0.5 grams, such as 0.4 grams, such as 0.3 grams.

The advantage of lozenges with a volume below the maximum declared volume is the possibility of using the lozenge separately. In addition, it provides the possibility of self-titration.

In a preferred embodiment of the invention, the lozenge has a total weight of from 0.2 to 1 gram, such as from 0.2 to 0.9 grams, such as from 0.2 to 0.75 grams, such as from 0.2 to 0.5 grams.

Lozenges that have a volume below the maximum stated volume may provide the user with the desired disintegration time and dissolution time.

In a preferred embodiment of the invention, the second module is combined by compression with the first module using a minimum compression force of at least 10 kN, such as at least 15 kN, such as at least 20 kN, such as at least 25 kN, such as at least 30 kN.

In an embodiment of the invention, the second module is combined with the first module by compression with the application of a minimum compression force of 10 to 40 kN, such as 15 to 40 kN, such as 20 to 40 kN, such as 25 to 40 kN, such as 30 to 40 kN.

In an embodiment of the invention, the second module is combined with the first module by compression with the application of a minimum compression force of 10 to 40 kN, such as 15 to 35 kN, such as 20 to 30 kN.

When referring to the pressing force, this refers to the force applied when using a round punch with a diameter of 10.0 mm, unless otherwise specified. When using punches of other diameters or shapes, the pressing force is adjusted according to the punch area to obtain the required pressing pressure. A higher pressing pressure results in a higher pressing force, and vice versa.

In a preferred embodiment of the invention, the first module and the second module are two layers joined by compression.

The layers or modules of the lozenge may be formed in many different ways within the scope of the invention. As can be seen from the above, the lozenge may be round, oval or bordered, such as square.

In an embodiment of the invention, the lozenge consists of a first module and a second module, where the first and second modules are two layers that are combined upon compression.

In an embodiment of the invention, the second module at least partially encapsulates the first module.

In an embodiment of the invention, the second module encapsulates the first module.

The production of a lozenge with a first module encapsulated by a second module can be accomplished by applying a pressable coating as a second module around the first module.

In a preferred embodiment of the invention, the lozenge comprises at least one sugar alcohol in an amount of at least 50% by weight of the lozenge, such as at least 60% by weight of the lozenge, such as at least 70% by weight of the lozenge.

In an embodiment of the invention, the lozenge comprises at least one sugar alcohol in an amount of from 50 to 97% by weight of the lozenge, for example from 60 to 95% by weight of the lozenge, for example from 70 to 90% by weight of the lozenge.

In an embodiment of the invention, the lozenge comprises at least one sugar alcohol in an amount of from 50 to 97% by weight of the lozenge, for example from 60 to 97% by weight of the lozenge, for example from 70 to 97% by weight of the lozenge.

In an embodiment of the invention, the lozenge comprises at least one sugar alcohol in an amount of at least 75% by weight of the lozenge, such as at least 80% by weight of the lozenge, such as at least 85% by weight of the lozenge.

In an embodiment of the invention, the lozenge comprises at least one sugar alcohol in an amount of from 75 to 97% by weight of the lozenge, for example from 80 to 97% by weight of the lozenge, for example from 85 to 97% by weight of the lozenge.

In a preferred embodiment of the invention, at least one sugar alcohol of the second module comprises at least one sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, or any combination thereof.

In an embodiment of the invention, at least one sugar alcohol of the second module is selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, or any combination thereof.

In an embodiment of the invention, at least one sugar alcohol in the second module comprises mannitol, erythritol or xylitol.

In a preferred embodiment of the invention, at least one sugar alcohol of the second module comprises mannitol.

In a preferred embodiment of the invention, at least one sugar alcohol of the second module comprises erythritol.

In a preferred embodiment of the invention, at least one sugar alcohol of the second module has a solubility in water, measured at 20 degrees Celsius, of maximum 1000 g/l.

In an embodiment of the invention, at least one sugar alcohol of the second module has a solubility in water when measured at 20°C of from 10 to 1000 g/l.

In a preferred embodiment of the invention, the second module comprises at least one sugar alcohol in an amount of at least 50% by weight of the second module, such as at least 60% by weight of the second module, such as at least 70% by weight of the second module.

In an embodiment of the invention, the second module comprises at least one sugar alcohol in an amount of from 50 to 97% by weight of the second module, for example from 60 to 95% by weight of the second module, for example from 70 to 90% by weight of the second module.

In an embodiment of the invention, the second module comprises at least one sugar alcohol in an amount of from 50 to 97% by weight of the second module, for example from 60 to 97% by weight of the second module, for example from 70 to 97% by weight of the second module.

In an embodiment of the invention, the second module comprises at least one sugar alcohol in an amount of at least 75% by weight of the second module, for example at least 80% by weight of the second module, for example at least 85% by weight of the second module.

In an embodiment of the invention, the second module comprises at least one sugar alcohol in an amount of from 75 to 97% by weight of the second module, for example from 80 to 97% by weight of the second module, for example from 85 to 97% by weight of the second module.

In a preferred embodiment of the invention, at least one sugar alcohol of the second module comprises a non-DC (non-direct compression) sugar alcohol.

In a preferred embodiment of the invention, at least one sugar alcohol of the first module comprises at least one sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, or any combination thereof.

In an embodiment of the invention, at least one sugar alcohol of the first module is selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, or any combination thereof.

In a preferred embodiment of the invention, at least one sugar alcohol of the first module is selected from the group consisting of mannitol, erythritol, isomalt, sorbitol, or any combination thereof.

In a preferred embodiment of the invention, the first module comprises at least one sugar alcohol in an amount of at least 50% by weight of the first module, for example at least 60% by weight of the second module, for example at least 70% by weight of the first module.

In an embodiment of the invention, the first module comprises at least one sugar alcohol in an amount of from 50 to 97% by weight of the first module, for example from 60 to 95% by weight of the first module, for example from 70 to 90% by weight of the first module.

In an embodiment of the invention, the first module comprises at least one sugar alcohol in an amount of from 50 to 97% by weight of the first module, for example from 60 to 97% by weight of the first module, for example from 70 to 97% by weight of the first module.

In an embodiment of the invention, the first module comprises at least one sugar alcohol in an amount of at least 75% by weight of the first module, for example at least 80% by weight of the second module, for example at least 85% by weight of the first module, for example at least 90% by weight of the first module.

In an embodiment of the invention, the first module comprises at least one sugar alcohol in an amount of from 75 to 97% by weight of the first module, for example from 80 to 97% by weight of the first module, for example from 85 to 97% by weight of the first module, for example from 90 to 97% by weight of the first module.

In a preferred embodiment of the invention, the lozenge is substantially free of mono- and disaccharides.

In an embodiment of the invention, the lozenge does not contain sugar. Thus, in this embodiment, the lozenge does not contain sugar.

In a preferred embodiment of the invention, the lozenge contains a pH regulating agent.

In a preferred embodiment of the invention, the pH adjusting agent is selected from carbonates including monocarbonate, bicarbonate and sesquicarbonate, glycerol, phosphate, glycerophosphate, alkali metal acetate, glyconate or citrate, ammonium, Tris buffer, amino acids and any combination thereof.

In an embodiment of the invention, an encapsulated buffer such as Effersoda can also be used.

In a preferred embodiment of the invention, the pH adjusting agent is selected from sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, potassium bicarbonate, and any combination thereof.

Combinations of carbonate and bicarbonate may be particularly preferred. Such a combination may be, for example, a sodium carbonate-sodium bicarbonate buffer system, for example sodium carbonate and sodium bicarbonate in a weight ratio of 5:1 to 2.5:1, preferably in a weight ratio of 4.1:1 to 3.5:1.

In a preferred embodiment of the invention, the pH adjusting agent comprises or is sodium carbonate.

In a preferred embodiment of the invention, the lozenge comprises a pH regulating agent in an amount of at least 0.2% by weight of the lozenge, such as at least 0.3% by weight of the lozenge, such as at least 0.4% by weight of the lozenge, such as at least 0.5% by weight of the lozenge.

In an embodiment of the invention, the lozenge comprises a pH regulating agent in an amount of from 0.2 to 7% by weight of the lozenge, for example from 0.2 to 6% by weight of the lozenge, for example from 0.2 to 5% by weight of the lozenge, for example from 0.3 to 4% by weight of the lozenge, for example from 0.4 to 3% by weight of the lozenge, for example from 0.5 to 2% by weight of the lozenge.

In a preferred embodiment of the invention, the lozenge does not contain a pH adjusting agent.

In an embodiment of the invention, the lozenge comprises no more than 0.5% by weight of the pH regulating agent, such as no more than 0.2% by weight of the pH regulating agent, such as no more than 0.1% by weight of the pH regulating agent. Thus, in this embodiment, the lozenge may not comprise a pH regulating agent, or may comprise a pH regulating agent in an amount of no more than 0.5% by weight of the lozenge, such as no more than 0.2% by weight of the lozenge, such as no more than 0.1% by weight of the lozenge.

In a preferred embodiment of the invention, the first module comprises a pH regulating agent.

In a preferred embodiment of the invention, the first module comprises a pH regulating agent in an amount of at least 0.2% by weight of the first module, such as at least 0.3% by weight of the first module, such as at least 0.4% by weight of the first module, such as at least 0.5% by weight of the first module.

In an embodiment of the invention, the first module comprises a pH regulating agent in an amount of from 0.2 to 7% by weight of the first module, for example from 0.2 to 6% by weight of the first module, for example from 0.2 to 5% by weight of the first module, for example from 0.3 to 4% by weight of the first module, for example from 0.4 to 3% by weight of the first module, for example from 0.5 to 2% by weight of the first module.

In an embodiment of the invention, the first module does not contain a pH regulating agent.

In an embodiment of the invention, the first module comprises no more than 0.5% by weight of the pH regulating agent, for example no more than 0.2% by weight of the pH regulating agent, for example no more than 0.1% by weight of the pH regulating agent. Thus, in this embodiment, the first module may not contain the pH regulating agent, or contain the pH regulating agent in an amount of no more than 0.5% by weight of the first module, for example no more than 0.2% by weight of the first module, for example no more than 0.1% by weight of the first module.

In a preferred embodiment of the invention, the second module comprises a pH regulating agent.

In a preferred embodiment of the invention, the second module comprises a pH regulating agent in an amount of at least 0.2% by weight of the second module, for example at least 0.3% by weight of the second module, for example at least 0.4% by weight of the second module, for example at least 0.5% by weight of the second module.

In an embodiment of the invention, the second module comprises a pH regulating agent in an amount of from 0.2 to 7% by weight of the second module, for example from 0.2 to 6% by weight of the second module, for example from 0.2 to 5% by weight of the second module, for example from 0.3 to 4% by weight of the second module, for example from 0.4 to 3% by weight of the second module, for example from 0.5 to 2% by weight of the second module.

pH adjusting agents, such as alkaline buffering agents, suitable for use in the present invention include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, and potassium bicarbonate. In one embodiment, the buffering agents are selected from potassium bicarbonate, sodium carbonate, and mixtures thereof. The pH adjusting agents, such as buffering agents, can be included in the first and/or second module. The total amount of buffer present in the compositions of the present invention is from about 5 mg to about 20 mg. In one embodiment, the total amount of buffer present in the compositions of the present invention is from about 8 mg to about 12 mg. In one embodiment, the ratio of nicotine to total buffer is from about 3:1 to about 1:3 by total weight.

In an embodiment of the invention, the second module comprises a pH regulating agent in an amount of from 2.0 to 8.0% by weight of the second module, for example from 2.7 to 5.7% by weight of the second module.

In an embodiment of the invention, the second module does not contain a pH regulating agent.

In an embodiment of the invention, the second module comprises no more than 0.5% by weight of the pH regulating agent, for example no more than 0.2% by weight of the pH regulating agent, for example no more than 0.1% by weight of the pH regulating agent. Thus, in this embodiment, the second module may not contain the pH regulating agent, or contain the pH regulating agent in an amount of no more than 0.5% by weight of the second module, for example no more than 0.2% by weight of the second module, for example no more than 0.1% by weight of the second module.

In a preferred embodiment of the invention, the pH adjusting agent is a basic pH adjusting agent.

Thus, in the above embodiment, the pH adjusting agent of the first and/or second module is a primary pH adjusting agent.

In a preferred embodiment of the invention, the pH adjusting agent is a buffering agent.

Thus, in the above embodiment, the pH adjusting agent of the first and/or second module is a buffering agent.

In a preferred embodiment of the invention, the pH adjusting agent is a basic buffering agent.

Thus, in the above embodiment, the pH adjusting agent of the first and/or second module is a primary buffering agent.

In an embodiment of the invention, nicotine and a pH regulating agent are contained in the same module.

In an embodiment of the invention, nicotine and a pH-regulating agent are contained in opposite modules. In this embodiment, when the lozenge does not have additional modules in relation to the first and second modules, nicotine and a pH-regulating agent can be included in the first module and the second module, respectively, or vice versa.

In an embodiment of the invention, the first module comprises nicotine and a pH regulating agent.

In an embodiment of the invention, nicotine and a pH regulating agent are contained in the first module. Thus, the second module does not contain nicotine and a pH regulating agent.

One of the advantages of the above embodiment may be an improved taste and mouthfeel while maintaining the desired release and absorption of nicotine. In order to obtain the desired absorption of nicotine, it is desirable that nicotine is released into saliva with a relatively high pH. However, a pH adjusting agent added to obtain such a high pH may cause an unpleasant taste and mouthfeel, especially if it is located in the second module. However, by having a second module without a pH adjusting agent and instead including a pH adjusting agent in the first module, an acceptable pH of saliva can be obtained, thereby facilitating the absorption of nicotine, while giving the consumer the desired taste and mouthfeel without any unpleasant alkaline sensation.

In an embodiment of the invention, the second module comprises nicotine and a pH regulating agent.

In a preferred embodiment of the invention, nicotine and a pH regulating agent are contained in the second module.

Thus, in the above embodiment, the first module does not contain nicotine and a pH regulating agent.

In an embodiment of the invention, the first module comprises nicotine and the second module comprises a pH regulating agent.

In an embodiment of the invention, nicotine is contained in the first module and the pH regulating agent is contained in the second module. Thus, the first module does not contain the pH regulating agent and the second module does not contain nicotine.

In an embodiment of the invention, the second module comprises nicotine and the first module comprises a pH regulating agent.

In an embodiment of the invention, nicotine is contained in the second module, and the pH regulating agent is contained in the first module. The first module does not contain nicotine, and the second module does not contain the pH regulating agent.

In a preferred embodiment of the invention, the composition provides a peak nicotine concentration in saliva of greater than 0.3 mg/ml, such as greater than 0.5 mg/ml.

In a preferred embodiment of the invention, the composition provides a peak salivary pH of greater than 8 within the first 120 seconds after oral administration.

In a preferred embodiment of the invention, the lozenge contains a high intensity sweetener.

In an embodiment of the invention, the high intensity sweetener is selected from sucralose, aspartame, acesulfame salts such as acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside, and any combination thereof.

In an embodiment of the invention, the first module comprises a high intensity sweetener.

In a preferred embodiment of the invention, the high intensity sweetener is contained in the first module.

Thus, in the above embodiment, all of the high-intensity sweetener is contained in the first module, i.e., the second module does not contain high-intensity sweetener. An advantage of this embodiment may be that the lozenge is relatively easy to manufacture due to the limited amount of ingredients in each module, while still achieving unexpectedly good results in terms of taste and aroma perception for consumers.

In an embodiment of the invention, the second module does not contain a high intensity sweetener.

In an embodiment of the invention, the second module contains no more than 0.2% by weight of the high intensity sweetener, for example, no more than 0.1% by weight of the high intensity sweetener. Thus, in this embodiment, the second module may not contain the high intensity sweetener or may contain the high intensity sweetener, but only up to 0.2% by weight of the second module, for example, up to 0.1% by weight of the second module.

In an embodiment of the invention, the second module comprises a high intensity sweetener.

In an embodiment of the invention, the high intensity sweetener is contained in the second module.

Thus, in the above embodiment, all of the high intensity sweetener is contained in the second module, i.e. the first module does not contain any high intensity sweetener.

In an embodiment of the invention, the high intensity sweetener is contained in the first and second modules.

Thus, in the above embodiments, both the first and second modules comprise a high intensity sweetener.

In a preferred embodiment of the invention, the lozenge contains a flavoring agent.

In a preferred embodiment of the invention, the lozenge contains a flavoring agent in an amount of at least 0.1% by weight of the lozenge.

In an embodiment of the invention, the lozenge contains a flavoring agent in an amount of 0.1 to 15.0% by weight of the lozenge, for example, 0.1 to 10.0% by weight of the lozenge, for example, 0.1 to 5.0% by weight of the lozenge, for example, 0.2 to 3.0% of the weight of the lozenge.

In an embodiment of the invention, the first module comprises a flavoring agent.

In an embodiment of the invention, the first module contains a flavoring agent in an amount of at least 0.1% of the weight of the first module.

In an embodiment of the invention, the first module contains a flavoring agent in an amount of 0.1 to 15.0% by weight of the first module, for example, 0.1 to 10.0% by weight of the first module, for example, 0.1 to 5.0% by weight of the first module, for example, 0.2 to 3.0% by weight of the first module.

In a preferred embodiment of the invention, the flavoring agent is contained in the first module.

Thus, in the above embodiment, all of the flavoring agent is contained in the first module, i.e. the second module does not contain any flavoring agent.

An advantage of the above embodiment may be that the stability of nicotine is increased by facilitating the separation of nicotine from the flavouring agent and thus minimising any degradation of nicotine caused by the flavouring agent in the second module. An additional advantage of the above embodiment may be that the lozenge is relatively easy to manufacture due to the limited number of ingredients in each module, while still achieving unexpectedly good results in terms of taste and flavour perception for consumers.

In an embodiment of the invention, the second module contains no more than 0.2% by weight of the flavoring agent, for example, no more than 0.1% by weight of the flavoring agent. Thus, in this embodiment, the second module may not contain the flavoring agent or may contain the flavoring agent, but only up to 0.2% by weight of the second module, for example, up to 0.1% by weight of the second module.

In an embodiment of the invention, the second module contains a flavoring agent.

In an embodiment of the invention, the second module contains a flavoring agent in an amount of at least 0.1% of the weight of the second module.

In an embodiment of the invention, the second module contains a flavoring agent in an amount of 0.1 to 15.0% by weight of the second module, for example, 0.1 to 10.0% by weight of the second module, for example, 0.1 to 5.0% by weight of the second module, for example, 0.2 to 3.0% by weight of the second module.

In an embodiment of the invention, the flavoring agent is contained in the second module. Thus, in this embodiment, all of the flavoring agent is contained in the second module, i.e., the first module does not contain the flavoring agent.

In an embodiment of the invention, the first module contains no more than 0.2% by weight of the flavoring agent, for example, no more than 0.1% by weight of the flavoring agent. Thus, in this embodiment, the first module may not contain the flavoring agent or may contain the flavoring agent, but only up to 0.2% by weight of the first module, for example, up to 0.1% by weight of the first module.

In an embodiment of the invention, the flavoring agent is contained in the first and second modules, i.e. both modules contain the flavoring agent.

In an embodiment of the invention, nicotine and flavoring are contained in opposite modules.

An advantage of the above embodiment may be that the stability of nicotine is increased by facilitating the separation of nicotine from the flavoring agent and thus minimizing any degradation of nicotine caused by the flavoring agent.

In an embodiment of the invention, nicotine is contained in a first module and flavoring is contained in a second module.

In a preferred embodiment of the invention, nicotine is contained in the second module and flavoring is contained in the first module.

In a preferred embodiment of the invention, the flavoring agent is selected from the group consisting of menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, coffee, cinnamon, clove, tobacco, citrus and fruit flavoring agents and mixtures thereof.

Flavorings may, for example, be present in an amount of from about 1 mg to about 100 mg per lozenge.

In a preferred embodiment of the invention, the first module contains at least one mucoadhesive agent in an amount of 0.5 to 10% by weight of the first module.

In a preferred embodiment of the invention, the first module comprises dissolution modifiers.

In a preferred embodiment of the invention, dissolution modifiers include, but are not limited to, acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum and mixtures thereof.

In one embodiment, the dissolution modifiers included in the formulations of the present invention may be selected from the group consisting of alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum, and mixtures thereof. In one embodiment, the dissolution modifier is used in an amount of from about 10 to about 30 mg per lozenge, in another embodiment from about 15 to about 25 mg per lozenge.

In a preferred embodiment of the invention, the second module comprises a binding agent such as microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof.

In a preferred embodiment of the invention, the first module comprises a binding agent such as microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof.

In a preferred embodiment of the invention, the lozenge has a breaking point of at least 100 N, such as at least 150 N, such as at least 200 N.

In an embodiment of the invention, the lozenge has a breaking point of from 100 N to 400 N, such as from 150 N to 400 N, such as from 200 N to 400 N.

In an embodiment of the invention, the breakpoint is measured using a PTB 311 from Pharma Test.

The invention also relates to a method for producing a water-soluble pressed nicotine lozenge for oral use, wherein the method comprises the steps

- providing a first powder composition and a second powder composition, wherein the first powder composition comprises at least one sugar alcohol, the second powder composition comprises at least one sugar alcohol and nicotine,

- pressing the first powder composition and the second powder composition to obtain a modular lozenge combined by pressing with an FDT module.

In a preferred embodiment of the invention, the method comprises

- pressing the first powder composition to obtain a modular lozenge, and

- pressing the modular lozenge and the second powder composition to obtain an FDT module, combined by pressing with the modular lozenge.

In a preferred embodiment of the invention, the method comprises

- pressing the second powder composition to obtain an FDT module, and

- pressing the FDT module and the first powder composition to obtain a modular lozenge combined with the FDT module by pressing.

In a preferred embodiment, the pressing is carried out with a pressing force of at least 5 kN, such as at least 10 kN, such as at least 15 kN, such as at least 20 kN.

When referring to the pressing force, this refers to the force applied when using a round punch with a diameter of 10.0 mm, unless otherwise specified. When using punches of other diameters or shapes, the pressing force is adjusted according to the punch area to obtain the required pressing pressure. A higher pressing pressure results in a higher pressing force, and vice versa.

In an embodiment of the invention, pressing is carried out with a pressing force of 5 to 40 kN, for example 10 to 40 kN, for example 15 to 40 kN, for example 20 to 40 kN.

In an embodiment of the invention, a water-soluble compressed nicotine lozenge for oral use according to the invention or any of its variants is obtained by the method according to the invention or any of its variants of implementation.

In a preferred embodiment of the invention, The lozenge does not contain a coating.

In a preferred embodiment of the invention, the second module has a water content of less than 10 wt.%, such as less than 5 wt.%, such as less than 2 wt.%, such as less than 1 wt.%.

An advantage of the above embodiment may be that the stability of the second module is increased. This is possible in particular if the second module contains a disintegrant, such as a super disintegrant.

In an embodiment of the invention, the water content in the second module is 0-10% by weight, such as 0.01-5% by weight, such as 0.05-2% by weight, such as 0.1-1% by weight.

That is, in the above embodiments, the second module may not contain water.

In an embodiment of the invention, the first module has a water content of less than 10 wt.%, such as less than 5 wt.%, such as less than 2 wt.%, such as less than 1 wt.%.

In an embodiment of the invention, the first module has a water content of 0-10% by weight, such as 0.01-5% by weight, such as 0.05-2% by weight, such as 0.1-1% by weight.

That is, in the above embodiments, the first module may not contain water.

In a preferred embodiment of the invention, the water-soluble compressed nicotine lozenge for oral use has a water content of less than 10% by weight, such as less than 5% by weight, such as less than 2% by weight, such as less than 1% by weight.

In an embodiment of the invention, the water-soluble compressed nicotine lozenge for oral use has a water content of 0-10% by weight, such as 0.01-5% by weight, such as 0.05-2% by weight, such as 0.1-1% by weight.

That is, in the above embodiments, the water-soluble compressed nicotine lozenge for oral use may not contain water.

The invention also relates to a water-soluble pressed nicotine lozenge for oral use comprising a first module and a second module,

the first and second modules are joined by pressing,

the first module is a modular lozenge, and

The second module is an FDT module containing nicotine.

In an embodiment of the invention, a water-soluble compressed nicotine lozenge for oral use according to an embodiment is manufactured according to the first described water-soluble compressed nicotine lozenge for oral use or any of its embodiments, or is manufactured by the method of the invention, or any other embodiment thereof.

DRAWINGS

The invention will now be described with reference to the drawings, where

Fig. 1 shows the relief of traction using lozenges according to an embodiment of the invention.

DETAILED DESCRIPTION

As used herein, the term "water-soluble compressed nicotine lozenge for oral use" refers to a compressed tablet that generally dissolves slowly in water. Although the nicotine lozenge of the invention comprises a fast-dissolving FDT module, it also comprises a slowly dissolving modular lozenge. The nicotine lozenge, of course, does not comprise, for example, chewing gum modules that do not dissolve in water. In addition, the nicotine lozenge is water-soluble in the sense that it disintegrates and the main components dissolve in water. The nicotine lozenge of the invention is a compressed lozenge formed by compressing at least a first powder composition and a second powder composition to form a first and second layer, respectively. The nicotine lozenge may contain a certain amount of water-insoluble material, such as, for example, MCC. For example, the nicotine lozenge may dissolve within at least 2 minutes when administered orally, such as at least 3 minutes, such as at least 4 minutes, such as at least 5 minutes.

As used herein, the term "FDT module" (lozenge tablet module) refers to a lozenge module for oral administration. The FDT module disintegrates in the oral cavity relatively quickly after administration, for example, within about 60 seconds after oral administration.

As used herein, the term "modular lozenge" refers to a module that imparts lozenge properties, i.e., a module that slowly dissolves or disintegrates in the mouth, resulting in a slow release of its constituents, such as pH adjusting agents, flavoring, nicotine, etc., depending on the specific embodiment. For example, a modular lozenge can dissolve within at least 2 minutes when administered orally, such as at least 3 minutes, such as at least 4 minutes, such as at least 5 minutes.

As used herein, the term “disintegration” refers to the reduction of an object to components, fragments or particles. Disintegration times can be measured in vitro or in vivo. Unless otherwise specified, in vitro measurements are carried out in accordance with the European Pharmacopoeia 9.0, section 2.9.1, Disintegration of tablets and capsules.

As used herein, the term "dissolution" is the process by which a solid substance enters a solvent (saliva in the mouth) to form a solution. Unless otherwise specified, dissolution means complete dissolution of the compound in question.

As used herein, the term "disintegrant" refers to an ingredient that facilitates the disintegration of an FDT module when the FDT module comes into contact with saliva. Disintegrants useful within the scope of the invention may include starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate and starch derivatives), cellulose, microcrystalline cellulose, alginates, ion exchange resin and super disintegrants such as cross-linked cellulose (such as sodium carboxymethyl cellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural super disintegrants and calcium silicate. Disintegrants can often be thought of as a means of helping the module break down into smaller fragments when injected to facilitate the release of nicotine and eventual absorption.

As used herein, the term "nicotine" refers to nicotine in any form, including nicotine in the form of free base, nicotine salts, nicotine bound to ion exchange resins such as nicotine polacrilex, nicotine bound to zeolites; nicotine bound to cellulose such as microcrystalline cellulose fibers, for example of microbial origin, or starch microspheres, nicotine bound to CaCO3, and mixtures thereof. Thus, when referring to amounts of nicotine, also meant as a dose of nicotine, the amounts refer to the amount of pure nicotine. Thus, when measuring the concentration of nicotine added as a nicotine salt, the mass of the equivalent amount of pure nicotine is important, and not the mass of the salt. Nicotine also includes nicotine not obtained from tobacco, often referred to as synthetic nicotine. Nicotine is included in the second layer, and in some embodiments, also in the first layer. In other embodiments, nicotine is included in the second layer but not included in the first layer.

As used herein, the term "nicotine salt" refers to nicotine in ionized form associated with a counterion.

As used herein, the term "NBT" refers to nicotine bitartrate and its hydrates.

As used herein, the terms "%" and "percent" refer to mass percentages unless otherwise specified.

As used herein, the term "nicotine release" refers to nicotine that is made bioavailable, i.e. available for absorption through the mucous membranes in the oral cavity. While some forms of nicotine require dissolution to be bioavailable, other forms can be readily absorbed into the body without dissolution. For example, for nicotine to be bioavailable, the matrix of a solid formulation must disintegrate. Some forms of nicotine require further release of nicotine, such as from a carrier, such as nicotine from a nicotine ion exchange resin such as nicotine polacrilex. Other forms of nicotine, such as nicotine salts called nicotine bitartrate, can readily dissolve upon disintegration of the solid matrix. However, some forms of nicotine may not require dissolution. This is the case, for example, with nicotine freebase, which is released upon disintegration of the solid matrix.

The term "pH adjusting agent" as used herein refers to agents that actively adjust and regulate the pH of a solution to which they have been added or are to be added. Thus, pH adjusting agents can be acids and bases, including acidic buffering agents and alkaline buffering agents. On the other hand, pH adjusting agents do not include substances and compositions that can affect the pH only by dilution. In addition, pH adjusting agents do not include, for example, flavoring agents, fillers, etc.

As used herein, the term "buffering agent" is used interchangeably with "buffer" and refers to agents for producing a buffer solution. Buffering agents include acidic buffering agents, i.e., for producing a buffer solution with an acidic pH, and alkaline buffering agents, i.e., for producing a buffer solution with an alkaline pH.

When referring to amounts of an ingredient using terms such as "less than" or "no more than" it usually refers to the specific ingredient being absent or present in a range from trace amounts to the stated maximum amount.

In embodiments where the lozenge comprises fillers, various fillers can be used. Microcrystalline cellulose can be used as a filler in some embodiments of the invention. Examples of fillers suitable for use include magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds such as magnesium aluminum silicate, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers such as wood, starch polymers, fibers and combinations thereof.

In embodiments of the invention, mannitol is used as a bulk sweetener. Other suitable sweeteners include a sugar sweetener and/or a sugar-free sweetener.

Sweeteners can often support the flavor profile of a formulation.

Sugar sweeteners typically include, but are not limited to, saccharide-containing components such as sucrose, dextrose, maltose, sucrose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, glucose syrup, hydrogenated glucose syrup and the like, alone or in combination. These sugar sweeteners may also be included as a humectant.

Sugar-free sweeteners typically include, but are not limited to, sugar alcohols (also sometimes called polyols) such as sorbitol, erythritol, xylitol, maltitol, mannitol, lactitol, and isomalt.

Examples of suitable disintegrants include starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate and starch derivatives), cellulose, microcrystalline cellulose, alginates, ion exchange resin and super disintegrants such as crospovidone, sodium croscarmellose and sodium starch glycolate, cross-linked cellulose (such as sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural super disintegrants and calcium silicate, and combinations thereof.

Suitable high intensity sweeteners include, but are not limited to, sucralose, aspartame, acesulfame salts such as acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside and the like, alone or in combination.

Flavors used include Almond, Almond Amaretto, Apple, Bavarian Cream, Black Cherry, Black Sesame Seed, Blueberry, Brown Sugar, Bubblegum, Toffee, Cappuccino, Caramel, Caramel Cappuccino, Cheesecake (Graham Crust), Cinnamon Red Hot, Cotton Candy, Circus Cotton Candy, Clove, Coconut, Coffee, Pure Coffee, Double Chocolate, Energy Cow, Whole Grape Cracker, Grape Juice, Green Apple, Hawaiian Punch, Honey, Jamaican Rum, Kentucky Bourbon, Kiwi, Kool-Aid, Lemon, Lemon-Lime, Tobacco, Maple Syrup, Maraschino Cherry, Marshmallow, Menthol, Milk Chocolate, Mocha, Mountain Dew, Peanut Butter, Pecan, Peppermint, Raspberry, Banana, ripe banana, root beer, RY 4, peppermint, strawberry, sweet cream, sweet pie, sweetener, toasted almond, tobacco, tobacco blend, vanilla ice cream, vanilla cupcake, vanilla swirl, vanillin, waffle, Belgian waffle, watermelon, whipped cream, white chocolate, wintergreen, amaretto, banana cream, black walnut, blackberry, buttercream, creamy rum, cherry, chocolate hazelnut, cinnamon roll, cola, creme de menthe, eggnog, english toffee, guava, lemonade, licorice, maple, mint chocolate chip, orange cream, peach, pina colada, pineapple, plum, pomegranate, praline and cream, red licorice, sea salt toffee, strawberry banana, strawberry kiwi, tropical punch, tutti-frutti, vanilla or any combination of the two.

According to an embodiment of the invention, the flavoring agent may be used to mask the taste of nicotine.

In some embodiments of the invention, the first and/or second module comprises a pH adjusting agent.

In some embodiments of the invention, the pH adjusting agent comprises a buffer.

Buffering agents used include carbonate, including monocarbonate, bicarbonate and sesquicarbonate, glycerinate, phosphate, glycerophosphate, acetate, gluconate or citrate of an alkali metal, ammonium, Tris buffer, amino acids and mixtures thereof. An encapsulated buffer such as Effersoda may also be used.

A buffering agent may be added to the first and/or second module along with the water-soluble ingredients. The buffering agent in the lozenge may be used to achieve desired pH values in the saliva of the lozenge consumer.

In some embodiments, the buffering agent comprises sodium carbonate and sodium bicarbonate, for example, in a weight ratio of 5:1 to 2.5:1, preferably in a weight ratio of 4.1:1 to 3.5:1.

Silicon dioxide can be used as a glidant. Other glidants that can be used in the composition can also be used within the scope of the invention.

Magnesium stearate and/or sodium stearyl fumerate may be used as a lubricant. Other lubricants used in the composition may also be used within the scope of the invention.

Ready-to-use systems may be used within the scope of the invention. Typically, such ready-to-use systems may, for example, replace a filler, disintegrant, glidant or the like with a single powder mixture. Suitable ready-to-use systems for this purpose include, but are not limited to, Pearlitol Flash (Roquette), Pharmaburst 500 (SPI Pharma), Ludiflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (Fuji Chemical), SmartEx50 or SmartEx100 (Shin Etsu/Harke Pharma). The use of ready-to-use systems containing a disintegrant may be particularly advantageous.

To obtain an FDT module designed to disintegrate within 60 seconds when administered orally, a number of parameters can be adjusted.

First, by changing the composition, the disintegration time can be changed. Using ingredients with high solubility in water can help reduce the disintegration time.

In particular, the inclusion of a leavening agent can significantly affect the disintegration time depending on the overall composition of the second module. In addition, by changing the amount and type of leavening agent, the disintegration time can be further controlled. For example, if it is desired that the second layer has a shorter disintegration time, the proportion of leavening agent can be increased and/or the type of leavening agent can be at least partially replaced by a more effective leavening agent.

In addition, decreasing the particle size of the leavening agent results in a decrease in disintegration time, probably due to an increase in the surface area to volume ratio.

In addition, the compression force used to press the second module significantly correlates with the obtained hardness of the second module, so that a high compression force usually increases the hardness of the obtained second module. By adjusting the hardness of the second module, it is also possible to influence the disintegration time, so that a lower hardness usually gives a shorter disintegration time. In this case, for a number of compositions, it was found that by applying the correct compression force, it is possible to achieve a disintegration time of less than 60 seconds when administered orally, whereas too high a compression force can lead to a longer disintegration time, exceeding 60 seconds. In this regard, it is noted that the threshold compression force can vary significantly depending on other parameters, such as the overall composition, the content and type of disintegrant, etc. When, for example, a certain setting leads to too slow disintegration, a further method of adjustment may consist in replacing the normal disintegrant with a super disintegrant, i.e. which facilitates disintegration in a more effective manner.

Increasing water solubility can also be achieved by replacing ingredients with low water solubility with ingredients with higher water solubility. For example, using sugar alcohols as fillers can be very beneficial because sugar alcohols have higher water solubility than alternative fillers.

In addition, the use of sugar alcohols with lower compressibility results in a reduction in disintegration time. Too low compressibility may compromise the mechanical strength of the second module and the pastille and lead to undesirably high brittleness and the risk of cracking, etc.

Additional examples of parameters that can be adjusted to achieve a second module designed to disintegrate within 60 seconds when administered orally include the size and shape of the second module and lozenge. The larger the volume of the second module, the longer the disintegration time and therefore the release time of nicotine and pH adjusting agent.

For example, increasing the flatness (e.g. quantified by the diameter to height ratio) for, e.g., disk pastilles typically reduces the disintegration time by increasing the surface to volume ratio. As long as the pastille has satisfactory mechanical strength, the flatness can be increased.

In addition, changing the cross-sectional profile of the convex type lozenge to a concave lozenge reduces the disintegration time. It is noted that this may reduce the mechanical strength of the lozenge to some extent, but as long as it is satisfactory, the concave cross-section can help to increase disintegration and thus reduce the disintegration time.

Furthermore, when using binding agents, for example to obtain higher cohesivity and mechanical strength of the lozenge, the amount of such binding agents can be reduced as much as possible to obtain a higher disintegration rate and thus a shorter disintegration time. Some disintegrants can also act as binding agents, for example PVP.

Additionally, by adding a salivary inducing agent to the nicotine lozenge, it is possible to provide increased amounts of saliva near the lozenge, which again promotes dissolution and disintegration of the second module to reduce disintegration time.

In addition, the type and amount of lubricant, if any, can be adjusted to optimize disintegration time. For example, the use of sodium stearyl fumarate (SSF) generally results in a shorter disintegration time compared to the use of magnesium stearate MgSt.

Thus, when designing a second module with a disintegration time of 60 seconds when administered orally, a wide range of parameters can be adjusted.

Typically, the composition of the second module may include ingredients selected from the group consisting of bulk sweeteners, fillers, ready-to-use systems, flavors, dry binders, disintegrants, further super disintegrants, tabletting additives, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffering agents, high-intensity sweeteners, colors, glidants, lubricants or any combinations thereof. Absorption enhancers may include, for example, pH adjusting agents such as buffering agents and mucoadhesive agents.

According to an embodiment of the invention, at least a portion of the nicotine adheres to particles of the dry binding agent.

According to an embodiment of the invention, a certain amount of a dry binding agent is used to adhere nicotine to the bulk sweetener.

EXAMPLES

Examples 1-8 - changing the amount of nicotine

They make 500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

Layer 1 composition is prepared by pouring approximately half of the sugar alcohol into a mixing bowl, then adding the remaining ingredients except the lubricant, and finally the remaining sugar alcohol. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 minutes at 49 rpm.

A pre-mixed MgSt-sugar alcohol mixture prepared by mixing MgSt with approximately 5% sugar alcohol in a mixer (Turbula or Duma) for 1 min at 49 rpm is added and the ingredients are further mixed for 1-2 min at 49 rpm.

Layer 2 is prepared by pouring all ingredients except the lubricant into a mixing bowl. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 minutes at 49 rpm.

A pre-mixed MgSt-sugar alcohol mixture prepared by mixing MgSt with approximately 5% sugar alcohol in a mixer (Turbula or Duma) for 1 min at 49 rpm is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The lubricated powder mixtures are transferred sequentially into the hopper of the tablet machine.

Layer 1 is then compressed with a compressive force of approximately 3 kN, after which layer 2 is combined by compression with layer 1 with a compressive force of approximately 15-20 kN. The punch used is 10.00 mm, round, shallow concave, tool D.

Lozenges are manufactured on laboratory machines, such as the RIVA Piccola dual-layer tablet press. The tablet press is prepared by adjusting the filling depth and compression force so that the lozenge weight and hardness meet the acceptance criteria. Pre-compression force can be switched on to avoid clogging.

Table 1. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight) Example 1 2 3 4 5 6 7 8 Raw material layer 1 Content in mass fractions of layer 1 Mannitol 97.75 97.75 97.75 97.75 97.75 97.75 97.75 97.75 Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw material layer 2 Content in mass fractions of layer 2 Mannitol 88.75 87.25 85.75 84.25 82.75 81.25 78.25 75.25 Baking powder 8 8 8 8 8 8 8 8 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 1.5 3.0 4.5 6.0 7.5 9 12.0 15.0 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

Mannitol can be used as a sugar alcohol in layer 1 and layer 2. Other useful sugar alcohols for use in layer 1 can include sorbitol, erythritol, xylitol, maltitol, lactitol and isomalt. Of these, isomalt, erythritol and sorbitol are particularly preferred. Other useful sugar alcohols for use in layer 2 can include sorbitol, erythritol, xylitol, maltitol, lactitol and isomalt. The disintegrant in layer 2 can be, for example, a starch-based disintegrant. In embodiments of the invention, the disintegrant can be supplied as part of a ready-to-use system, for example, Pearlitol Flash from Roquette, a mannitol-based product containing about 17% by weight of disintegrant. Examples of other ready-to-use systems include, for example, Pharmaburst 500 (SPI Pharma), Ludiflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (Fuji Chemical), SmartEx50 or SmartEx100 (Shin Etsu/ Harke Pharma).

Preferred high intensity sweeteners (HIS) may be, for example, sucralose, acesulfame potassium and mixtures thereof. Other high intensity sweeteners, such as aspartame, acesulfame salts such as acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside, individually or in combination, may also be used within the scope of the invention.

Menthol, peppermint and mixtures thereof may be used in the above compositions as flavoring agents. Other flavoring agents may also be used within the scope of the invention.

Sodium carbonate can be used as a buffer. Additional buffers that can be used include other carbonates including monocarbonates, bicarbonates, and sesquicarbonates, glycerol, phosphate, glycerophosphate, alkali metal acetate, gluconate, or citrate, ammonium, Tris buffer, amino acids, and mixtures thereof.

Above, MgSt (magnesium stearate) is used as a lubricant. Other lubricants, such as sodium stearyl fumerate, may also be used within the scope of the invention.

In Examples 1-8, starch is used as a disintegrating agent. Examples of other disintegrating agents suitable for use include, for example, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate and starch derivatives), cellulose, microcrystalline cellulose, alginates and ion exchange resin.

Examples 9-16 - Using Super Baking Powder

500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

The lozenges are prepared as described for examples 1-8.

Table 2. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight) Example 9 10 11 12 13 14 15 16 Raw materials Content in mass fractions of layer 1 Mannitol 97.75 97.75 97.75 97.75 97.75 97.75 97.75 97.75 Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Mannitol 94.25 93.25 91.25 89.25 87.25 85.25 83.25 81.25 Super baking powder 1 2 4 6 8 10 12 14 Taste 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

In Examples 9-16, crospovidone is used as a super disintegrant. Alternative super disintegrants may, for example, include cross-linked cellulose (such as sodium carboxymethylcellulose), cross-linked starch, cross-linked alginic acid, natural super disintegrants, low-substituted hydroxypropyl cellulose (L-HPC), and calcium silicate.

Alternative ingredients as described with respect to Examples 1-8 may also be used for Examples 9-16.

Examples 17-24 - Using baking powder

500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

The lozenges are prepared as described for examples 1-8.

Table 3. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight) Example 17 18 19 20 21 22 23 24 Raw materials Content in mass fractions of layer 1 Mannitol 97.75 97.75 97.75 97.75 97.75 97.75 97.75 97.75 Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Content of starch leavening agent 2 4 6 8 10 12 14 16 Mannitol 84.95 73.25 61.45 49.65 37.95 26.15 14.35 2.65 Pearlitol Flash 11.8 23.5 35.3 47.1 58.8 70.6 82.4 94.1 Flavor additive 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

The stated starch leavening agent content is included in Pearlitol Flash, a commercially available ready-to-use system from Roquette.

Pearlitol Flash is used, containing approximately 17% by weight of starch disintegrant. Examples of other ready-to-use systems include, for example, Pharmaburst 500 (SPI Pharma), Ludiflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (Fuji Chemical), SmartEx50 or SmartEx100 (Shin Etsu/Harke Pharma).

The alternative ingredients described in relation to Examples 1-16 may also be used for Examples 17-24.

Examples 25-32

500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

The lozenges are prepared as described for examples 1-8.

Table 4. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight), NPR = nicotine polacrilex resin (nicotine content 15% by weight) Example 25 26 27 28 29 30 31 32 Raw materials Content in mass fractions of layer 1 Mannitol 95.85 93.95 92.05 90.15 97.75 97.75 97.75 97.75 Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NPR 1.9 3.8 5.7 7.6 - - - - MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Mannitol 88.75 88.75 88.75 88.75 87.75 86.75 85.75 83.75 Super baking powder 8 8 8 8 8 8 8 8 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Buffer - - - - 1 2 3 5 Total layer 2 100 100 100 100 100 100 100 100

The alternative ingredients described with respect to Examples 1-24 may also be used for Examples 25-32.

Examples 25A-32A

500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

The lozenges are prepared as described for examples 1-8.

Table 4A. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight), NPR = nicotine polacrilex resin (nicotine content 15% by weight) Example 25A 26A 27A 28A 29A 30A 31A 32A Raw materials Content in mass fractions of layer 1 Mannitol 96.35 94.45 92.55 90.65 94.35 94.45 90.55 86.65 Buffer - - - - 2.0 - 2.0 4.0 Flavor additive 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NPR 1.9 3.8 5.7 7.6 1.9 3.8 5.7 7.6 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Mannitol 83.75 83.75 83.75 83.75 85.75 88.75 85.75 87.75 Super baking powder 8 8 8 8 8 8 8 8 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Buffer 5 5 5 5 3 - 3 1 Total layer 2 100 100 100 100 100 100 100 100

The alternative ingredients described with respect to Examples 1-24 may also be used for Examples 25A-32A.

Examples 33-40 - Various sugar alcohols

500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

The lozenges are prepared as described for examples 1-8.

Table 5. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight) Example 33 34 35 36 37 38 39 40 Raw materials Content in mass fractions of layer 1 Mannitol 97.75 - - - 50,00 50,00 50,00 - Isomalt - 97.75 - - 47.75 - - 50,00 Sorbitol - - 97.75 - - 47.75 - 47.75 Maltitol - - - 97.75 - - 47.75 - Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Mannitol 88.75 78,75 68.75 58.75 48.75 38.75 - 58.75 Erythritol - 10 20 30 40 50 88.75 - Xylitol - - - - - - - 30 Baking powder 8 8 8 8 8 8 8 8 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

The alternative ingredients described with respect to Examples 1-32 may also be used for Examples 33-40.

Examples 41-48

Examples 41-42 are 400 mg nicotine lozenges, each consisting of 300 mg of the first module and 100 mg of the second module.

Examples 43-48 are 500 mg nicotine lozenges, each consisting of 350 mg of the first module and 150 mg of the second module.

Taking into account the above, lozenges are obtained as described for examples 1-8.

Table 6. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight) Example 41 42 43 44 45 46 47 48 Raw materials Content in mass fractions of layer 1 Mannitol 93.3 - - - - - - - Isomalt - 93.3 98.20 98.20 98.20 98.20 - 96.06 Sorbitol - - - - - - 98.20 0 HIS 1.7 1.7 0.25 0.25 0.25 0.25 0.25 0.25 Flavor additive 4.0 4.0 1.05 1.05 1.05 1.05 1.05 1.05 Xanthan gum - - - - - - - 2.14 MgSt 1.0 1.0 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Mannitol 75,00 75,00 95.25 46,42 - 46.08 95.25 95.25 Erythritol - - - - - 49.07 - - Pearlitol Flash - - - 48.83 95.25 - - - MCC 5.00 5.00 - - - - - - Super baking powder 10.00 10.00 - - - - - - Buffer 5.00 5.00 - - - - - - HIS - - 0.25 0.25 0.25 0.25 0.25 0.25 Flavor additive - - 1.00 1.00 1.00 1.00 1.00 1.00 MgSt - - 0.50 0.50 0.50 0.60 0.50 0.50 Sodium stearyl fumerate 2.00 2.00 - - - - - - NBT 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Total layer 2 100 100 100 100 100 100 100 100

Examples 41-42 illustrate the use of MCC (microcrystalline cellulose) as a binder in layer 2 and sodium stearyl fumerate as a glidant in layer 2.

The alternative ingredients described with respect to Examples 1-40 may also be used for Examples 41-48.

Examples 41A-48A

Examples 41A-48A are 300 mg nicotine lozenges, each consisting of 225 mg of a first module and 75 mg of a second module.

Taking into account the above, lozenges are obtained as described for examples 1-8.

Table 6A. Compositions of the first and second layers. NBT = nicotine bitartrate (nicotine content 32.38% by weight) Example 41A 42A 43A 44A 45A 46A 47A 48A Raw materials Content in mass fractions of layer 1 Mannitol 94.0 94.0 94.0 94.0 94.0 - 94.0 94.0 Isomalt - - - - - 94.0 - - HIS 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Flavor additive 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 MgSt 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Total layer 1 100 100 100 100 100 100 100 100 Raw materials Content in mass fractions of layer 2 Mannitol 75.0 75.0 78.0 80.5 79.5 78.5 85.0 83.0 MCC 5.0 4.0 2.0 2.0 2.0 2.0 2.0 2.0 Super baking powder 10.0 10.0 10.0 7.5 7.5 7.5 5.0 5.0 Buffer 5.0 5.0 5.0 5.0 5.0 5.0 3.0 3.0 HIS - - - - - 1.0 - 1.0 Flavor additive - 1.0 - - 1.0 1.0 - 1.0 MgSt 1.0 - - 1.0 1.0 1.0 - - Sodium stearyl fumerate - 1.0 1.0 - - - 1.0 1.0 NBT 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Total layer 2 100 100 100 100 100 100 100 100

The alternative ingredients described with respect to Examples 1-40 may also be used for Examples 41A-48A.

Examples 49-56 - Nicotine sources and ready-to-use systems

500 mg nicotine lozenges, each containing 350 mg of the first module and 150 mg of the second module.

The lozenges are prepared as described for examples 1-8.

Table 7. Compositions of the first and second layers. NBT=nicotine bitartrate (nicotine content 32.38% by weight). Example 49 50 51 52 53 54 55 56 Raw material layer 1 Content in mass fractions of layer 1 Mannitol 97.75 97.75 97.75 97.75 97.75 97.75 97.75 97.75 Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw material layer 2 Content in mass fractions of layer 2 Nicotine calcium carbonate* 3.0 - - - - - - - Nicotine-MCC* - 3.0 - - - - - - Nicotine Soluble Fiber* - - 3.0 - - - - - Nicotine sugar alcohol* - - - 3.0 - - - - NBT - - - - 3.0 3.0 3.0 3.0 Mannitol 79.7 79.7 79.7 79.7 - - - - Ludiflash - - - - 84.7 - - - SmartEx QD50 - - - - - 84.7 - - F-Melt - - - - - - 84.7 - ProSolv ODT G2 - - - - - - - 84.7 Crospovidone 5.0 5.0 5.0 5.0 - - - - Flavor additive 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 HIS 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Buffer 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 MgSt 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Total 100,0 100,0 100,0 100,0 100,0 100,0 100,0 100,0 *free nicotine base, sorbed on the carrier in a mass ratio of 1:2

The alternative ingredients described with respect to Examples 1-48 may also be used for Examples 49-56.

Examples 57-64 - Sugar Alcohol Particle Size and Dissolution Modifiers

The lozenges are prepared as described for examples 1-8.

Table 8. Compositions of the first and second layers. NBT=nicotine bitartrate (nicotine content 32.38% by weight). Example 57 58 59 60 61 62 63 64 Raw material layer 1 Content in mass fractions of layer 1 Mannitol DC 300 97.75 - - 92.25 92.25 92.25 95.50 95.50 Mannitol 150 SD - 97.75 - - - - - - Mannitol 200 SD - - 97.75 - - - - - Sodium alginate - - - 5.5 - - - 2.25 Calcium polycarbophil - - - - 5.5 - - - Xanthan gum - - - - - 5.5 2.25 - Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw material layer 2 Content in mass fractions of layer 2 Mannitol 88.75 87.25 85.75 84.25 82.75 81.25 78.25 75.25 Baking powder 8 8 8 8 8 8 8 8 Flavor additive 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 NBT 1.5 3.0 4.5 6.0 7.5 9 12.0 15.0 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

Mannitol DC 300, Mannitol 150 SD and Mannitol 200 SD are commercially available from Roquette and have different average particle sizes.

The alternative ingredients described with respect to Examples 1-56 may also be used for Examples 57-64.

Example 65. Estimates - first layer of examples 43 and 47

Each of examples 43 and 47 is prepared in three variants, where the applied pressure used to press the first layer is 10 kN, 20 kN and 30 kN (single punch device with a punch diameter of 10.0 mm), respectively. For each of these versions, five nicotine lozenges are prepared.

For each variant of lozenges 43 and 47, a break point test, a brittleness test and a dissolution time measurement are carried out for the first layer.

To measure the breakpoint, use the PTB 311 from Pharma Test.

The brittleness test involves assessing the number of broken layers obtained. When all five are intact, a "pass" rating is assigned, while one or more broken layers are indicated by the number of broken layers. Alternatively, brittleness can be used as a measure of brittleness.

The following method is used to test the dissolution time. 15 ml of 0.02 M potassium dihydrogen phosphate buffer (pH adjusted to 7.4) is added to 50 ml of water in a screw-capped measuring tube. The lozenge is inserted into the measuring tube and the cap is screwed on. The measuring tube is fixed horizontally. The measuring tube is shaken at approximately 110 rpm so that the lozenge can move back and forth in the measuring tube. The measuring tube is shaken until the lozenge or module in question is completely dissolved, and the shaking time is noted as the dissolution time.

Table 9. Fragility test indicates the number of lozenges broken during testing or “passed” if no lozenges were broken. Test Compression force [kN] Example 43
Layer 1 (pastille) Example 47
Layer 1 (pastille) Example 48
Layer 1 (pastille) Breaking point 10
20
30 193 N
232 N
205 N 237 H
239 H
249 H 195 N
229 H
220 N Fragility 10
20
30 Passed
Passed
Passed Passed
Passed
Passed Passed
Passed
Passed Dissolution time 10
20
30 9 min, 7 sec
9 min 41 sec
9 min 50 sec 6 min, 12 sec
6 min, 38 sec
7 min 05 sec 12 min 10 sec
13 min 32 sec
16 min 0 sec

As can be seen from Table 9, the breaking point test shows that Example 47, having a first layer based on sorbitol as the sugar alcohol, gives a higher breaking point than Example 43, having a first layer based on isomalt as the sugar alcohol. Example 43 showed that the version pressed with a force of 30 kN actually has a lower breaking point than the version pressed with a force of 20 kN, indicating that the pressing force of 30 kN would be too high and that the direct compressibility of the sugar alcohol (isomalt) is impaired.

Additionally, it was noted that all layers tested passed the brittleness test, meaning that none of the five layers of each version were rated as brittle or fractured during production.

In addition, dissolution time testing showed that sorbitol-based example 47 generally dissolves faster than isomalt-based example 43. In addition, higher compression forces result in longer dissolution times.

Finally, example 48 is compared with example 43. Example 48 is somewhat similar to example 43, but additionally contains xanthan gum. As can be seen from Table 9, the addition of xanthan gum did not noticeably affect the breaking point test or the friability test, but the dissolution time increased significantly from about 9-10 minutes, such as 43, to about 12-16 minutes, such as 48, demonstrating the effect of xanthan gum in slowing down the dissolution and therefore the release of its components such as sugar alcohol, flavor, nicotine (if any), etc. In obtaining the above, no reduction in the masking effect of the first layer is observed.

Example 66. Evaluation - the second layer of examples 43, 44, 45 and 46.

Each of examples 43, 44 and 45 are prepared in three versions, where the applied pressure used to press the first layer is 10 kN, 20 kN and 30 kN, respectively. For each of these versions, five nicotine lozenges are prepared.

For each variant of lozenges 43, 44 and 45, a break point test, a brittleness test and a dissolution time measurement are carried out on the second layer.

Table 10. The friability test indicates the number of lozenges crushed during the test, or “pass” if no lozenges were crushed. Test Compression force [kN] Example 43
Layer 2 (FDT) Example 44
Layer 2 (FDT) Example 45
Layer 2 (FDT) Example 46
Layer 2 (FDT) Breaking point 10
20
30 50 N
N/A
N/A 46 H
55 N
72 H 43 H
62 H
73 H 13n
20 N
11 H Fragility 10
20
30 1 lozenge
N/A
N/A 1 lozenge
Passed
Passed 1 lozenge
Passed
Passed 5 lozenges
5 lozenges
5 lozenges Dissolution time 10
20
30 2 min, 20 sec
N/A
N/A 50 sec
1 min, 15 sec
2 min 08 sec 50 sec
50 sec
1 min 17 sec 35 sec
1 min 40 sec
2 min 50 sec

Firstly, looking at Examples 43-45, Table 10 shows that the rupture point of the second layers of the obtained pastille generally increases with increasing compression force from 10 kN to 30 kN.

However, Table 10 also shows that fragility may be a concern. It should be noted that Example 43 performed quite well, with only 1 lozenge breaking during testing.

Table 10 also shows that there may be a trade-off between applying enough compressive force to produce a non-brittle second layer, but increasing compressive force also affects dissolution time.

In addition, it was noted that the use of a leavening agent in the second layer (examples 44-45) resulted in a reduction in dissolution time compared to the absence of a leavening agent in the second layer (example 43), and, in addition, an increase in the amount of leavening agent, as in example 45, compared to example 44, resulted in a further reduction in dissolution time.

Also taking into account example 46, it should be noted that, despite the fact that very fragile second modules were obtained, a rather short dissolution time was measured. It is noted that when evaluating the particle size distribution of mannitol used in examples 43-44 and 46, Pearlitol Flash used in example 44-45 and erythritol used in example 46, Pearlitol Flash showed the smallest particle size, then mannitol, while the erythritol used (non-DC erythritol) has significantly larger particles. The use of non-DC erythritol with larger particles leads to a relatively fast dissolution.

Example 67. Evaluation of example 45.

The lozenges of Example 45 are obtained with the compression forces indicated in Table 11.

Table 11. Compression force
Layer 1 Compression force
Layer 2 Fragility Dissolution time 10 kN 5 kN Brittle. Separation of layer 1 from layer 2 N/A 5 kN 5 kN Not fragile. No separation. layer 1: 5 min 20 sec
layer 2: 1 min 8 kN 5 kN Not fragile. No separation. layer 1: 6 min.
layer 2: 1 min. 5 kN 2 kN Not fragile. No separation. Layer 1: 5 min 30 sec.
Layer 2: 45 sec.

Table 11 shows that it is possible to compress layer 1 with a compression force that is higher than the compression force applied to layer 2, while still obtaining nicotine lozenges that are not too brittle. However, it should be noted that separation of layer 2 from layer 1 can be avoided if the compression force applied to layer 1 is not too high. In addition, the measured dissolution times were entirely acceptable, especially since the second layers dissolved within 1 minute, while it took more than 5 minutes for all the first layers to dissolve.

Example 68. Overall assessment

The lozenges from examples 41-43 and 45 are assessed by a panel of 7 trained experts.

Lozenges are generally assessed as providing improved release compared to conventional nicotine lozenges, for example in terms of nicotine release and prolonged masking.

Example 69. In vivo release testing

A sample of the tablet is tested in a group of 8 test subjects. The test subjects refrain from eating or drinking for at least 30 minutes prior to the start of any test. The test subject is a healthy subject, assigned on an objective basis in accordance with established requirements.

For testing, the tablet is weighed and placed in the mouth between the tongue and the roof of the mouth. The tablet is sucked and turned over every 0.5 minutes. After 0, 0.5, 1, 2, 3 and 5 minutes, the nicotine content of the remaining tablet residue, if still present, is measured. Once the desired test time has been reached (0, 0.5, 1, 2, 3 and 5 min), the tablet is removed and weighed directly into the measuring cup, which is used for the nicotine analysis. The nicotine content is analyzed using a standard HPLC method after extraction into an appropriate buffer.

The tablet is re-measured for each of the 8 test subjects, giving a total of 16 measurements for each sample. The average of the 16 measurements is calculated and the mass % released is calculated based on the original nicotine content of the sample.

Using the method described above, an in vivo dissolution profile is obtained for the selected samples.

Table 12: The tablet samples from Table 4 were tested for in vivo release over 0-5 minutes. The value indicates the mass % of nicotine released from the tablet sample. *=100% release already achieved. Sample tablet number % nicotine release from a tablet at different time intervals (minutes) 0 1 2 3 5 25 0 61 73 82 100 29 0 100 N/A* N/A* N/A*

Example 70. Evaluation of traction relief

The lozenge of Example 41A is assessed for its effect on nicotine craving (urge to smoke) over time after administration.

The assessments are carried out by a panel of 103 experts. Each expert marks the urge to smoke on a scale of 1 to 15 at certain intervals. The results are shown in Table 13, where the listed values are the average values of the experts' results.

In addition, a commercially available conventional lozenge (NiQuitin Lozenge 2 mg, GlaxoSmithKline), a nicotine FDT (1 mg) and a cigarette are tested in the same manner. For the conventional lozenge and cigarette, the time intervals are slightly different from those for the FDT and the lozenge from Example 41A.

Table 13. Minutes 0 1 2 3 4 5 6 8 10 15 20 Desire to smoke Example 41A 9.4 - 7.0 - 5.6 - 4.6 4.0 3.6 3.1 2.8 FDT 9.4 - 7.1 - 6.2 - 5.7 5.3 4.9 4.2 4.0 Pastille 9.4 8.5 - 7.0 - 5.2 - - 4.5 - 3.7 Cigarette 9.4 5.3 - 3.1 - 2.5 - - 2.4 - 2.7

The results of Table 13 can also be seen in Figure 1. These results show that the lozenges of Example 41A show very remarkable results, as they provide a rapid reduction in the desire to smoke, clearly superior to conventional lozenges, while even providing slightly better results than nicotine FDT.

Additionally, it is noted that the lozenges of Example 41A provide sustained craving relief even as the effect of nicotine FDT wears off.

Finally, and most importantly, it should be noted that the lozenge of Example 41A containing 1 mg nicotine continues to provide significantly better craving relief than the conventional lozenge, even though it contains twice as much nicotine, i.e. 2 mg. This is very unexpected and demonstrates the superior effect of the lozenge of the present invention.

Claims (118)

1. A water-soluble compressed nicotine lozenge for oral use, comprising a first module and a second module, the first and second modules are connected by compression, the first and second modules are formed by a plurality of compressed particles, the first module is a resorption module containing at least one sugar alcohol in an amount of at least 50% by weight of the first module, and the second module is an FDT module containing at least one sugar alcohol in an amount of at least 50% by weight of the second module and nicotine, where the second module contains a leavening agent, where the second module contains nicotine in an amount of from 0.2 to 5% by weight of the second module, where the baking powder contains super baking powder, where the super-disintegrant includes cross-linked polymers, where the amount of super-leavening agent is from 1 to 14% by weight of the second module, where the first module does not contain nicotine and where the first module contains a flavoring agent. 2. A water-soluble compressed nicotine lozenge for oral use according to claim 1, wherein the second module contains nicotine in an amount of less than 3% by weight of the second module, for example less than 2% by weight of the second module. 3. A water-soluble pressed nicotine lozenge for oral use according to claim 1 or 2, wherein the mass of the second modules is from 50 to 250 mg, for example from 75 to 150 mg. 4. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 3, wherein the second module contains at least 0.2 mg of nicotine. 5. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 4, wherein the second module contains from 0.2 to 5.0 mg nicotine, for example from 0.5 to 4.0 mg nicotine, for example from 1.0 to 3.0 mg nicotine. 6. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 5, wherein the lozenge contains nicotine in an amount of at least 0.5 mg, such as at least 1.0 mg, such as at least 2.0 mg. 7. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 6, wherein the second module contains a nicotine salt. 8. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 7, wherein the second module comprises nicotine bitartrate. 9. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 8, wherein the second module contains free nicotine base. 10. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 9, wherein the first module contains nicotine. 11. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 10, wherein the lozenge further comprises a disintegrant selected from starch, pregelatinized starch, modified starch, cellulose, microcrystalline cellulose, alginates, ion exchange resin and calcium silicate and combinations thereof. 12. A water-soluble pressed nicotine lozenge for oral use according to any one of claims 1 to 11, wherein the disintegrant additionally contains starch. 13. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 12, wherein the disintegrant additionally contains low-substituted hydroxypropyl cellulose (L-HPC). 14. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 13, wherein the amount of super-disintegrant is from 2 to 13% by weight of the second module, for example from 5 to 12% by weight of the second module. 15. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 14, wherein the super-disintegrants are selected from the group of sodium croscarmellose, crospovidone and sodium starch glycolate. 16. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 15, wherein the disintegrant comprises cross-linked polyvinylpyrrolidone. 17. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 16, wherein at least 50% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 50 μm. 18. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 17, wherein at least 25% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 15 μm. 19. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 18, wherein the second module comprises nicotine in an amount from 0.2 to 5 mg, sugar alcohol in an amount from 40 to 250 mg and baking powder in an amount of 5 to 50 mg. 20. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 19, wherein the average particle size used to compress the first module is greater than the average particle size used to compress the second module. 21. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 20, wherein the average particle size used to compress the second module is less than 350 μm, such as 250 μm, such as 150 μm. 22. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 21, wherein the particles used to compress the second module comprise particles with a particle size of at least 500 μm, such as at least 750 μm, such as at least 100 μm. 23. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 22, wherein the first module constitutes at least 50% by weight of the lozenge, for example at least 60% by weight of the lozenge. 24. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 23, wherein the first module constitutes from 50 to 90% by weight of the lozenge, for example from 50 to 90% by weight of the lozenge, for example from 60 to 90% by weight of the lozenge, for example from 70 to 90% by weight of the lozenge, for example from 70 to 80% by weight of the lozenge, for example from 80 to 90% by weight of the lozenge, for example from 65 to 75% by weight of the lozenge. 25. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 24, wherein the second module constitutes at least 10% by weight of the lozenge, for example at least 20% by weight of the lozenge. 26. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 25, wherein the second module comprises from 10 to 50% by weight of the lozenge, for example from 20 to 40% by weight of the lozenge, for example from 10 to 30% by weight of the lozenge, for example from 20 to 30% by weight of the lozenge. 27. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 26, wherein the second module has an open surface area comprising a maximum of 50% of the total open surface area of the lozenge, such as 40% of the total open surface area of the lozenge, such as 30% of the total open surface area of the lozenge, such as 20% of the total open surface area of the lozenge. 28. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 27, wherein the maximum total volume of the lozenge is 0.7 cm ³ , such as 0.6 cm ³ , such as 0.5 cm ³ , such as 0.4 cm ³ , such as 0.3 cm ³ . 29. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 28, wherein the maximum total mass of the lozenge is 1 g, such as 0.9 g, such as 0.75 g, such as 0.5 g, such as 0.4 g, such as 0.3 g. 30. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 29, wherein the second module is combined by compression with the first module with the application of a minimum compression force of at least 10 kN, such as at least 15 kN, such as at least 20 kN, such as at least 25 kN, such as at least 30 kN. 31. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 30, wherein the lozenge comprises at least one sugar alcohol in an amount of at least 60% by weight of the lozenge, for example at least 70% by weight of the lozenge. 32. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 31, wherein at least one sugar alcohol of the second module comprises at least one sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol or any combination thereof. 33. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 32, wherein at least one sugar alcohol of the second module comprises mannitol. 34. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 33, wherein at least one sugar alcohol of the second module comprises erythritol. 35. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 34, wherein at least one sugar alcohol of the second module has a solubility in water when measured at 20 degrees Celsius of a maximum of 1000 g/l. 36. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 35, wherein the second module comprises at least one sugar alcohol in an amount of at least 60% by weight of the second module, for example at least 70% by weight of the second module. 37. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 36, wherein at least one sugar alcohol of the second module comprises a non-DC (non-direct compression) sugar alcohol. 38. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 37, wherein at least one sugar alcohol of the first module comprises at least one sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol or any combination thereof. 39. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 38, wherein at least one sugar alcohol of the first module is selected from the group consisting of mannitol, erythritol, isomalt, sorbitol or any combination thereof. 40. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 39, wherein the first module comprises at least one sugar alcohol in an amount of at least 60% by weight of the first module, for example at least 70% by weight of the first module. 41. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 40, wherein the lozenge is substantially free of mono- and disaccharides. 42. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 41, wherein the lozenge contains a pH regulating agent. 43. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 42, wherein the pH regulating agent is selected from carbonates, including monocarbonate, bicarbonate and sesquicarbonate, glycerol, phosphate, glycerophosphate, acetate, gluconate or citrate of an alkali metal, ammonium, Tris buffer, amino acid and any combination thereof. 44. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 43, wherein the pH adjusting agent is selected from sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, potassium bicarbonate and any combination thereof. 45. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 44, wherein the pH adjusting agent comprises or is sodium carbonate. 46. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 45, wherein the lozenge comprises a pH-regulating agent in an amount of at least 0.2% by weight of the lozenge, for example at least 0.3% by weight of the lozenge, for example at least 0.4% by weight of the lozenge, for example at least 0.5% by weight of the lozenge. 47. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 41, wherein the lozenge does not contain a pH-regulating agent. 48. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 46, wherein the first module comprises a pH regulating agent. 49. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 46 and 48, wherein the first module comprises a pH regulating agent in an amount of at least 0.2% by weight of the first module, for example at least 0.3% by weight of the first module, for example at least 0.4% by weight of the first module, for example at least 0.5% by weight of the first module. 50. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-46 and 48, 49, wherein the second module contains a pH regulating agent. 51. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 46 and 48 to 50, wherein the second module comprises a pH regulating agent in an amount of at least 0.2% by weight of the second module, for example at least 0.3% by weight of the second module, for example at least 0.4% by weight of the second module, for example at least 0.5% by weight of the second module. 52. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-46 and 48-51, wherein the pH adjusting agent is a basic pH adjusting agent. 53. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-46 and 48-52, wherein the pH adjusting agent is a buffering agent. 54. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-46 and 48-53, wherein the pH adjusting agent is a basic buffering agent. 55. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 54, wherein the composition provides a peak nicotine concentration in saliva of more than 0.3 mg/ml, for example more than 0.5 mg/ml. 56. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 55, wherein the composition provides a peak saliva pH of greater than 8 within the first 120 s after oral administration. 57. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 56, wherein the lozenge contains a high intensity sweetener. 58. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 57, wherein the lozenge contains a flavoring agent. 59. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 58, wherein the lozenge contains a flavoring agent in an amount of at least 0.1% of the weight of the lozenge. 60. A water-soluble pressed nicotine lozenge for oral use according to any one of claims 1 to 59, wherein the flavoring agent is selected from the group of menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, coffee, cinnamon, cloves, tobacco, citrus and fruits and mixtures thereof. 61. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 60, wherein the first module contains at least one mucoadhesive agent in an amount of from 0.5 to 10% by weight of the first module. 62. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 61, wherein the first module contains dissolution modifiers. 63. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 62, wherein the dissolution modifiers include, but are not limited to, acacia, agar, alginic acid or a salt thereof, carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophil or a salt thereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, pullulan, starch, tragacanth, trehalose, xanthan gum and mixtures thereof. 64. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 63, wherein the second module comprises a binding agent such as microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof. 65. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 64, wherein the first module comprises a binding agent such as microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof. 66. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 65, wherein the lozenge has a breaking point of at least 100 N, such as at least 150 N, such as at least 200 N. 67. Method of production water-soluble compressed nicotine lozenge for oral use, comprising the steps of: - providing a first powder composition and a second powder composition, wherein the first powder composition comprises at least one sugar alcohol in an amount of at least 50% by weight of the first powder composition, the second powder composition comprises at least one sugar alcohol in an amount of at least 50% by weight of the second powder composition and nicotine, - pressing the first powder composition and the second powder composition to obtain a modular lozenge combined by pressing with an FDT module, wherein the second powder composition comprises a disintegrant, wherein the second powder composition contains nicotine in an amount of from 0.2 to 5% by weight of the second powder composition, where the baking powder contains super baking powder, where the super-disintegrant includes cross-linked polymers, where the amount of super-leavening agent is from 1 to 14% by weight of the second module, where the first module does not contain nicotine and where the first module contains a flavoring agent. 68. The method according to claim 67, wherein the method comprises pressing the first powder composition to obtain a modular lozenge and pressing the modular lozenge and the second powder composition to obtain an FDT module pressed together with the modular lozenge. 69. The method according to claim 67 or 68, wherein the method comprises pressing the second powder composition to obtain an FDT module and pressing the FDT module and the first powder composition to obtain a modular lozenge combined by pressing with the FDT module. 70. The method according to any one of claims 67 to 69, wherein the pressing is carried out with a pressing force of at least 5 kN, such as at least 10 kN, such as at least 15 kN, such as at least 20 kN. 71. The method according to any one of claims 67-70, wherein a water-soluble compressed nicotine lozenge for oral use is obtained according to any one of claims 1-66 or 72-80. 72. A water-soluble compressed nicotine lozenge for oral administration, comprising a first module and a second module, the first and second modules are joined by pressing, the first and second modules are formed by a plurality of compressed particles, the first module is a modular lozenge and the second module is an FDT module containing nicotine, where the second module contains a leavening agent, where the second module contains nicotine in an amount of from 0.2 to 5% by weight of the second module, where the baking powder contains super baking powder, where the super-disintegrant includes cross-linked polymers, where the amount of super-leavening agent is from 1 to 14% by weight of the second module, where the first module does not contain nicotine and where the first module contains a flavoring agent. 73. A water-soluble compressed nicotine lozenge for oral use according to claim 72 and any of claims 1-66 or obtained by the method according to any of claims 67-71. 74. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-66 or 72, 73, wherein the nicotine and the pH regulating agent are contained in the second module. 75. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-66 or 72-74, wherein the high intensity sweetener is contained in the first module. 76. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-66 or 72-75, wherein the flavoring agent is contained in the first module. 77. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-66 or 72-76, wherein the nicotine is contained in the second module and the flavoring agent is in the first module. 78. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-66 or 72-77, wherein the lozenge does not contain a coating. 79. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1 to 66 or 72 to 78, wherein the second module has a water content of less than 10% by weight, for example less than 5% by weight, for example less than 2% by weight, for example less than 1% by weight. 80. A water-soluble compressed nicotine lozenge for oral use according to any one of claims 1-66 or 72-78, wherein the water-soluble compressed nicotine lozenge for oral use has a water content of less than 10% by weight, such as less than 5% by weight, such as less than 2% by weight, such as less than 1% by weight.

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