RU2831119C2 - Solid oral nicotine formulation - Google Patents

Abstract

FIELD: smoking accessories.

SUBSTANCE: group of inventions relates to solid nicotine formulations for fast onset of nicotine craving relief. Compressed oral disintegrating nicotine tablet for rapid onset of nicotine craving, containing nicotine and a pH regulating agent, in which the tablet is intended to release the nicotine content for period of 60 seconds upon interaction with oral saliva and the tablet is intended to release the content of the pH regulating agent for period of 60 seconds when interacting with oral saliva, in which the tablet contains mannitol in an amount of more than 40 wt.% of the tablet, in which the tablet contains nicotine in amount of 0.5 to 10 mg, wherein the pH adjusting agent is an alkaline buffer agent, wherein the pH adjusting agent is selected from the group consisting of monocarbonate, bicarbonate, sesquicarbonate and any combination thereof, and in which the tablet contains a disintegrant in amount of 1–10 wt.% of the tablet, wherein the disintegrating agent is selected from a group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and any combination thereof. A method of relieving cravings for nicotine by administering an effective amount of said compressed oral disintegrating nicotine tablet.

EFFECT: above described nicotine tablet provides fast and effective onset of nicotine craving relief with reduction of burning sensation.

35 cl, 10 tbl, 7 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to the field of solid oral nicotine formulations.

LEVEL OF TECHNOLOGY

Nicotine-releasing formulations used to provide nicotine release in the oral cavity of a patient over a period of time are well known. In the prior art, much effort has been put into simulating the nicotine release and oral uptake of a cigarette when smoked by a patient, which means that the release profiles of nicotine formulations have been extensively investigated in the prior art.

However, it is a proven fact that a one-to-one imitation of smoking has not yet been achieved by means other than the cigarette.

ESSENCE OF THE INVENTION

The invention relates to a solid oral nicotine composition for the rapid onset of reducing craving for nicotine, containing nicotine and a pH-regulating agent, in which the composition is intended to release the nicotine content over a period of 90 seconds upon interaction with oral saliva, and the composition is designed to release the pH-regulating agent content over a period of 60 seconds upon interaction with oral saliva.

One significant advantage of the invention may be that the reduction of nicotine craving may be provided in a manner that is both rapid and pleasant for the patient, thereby facilitating more effective reduction of nicotine craving, since the critical time lag between use of the composition and reduction, during which the patient may otherwise be tempted to use tobacco products to satisfy the craving, is minimized, and since the otherwise common and highly unpleasant burning sensation may be avoided or minimized.

One advantage of the invention may be that rapid onset of nicotine craving relief may be achieved using the solid oral nicotine formulation of the invention, while avoiding or at least minimizing the burning sensation that is otherwise commonly associated with nicotine products, in particular rapid release nicotine products.

The rapid onset of nicotine craving relief is achieved by facilitating the release of nicotine content within 90 seconds upon interaction with oral saliva, providing a high concentration of nicotine in saliva, while promoting the release of pH regulating agent content within 60 seconds upon interaction with oral saliva, thus providing optimal conditions for rapid absorption of nicotine through the oral mucosa.

Contrary to expectations, experiments have shown that the permeability of nicotine through the buccal mucosa decreases relatively little with increasing nicotine concentration. For example, experiments have shown that increasing the nicotine concentration from 100 micrograms/mL to 14,000 micrograms/mL results in a decrease of approximately twofold. This is very surprising and is used in the pursuit of nicotine concentrations in the oral cavity that are much higher than previously observed or desired. Thus, the present delivery device is preferred and aimed at very high nicotine contents in the oral cavity, thereby increasing nicotine absorption. In addition, it was understood that the effect of nicotine concentrations is thus at least comparable to the effect of adjusting the pH in the oral cavity. This is contrary to any expectations.

The above was accomplished to the surprise of the inventors, since typical conventional products and conventional wisdom tend to delay the breakdown and slow down the dissolution of nicotine.

Thus, an advantage of the present invention may be that the solid oral nicotine formulation provides a highly effective rapid onset of nicotine craving relief that is pleasant for the patient because the burning sensation is reduced or avoided.

In an embodiment of the invention, the composition is designed to release nicotine content over a period of 5 to 90 seconds upon interaction with oral saliva, such as 10 to 90 seconds upon interaction with oral saliva.

In an embodiment of the invention, the composition contains nicotine in an amount of at least 0.5 mg.

According to an embodiment of the invention, the composition contains nicotine in an amount of from 0.5 mg to 10.0 mg, for example from 0.5 mg to 4.0 mg.

The amount of nicotine content is usually given in quantities per dose unless otherwise stated. If the dosage is in tablet form, the quantity will refer to the entire tablet.

Thus, according to an embodiment of the invention, the composition contains nicotine in an amount of at least 0.5 mg per dosage.

In an embodiment of the invention, the composition is designed to release nicotine content over a period of 60 seconds upon interaction with saliva in the oral cavity.

In an embodiment of the invention, the composition is designed to release nicotine content over a period of 5 to 60 seconds upon interaction with oral saliva, such as 10 to 40 seconds upon interaction with oral saliva.

According to an embodiment of the invention, the composition is designed to release nicotine content over a period of 30 seconds upon interaction with saliva in the oral cavity.

According to an embodiment of the invention, the composition is designed to release nicotine content over a period of 5 to 30 seconds upon interaction with oral saliva, such as 10 to 30 seconds upon interaction with oral saliva.

According to an embodiment of the invention, the composition is designed to release nicotine content over a period of 10 to 40 seconds upon interaction with saliva in the oral cavity.

According to an embodiment of the invention, the composition is designed to release nicotine content over a period of 30 to 60 seconds upon interaction with saliva in the oral cavity.

In an embodiment of the invention, the composition contains said pH regulating agent in an amount of at least 2.7 wt.% of the composition.

According to an embodiment of the invention, the composition contains said pH regulating agent in an amount of 2.7 to 5.7 wt.% of said composition.

In an embodiment of the invention, the composition is designed to release the pH regulating agent content over a period of 40 seconds upon interaction with oral saliva.

According to an embodiment of the invention, the composition is designed to release the pH regulating agent content over a period of 20 seconds upon interaction with oral saliva.

According to an embodiment of the invention, the composition is designed to release the pH regulating agent content over a period of 5-40 seconds upon interaction with oral saliva.

According to an embodiment of the invention, the composition is designed to release the pH regulating agent content over a period of 5-20 seconds upon interaction with oral saliva.

In an embodiment of the invention, the pH regulating agent content is released before the nicotine content.

In an embodiment of the invention, at least 50 wt.% of the pH regulating agent content is released to 50 wt.% of the nicotine content.

In an embodiment of the invention, the oral nicotine composition is provided in an orally disintegrating tablet.

One advantage of the above embodiment may be that the orally disintegrating tablet is a very suitable delivery vehicle for said oral nicotine formulation.

In an embodiment of the invention, the oral nicotine composition is provided in a sublingual orally disintegrating tablet.

In an embodiment of the invention, the composition is a sublingual composition, such as a sachet or tablet.

This is even more advantageous considering the fact that very high concentrations of nicotine can be obtained sublingually with only minimal throat burning. Very high sublingual absorption thus both maintains minimal throat burning and simultaneously increases nicotine absorption.

In an embodiment of the invention, the composition is designed to disintegrate within a period of less than 60 seconds after oral administration.

In an embodiment of the invention, the composition is designed to contain nicotine that dissolves in saliva within a period of less than 90 seconds after oral administration.

In an embodiment of the invention, the oral nicotine formulation is provided in the form of a powder formulation.

In an embodiment of the invention, said oral nicotine composition is provided in a sachet.

In an embodiment of the invention, nicotine is provided in the form of 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 their hydrates (e.g. nicotine zinc chloride monohydrate).

In an embodiment of the invention, the nicotine salt comprises nicotine bitartrate.

In the present context, nicotine bitartrate includes its hydrates.

According to an embodiment of the invention, the nicotine salt is a water-soluble nicotine salt.

In the present context, the term "water-soluble salt" is understood to mean a salt having a solubility in water of at least 10 g of salt per 100 ml of water under standard laboratory conditions including a temperature of 25 degrees Celsius, atmospheric pressure and a pH of 7.

It should also be understood that when nicotine contains a nicotine salt, possibly in combination with other forms of nicotine, the nicotine salt may consist of only one nicotine salt or may be a combination of two or more nicotine salts.

According to an embodiment of the invention, the nicotine salt comprises nicotine bitartrate.

In an embodiment of the invention, nicotine is provided in the form of nicotine free base.

In an embodiment of the invention, nicotine is selected from the group consisting of a nicotine salt, a free base form of nicotine, a nicotine derivative such as a nicotine cation exchange resin such as nicotine-polyacrylex resin, a nicotine inclusion complex or nicotine in any non-covalent binding; nicotine bound to zeolites; nicotine bound to cellulose such as microcrystalline or starch microspheres, and mixtures thereof.

In an embodiment of the invention, said nicotine is provided in the form of synthetic nicotine.

An advantage of the above embodiment may be that a more desirable flavor profile can be achieved by avoiding undesirable flavor notes that may be included in nicotine derived from tobacco.

In an embodiment of the invention, said nicotine is provided in the form of a complex between nicotine and an ion exchange resin.

In an embodiment of the invention, said complex between nicotine and an ion exchange resin is a nicotine polyacrylex resin (NPR).

In an embodiment of the invention, nicotine is provided in combination with a fatty acid.

In an embodiment of the invention, nicotine is provided in an ionic complex with at least one mucoadhesive water-soluble anionic polymer.

In an embodiment of the invention, the composition provides a peak salivary nicotine concentration of greater than 0.3 mg/ml and a peak salivary pH of greater than 8 within the first 120 seconds after oral administration.

In an embodiment of the invention, the composition provides a peak salivary nicotine concentration of greater than 0.4 mg/ml and a peak salivary pH of greater than 8 within the first 120 seconds after oral administration.

In an embodiment of the invention, the composition provides a peak salivary nicotine concentration of greater than 0.5 mg/ml and a peak salivary pH of greater than 8 within the first 120 seconds after oral administration.

In embodiments in which the formulation provides a peak salivary nicotine concentration of greater than 0.3 mg/mL, such as greater than 0.5 mg/mL, during the first 120 seconds after oral administration, the amount of nicotine in the formulation should be adjusted to at least the amount necessary to obtain this. Depending on the specific formulation and delivery vehicle, the amount of nicotine in the formulation may exceed 0.5 mg in some embodiments, such as, for example, at least 1 mg or at least 2 mg.

In an embodiment of the invention, the composition is intended to contain nicotine that dissolves in the saliva of the oral cavity within a period of less than 90 seconds after oral administration, and in which at least 40% by weight of the nicotine is absorbed through the mucous membrane of the oral cavity.

In an embodiment of the invention, the composition is intended to contain nicotine that dissolves in the saliva of the oral cavity within a period of less than 90 seconds after oral administration and in which at least 40 wt.% to less than 50 wt.% of the nicotine is absorbed through the mucous membrane of the oral cavity.

In an embodiment of the invention, the composition is designed to contain nicotine that dissolves in the saliva of the oral cavity within a period of less than 90 seconds after oral administration and

- in which at least 40% by weight to less than 50% by weight of nicotine is absorbed through the oral mucosa or

- in which at least 50% by weight of nicotine is absorbed through the oral mucosa.

In an embodiment of the invention, the composition is intended to contain nicotine that dissolves in the saliva of the oral cavity within a period of less than 90 seconds after oral administration and in which at least 50% by weight of the nicotine is absorbed through the mucous membrane of the oral cavity.

In an embodiment of the invention, the composition comprises at least one polyol, wherein the polyol constitutes more than 40% by weight of the composition.

In an embodiment of the invention, the composition additionally contains a disintegrant.

One advantage of the above embodiment may be that said disintegrant facilitates the disintegration and dissolution of the composition, thereby achieving the release of nicotine and the pH controlling agent.

In an embodiment of the invention, the composition contains a disintegrant in an amount of 1-10% by weight of the composition.

According to an embodiment of the invention, the composition comprises a disintegrant in an amount of 2-8 wt.% of the composition, for example 4-6 wt.% of the composition, for example approximately 5 wt.% of the composition.

Preferably, the level of disintegrant is high enough to ensure rapid disintegration, but not too high, as large amounts may unnecessarily increase production costs.

In an 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 superdisintegrants such as crosslinked cellulose (such as sodium carboxymethyl cellulose), crosslinked polyvinylpyrrolidone (PVP), crosslinked starch, crosslinked alginic acid, natural superdisintegrants 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 cross-linked polyvinylpyrrolidone.

An advantage of using cross-linked polyvinylpyrrolidone, also known as crospovidone, as a disintegrant may be that it reduces the dependence of disintegration time on compression force, while still providing a fairly low disintegration time. This may be advantageous especially for rapidly disintegrating tablets. In addition, due to the greater independence from compression force, there is less variation between tablets due to changes in compression force.

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

This corresponds to the commercial grades of crospovidone Kollidon CL-F and CL-SF.

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

This corresponds to the commercial grade of crospovidone Kollidon CL-SF.

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

In an embodiment of the invention, the solid oral nicotine formulation is provided as a tablet having a mass of from 25 to 200 mg, such as from 50 to 150 mg, such as 70-120 mg, such as about 75 mg or about 100 mg.

An advantage of the above embodiment may be that it provides the desired short disintegration time while still allowing a sufficiently large amount of nicotine to be included in the tablet.

In an embodiment of the invention, the solid oral nicotine formulation is provided as a powder formulation in an amount of from 100 to 800 mg, such as from 200 to 600 mg, such as about 400 mg.

In an embodiment of the invention, the composition comprises sodium stearyl fumarate (SSF) as a lubricant.

An advantage of the above embodiment may be that it provides a shorter disintegration time of the composition.

In an embodiment of the invention, the composition contains microcrystalline cellulose in an amount of 1-10% by weight of the composition.

The advantage of the above embodiment is that lower attrition can be achieved without deteriorating the taste sensation. Including too much microcrystalline cellulose can lead to a dusty taste sensation.

According to an embodiment of the invention, the composition comprises microcrystalline cellulose in an amount of 2-8 wt.% of the composition, for example 4-6 wt.% of the composition, for example approximately 5 wt.% of the composition.

According to an embodiment of the invention, the composition contains mannitol as a bulk sweetener.

According to an embodiment of the invention, the composition further comprises an amount of an insoluble composition.

An advantage of the above embodiment may be that a residue remains even after using the sachet containing the composition. This may result in a pleasant perception of the sachet by patients, for example due to the similarity with products containing tobacco.

According to an embodiment of the invention, the insoluble composition comprises at least one selected from dibasic calcium phosphate, calcium carbonate DC, mono-, diglyceride powder, hydrogenated vegetable oil and combinations thereof.

According to an embodiment of the invention, the amount of insoluble composition is from 5 to 50% by weight of the composition, for example from 10 to 30% by weight of the composition.

Mannitol is preferred due to its lower compactibility compared to, for example, sorbitol, isomalt and xylitol, i.e. for a given compression force, a lower tablet hardness is achieved when using mannitol compared to sorbitol, isomalt or xylitol.

The invention further relates to a solid oral nicotine composition for use in alleviating nicotine cravings, containing nicotine and a pH-regulating agent, in which the composition is intended to release nicotine content over a period of 90 seconds upon interaction with oral saliva and the composition is intended to release pH-regulating agent content over a period of 60 seconds upon interaction with oral saliva.

In the present context, it should be understood that the said use for reducing craving for nicotine includes administering the said solid oral nicotine formulation orally.

In an embodiment of the invention, a solid oral nicotine formulation according to the invention or any of its embodiments is used to reduce cravings for nicotine.

In an embodiment of the invention, nicotine is not in an ionic complex with the mucoadhesive water-soluble anionic polymer.

In an embodiment of the invention, the nicotine does not comprise a nicotine complex.

In an embodiment of the invention, a solid oral nicotine formulation for rapid onset of nicotine craving reduction comprises nicotine and a pH regulating agent, wherein the formulation is designed to release nicotine content over a period of 90 seconds upon interaction with oral saliva and the formulation is designed to release pH regulating agent content over a period of 60 seconds upon interaction with oral saliva and wherein the formulation contains nicotine in an amount of at least 0.5 mg, for example nicotine in an amount of 0.5 mg to 10.0 mg, for example 0.5 mg to 4.0 mg.

In an embodiment of the invention, a solid oral nicotine formulation for rapid onset of nicotine craving reduction comprises nicotine and a pH adjusting agent, wherein the formulation is designed to release a nicotine content over a period of 90 seconds upon interaction with oral saliva and the formulation is designed to release a pH adjusting agent content over a period of 60 seconds upon interaction with oral saliva and wherein the formulation contains nicotine in an amount of at least 0.5 mg, for example, nicotine in an amount of from 0.5 mg to 8 mg, wherein said nicotine is provided as a nicotine salt and wherein the nicotine salt is selected from nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine bitartrate, nicotine chloride (for example, nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, hencitate nicotine, 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 their hydrates (e.g. zinc chloride nicotine monohydrate).

In an embodiment of the invention, a solid oral nicotine formulation for rapid onset of nicotine craving reduction comprises nicotine and a pH regulating agent, wherein the formulation is designed to release nicotine content over a period of 90 seconds upon interaction with oral saliva and the formulation is designed to release pH regulating agent content over a period of 60 seconds upon interaction with oral saliva and wherein the formulation contains nicotine in an amount of at least 0.5 mg, for example nicotine, wherein the formulation contains said pH regulating agent in an amount of at least 2.7 wt.% of the formulation and wherein the nicotine is a salt in the form of nicotine bitartrate.

In an embodiment of the invention, the tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent and wherein the tablet is designed to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration.

In an embodiment of the invention, the tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent, and wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, and wherein the nicotine salt is soluble in water.

In an embodiment of the invention, an orally disintegrating nicotine tablet for use in reducing nicotine cravings, comprising a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition comprising an amount of nicotine and a pH adjusting agent.

In the present context, it should be understood that the said use for reducing craving for nicotine includes administering the said orally disintegrating nicotine tablet orally.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine salt and a pH adjusting agent, in which the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration.

In an embodiment of the invention, nicotine is not in an ionic complex with the mucoadhesive water-soluble anionic polymer.

In an embodiment of the invention, the nicotine does not comprise a nicotine complex.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, and in which the tablet is designed to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration and in which nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine salt and a pH adjusting agent, in which the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration and in which the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the tablet contains nicotine in an amount of from 0.5 mg to 4 mg for administration and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

According to an embodiment of the invention, an orally disintegrating nicotine sublingual tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, and in which the tablet is designed to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration.

According to an embodiment of the invention, an orally disintegrating nicotine sublingual tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration and in which nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, an orally disintegrating sublingual nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine salt and a pH adjusting agent, in which the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration and in which the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg.

In an embodiment of the invention, an orally disintegrating sublingual nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg for administration, and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH regulating agent, and in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration, and in which the compressed powder contains at least one polyol, and in which the polyol makes up more than 50% by weight of the tablet.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration, in which the compressed powder contains at least one polyol, and in which the polyol makes up more than 50% by weight of the tablet, and in which the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition comprises an amount of nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the compressed powder contains at least one polyol, and wherein the polyol makes up more than 50% by weight of the tablet, and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition comprises an amount of a nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the compressed powder comprises at least one polyol, and wherein the polyol makes up more than 50% by weight of the tablet, and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg for administration, and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, the tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent, and wherein the tablet is designed to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration.

In an embodiment of the invention, the tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent, and wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, and wherein the nicotine salt is soluble in water.

In an embodiment of the invention, an orally disintegrating nicotine tablet for use in reducing cravings for nicotine, comprising a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition comprising an amount of nicotine and a pH adjusting agent.

In the present context, it should be understood that the said use for reducing craving for nicotine includes administering the said orally disintegrating nicotine tablet orally.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine salt and a pH adjusting agent, in which the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration.

In an embodiment of the invention, nicotine is not in an ionic complex with the mucoadhesive water-soluble anionic polymer.

In an embodiment of the invention, the nicotine does not comprise a nicotine complex.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, and in which the tablet is designed to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration, and in which the composition is designed to release the nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, wherein the composition is intended to release the nicotine content within a period of 90 seconds upon interaction with the saliva of the oral cavity, the powder composition contains an amount of nicotine and a pH adjusting agent, wherein the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration and wherein the nicotine is provided in the form of a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, wherein the composition is designed to release nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, the powder composition contains an amount of nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition comprises an amount of a nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the composition is designed to release the nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg for administration, and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

According to an embodiment of the invention, an orally disintegrating nicotine sublingual tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH regulating agent, and in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration, and in which the composition is intended to release the nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity.

According to an embodiment of the invention, an orally disintegrating nicotine sublingual tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH adjusting agent, in which the composition is intended to release the nicotine content within a period of 90 seconds upon interaction with the saliva of the oral cavity, in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration and in which the nicotine is provided in the form of a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, an orally disintegrating sublingual nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, wherein the composition is designed to release nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, the powder composition contains an amount of nicotine and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg.

In an embodiment of the invention, an orally disintegrating sublingual nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of a nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the composition is designed to release the nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg for administration, and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, the powder composition contains an amount of nicotine and a pH regulating agent, and in which the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration, in which the composition is intended to release the nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, and in which the compressed powder contains at least one polyol, and in which the polyol makes up more than 50% by weight of the tablet.

According to an embodiment of the invention, an orally disintegrating nicotine tablet for reducing craving for nicotine comprises a compressed powder composition, wherein the tablet is intended to disintegrate within a period of less than 60 seconds after oral administration, wherein the composition is intended to release the nicotine content within a period of 90 seconds upon interaction with the saliva of the oral cavity, the powder composition contains an amount of nicotine and a pH adjusting agent, wherein the tablet is intended to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration, wherein the compressed powder contains at least one polyol, and wherein the polyol makes up more than 50% by weight of the tablet, and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, wherein the composition is designed to release nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, the powder composition contains an amount of nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the compressed powder contains at least one polyol, and wherein the polyol makes up more than 50% by weight of the tablet, and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg.

In an embodiment of the invention, an orally disintegrating nicotine tablet comprises a compressed powder composition, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration, the powder composition comprises an amount of a nicotine salt and a pH adjusting agent, wherein the tablet is designed to contain nicotine for dissolution within a period of less than 90 seconds after oral administration, wherein the composition is designed to release the nicotine content within a period of 90 seconds upon interaction with saliva in the oral cavity, wherein the compressed powder contains at least one polyol, and wherein the polyol makes up more than 50% by weight of the tablet, and wherein the tablet contains nicotine in an amount of from 0.5 mg to 4.0 mg for administration, and wherein the nicotine is provided as a nicotine salt. This salt should preferably be a water-soluble salt.

Furthermore, the invention relates to a method for reducing craving for nicotine by administering an effective amount of said solid oral nicotine composition according to the invention or any of the embodiments.

DETAILED DESCRIPTION

As used herein, the term "orally disintegrating tablet" refers to a tablet for oral administration that disintegrates in the oral cavity relatively quickly after administration, for example, within about three minutes after oral administration. Orally disintegrating tablets may be intended for use as a sublingual tablet for placement under the tongue, as a buccal tablet, as a tablet for melting on the tongue, or for other types of oral administration.

Orally disintegrating tablets may also be referred to as "orally disintegrating tablets" and these two terms are used interchangeably herein. These terms are also commonly referred to by their abbreviation, ODT. Similarly, the terms "rapidly disintegrating tablet" and "rapidly disintegrating tablet" as well as the abbreviation BDT, refer herein to an orally disintegrating tablet.

As used in this description, the term "disintegration" refers to the separation of the specified object into components, fragments or particles. Disintegration time is measured in vitro. 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 is introduced into 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 promotes the disintegration of an orally disintegrating tablet when the orally disintegrating tablet comes into contact with saliva. Disintegrants useful in the context 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 superdisintegrants such as crosslinked cellulose (such as sodium carboxymethyl cellulose), crosslinked polyvinylpyrrolidone (PVP), crosslinked starch, crosslinked alginic acid, natural superdisintegrants and calcium silicate. Disintegrants can often be thought of as a measure to promote the division of the dosage form into smaller fragments upon administration to allow for the initiation of drug dissolution and eventual absorption.

As used herein, the term "nicotine" refers to nicotine in any form, including free nicotine 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 such as microbial origin or starch microspheres, nicotine bound to CaCO ₃ , and mixtures thereof. Thus, when referring to amounts of nicotine, the amounts refer to the amount of pure nicotine. Thus, when measuring the concentration of nicotine added as a nicotine salt, it is the mass of the equivalent amount of pure nicotine, and not the mass of the salt, that is relevant. Nicotine also includes nicotine not derived from tobacco, often referred to as synthetic nicotine.

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

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

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

As used herein, the term "nicotine release" refers to nicotine that becomes bioavailable, i.e., available for absorption through the mucosal membrane in the oral cavity. While some forms of nicotine require dissolution in order to be bioavailable, other forms can be readily absorbed into the body without dissolution. For example, in order for nicotine to be bioavailable, the solid formulation matrix must disintegrate. Some forms of nicotine require that the nicotine be further released, 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, herein nicotine bitartrate, can readily dissolve after the solid formulation matrix disintegrates. However, some forms of nicotine may not require dissolution. This is the case, for example, for nicotine free base, which is released after the solid formulation matrix disintegrates.

As used herein, the term "peak salivary nicotine concentration" refers to the peak value of nicotine concentration in oral saliva, wherein the saliva includes the delivery vehicle for nicotine dissolved therein. It should also be understood that the peak salivary concentration is considered to be reached whenever the criterion is met. For example, if the peak salivary nicotine concentration is at least 0.5 mg/mL, this peak salivary concentration is reached whenever the nicotine concentration exceeds 0.5 mg/mL. The peak salivary nicotine concentration is measured as follows:

One dosage of the composition is administered sublingually to at least six patients. Saliva is collected at certain time intervals. The experiment is repeated. Thus, each nicotine concentration value is the arithmetic mean of 12 measurements, i.e., performed on saliva samples from six patients twice. The nicotine concentration in saliva is analyzed by HPLC after extraction into an appropriate buffer.

As used herein, the term "peak salivary pH" refers to the peak pH of the oral saliva, where saliva includes any delivery vehicle for the pH-regulating agent. It should also be understood that the peak salivary pH is considered to be reached whenever a criterion is met. For example, if the peak salivary pH is at least 7.5, this peak salivary pH is reached whenever the pH exceeds 7.5. The peak salivary pH is measured in vivo and is measured as follows:

At least 6 patients chewed the unbuffered chewing base for 1 minute, after which the initial pH value in the saliva sample of each patient was measured using a suitable pH electrode system, for example, a PHW77-SS stainless steel electrode. Only patients having an initial pH in the saliva within the range of 6.7 to 7.3 after chewing the unbuffered chewing base for one minute were selected. These patients were thus classified as average patients.

One dosage of the composition is administered sublingually to at least six patients. The pH in the saliva of each of the six patients is then measured at certain time intervals. Thus, each pH value is the arithmetic mean of six measurements performed on saliva samples from six patients.

The term "pH adjusting agent" as used in the present description refers to agents that actively adjust and regulate the pH value 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.

As used herein, the term "rapid onset of nicotine craving relief" refers to a reduction in nicotine craving for which the onset occurs relatively quickly, i.e., only within a relatively short period of time after oral administration. In embodiments of the invention, rapid onset refers to a period after oral administration until craving relief of no more than 180 seconds, such as no more than 120 seconds, such as no more than 60 seconds.

EXAMPLES

The following non-limiting examples illustrate various embodiments of the present invention.

Example 1

Obtaining a rapidly disintegrating tablet

In this example, six fast-disintegrating tablets (FDT) with 1 mg nicotine are prepared with the compositions as indicated in Table 1. The fast-disintegrating tablet is prepared with NBT (nicotine bitartrate). The punch used is 7.00 mm, round, shallow concave, D device. Tablet weight: 100.0 mg.

BRT(a) BRT(b) BRT(c) BRT(d) BRT(e) BRT(f) NBT 2,849 2,849 2,849 2,849 2,849 2,849 Microcrystalline cellulose - - - 40,175 40,175 40,175 Mannitol 81,351 81,351 81,351 40,175 40,175 40,175 Crospovidone 5.0 - - 5.0 - - Croscarmellose sodium - 5.0 - - 5.0 - Sodium starch glycolate - - 5.0 - - 5.0 Peppermint 4.0 4.0 4.0 4.0 4.0 4.0 Menthol 0.4 0.4 0.4 0.4 0.4 0.4 Sucralose 0.4 0.4 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 5.0 5.0 Silicon dioxide - - - 1.0 1.0 1.0 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 1.0 Total number 100,0 100,0 100,0 100,0 100,0 100,0

Table 1 - Rapidly disintegrating tablet formulations. Quantities are in mg. RDT=rapidly disintegrating tablet.

Raw materials are weighed from bags or buckets into separate weighing containers.

All excipients are sieved through a 800 micrometer sieve into a stainless steel or plastic container in the following order:

Half filler/bulk sweetener

API and all other excipients except magnesium stearate

The remaining half of the filling/bulk sweetener

They are mixed in a Turbula mixer for 4-10 minutes at 25 rpm. Then a lubricant, such as magnesium stearate, is sieved through a 800 micrometer sieve into the mixing container and lubrication is achieved by further mixing for 1-2 minutes at 25 rpm. The fill level of the mixing container is maintained at 40% to 70% in accordance with standard practice. The lubricant-coated powder mixture is transferred to the hopper of the tabletting machine.

Rapidly disintegrating tablets are manufactured on laboratory equipment, such as a RIVA Piccola dual-layer tablet press. The tablet press is commissioned by setting the filling depth and compression force so that the lozenge weight and hardness meet the acceptance criteria. A pre-compression force may be included to avoid clogging.

Parameter Target value Speed 10-20 rpm Mass of BRT 100 mg +/- 5% Compression force 2-8 kN Thickness n.d.⃰ Abrasion (100 rpm) ˂ 1%

Table 2: Recommended Startup Parameters ⃰Punch design is not fixed. Since curvature affects thickness, thickness is not a fixed target at this point in the design.

The acceptance criteria for friability must be met to be able to package the resulting rapidly disintegrating tablets, but in this embodiment the bulk sweetener and/or filler must have relatively good compactability and yet have rapid disintegration.

The rapidly disintegrating tablets according to the invention may contain coloring agents. According to an embodiment of the invention, the rapidly disintegrating tablets may contain coloring agents and brightening agents, such as FD&C type dyes and lakes, fruit and vegetable extracts, titanium dioxide and combinations thereof.

Example 2

Production of a rapidly disintegrating tablet using ready-to-use systems

Another way to produce rapidly disintegrating tablets would be to use a ready-to-use system. Suitable for this purpose may 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). These ready-to-use systems are co-processing systems in which the filler, disintegrant, glidant or similar substances are incorporated into a single powder mixture. This saves the processing of multiple excipients and ensures homogeneity between the excipients.

In this example, five fast-disintegrating tablets (BRT(g)-BRT(k)) without nicotine are prepared with ready-to-use systems in the formulations as indicated in Table 3A. The fast-disintegrating tablet is prepared without NBT (placebo). The addition of nicotine to the fast-disintegrating tablets is expected to have only a minor effect on disintegration time.

In this example, the following conditions apply. Punch used: 7.00 mm, round, shallow concave, B device. Tablet weight: 100.0 mg.

BRT(g) BRT(h) BRT(i) BRT(j) BRT(k) Ludiflash 81.7 - - - - Pearlitol Flash - 81.7 - - - SmartEx QD50 - - 81.7 - - F-Melt - - - 83.7 - ProSolv ODT G2 - - - - 83.7 Peppermint 4.4 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 5.0 Crospovidone 5.0 5.0 5.0 - - Croscarmellose sodium - - - 3.0 - Sodium starch glycolate - - - - 3.0 Magnesium stearate 2.0 2.0 2.0 2.0 2.0 Total number 100,0 100,0 100,0 100,0 100,0

Table 3A - Rapidly disintegrating tablet formulations with various ready-to-use systems. Amounts are in mg. RDT = rapid disintegrating tablet.

In addition, five rapidly disintegrating tablets (BRT(l)-BRT(p)) with nicotine are prepared with ready-to-use systems in formulations as shown in Table 3B.

In this example, the following conditions apply. Punch used: 7.00 mm, round, shallow concave, B device. Tablet weight: 100.0 mg.

BRT(l) BRT(m) BRT(n) BRT(o) BRT(p) NBT - - 3.0 3.0 3.0 NPR 6.7 6.7 - - - Ludiflash 75.0 - - - - Pearlitol Flash - 75.0 - - - SmartEx QD50 - - 78.7 - - F-Melt - - - 80.7 - ProSolv ODT G2 - - - - 80.7 Peppermint 4.4 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 5.0 Crospovidone 5.0 5.0 5.0 - - Croscarmellose sodium - - - 3.0 - Sodium starch glycolate - - - - 3.0 Magnesium stearate 2.0 2.0 2.0 2.0 2.0 Total number 100,0 100,0 100,0 100,0 100,0

Table 3B - Formulations of rapidly disintegrating tablets with different ready-to-use systems and nicotine as nicotine bitartrate, NBT or nicotine polyacrylex, NPR (15% nicotine loading). Amounts are in mg. RDT = rapidly disintegrating tablet.

Four rapidly disintegrating tablets (BRT(1)-BRT(4)) with nicotine were then prepared with different amounts of MCC (microcrystalline cellulose) as a filler, as indicated in Table 3C.

In this example, the following conditions apply. Punch used: 7.00 mm, round, shallow concave, B device. Tablet weight: 100.0 mg.

BRT(1) BRT(2) BRT(3) BRT(4) Nicotine calcium carbonate 3.0 3.0 3.0 3.0 Microcrystalline cellulose, MCC 0,0 5.0 10.0 20.0 Mannitol 79.7 74.7 69.7 59.7 Crospovidone 5.0 5.0 5.0 5.0 Peppermint 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 Magnesium stearate 1.0 1.0 1.0 1.0 Total number 100,0 100,0 100,0 100,0

Table 3C - Rapidly disintegrating tablet formulations with varying amounts of MCC and nicotine (1 mg/tablet) coated on calcium carbonate (synthetic nicotine free base coated on calcium carbonate in a 1:2 weight ratio). Amounts are in mg. RDT = rapid disintegrating tablet.

Four rapidly disintegrating tablets BRT(5)-BRT(8) with nicotine are prepared with different amounts of disintegrant, as indicated in Table 3D.

In this example, the following conditions apply. Punch used: 7.00 mm, round, shallow concave, B device. Tablet weight: 100.0 mg.

BRT(5) BRT(6) BRT(7) BRT(8) NBT 3.0 3.0 3.0 3.0 Mannitol 41.7 39.2 41.7 31.7 Microcrystalline cellulose 43 43 43 43 Crospovidone 0,0 2.5 5.0- 10.0 Peppermint 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 Magnesium stearate 1.0 1.0 1.0 1.0 Total number 100,0 100,0 100,0 100,0

Table 3D - Rapidly disintegrating tablet formulations with different amounts of disintegrant. Amounts are in mg. RDT = rapid disintegrating tablet.

Three rapidly disintegrating tablets BRT(9)-BRT(11) with nicotine are prepared with different types of glidants as shown in Table 3E.

In this example, the following conditions apply. Punch used: 7.00 mm, round, shallow concave, B device. Tablet weight: 100.0 mg.

BRT(9) BRT(10) BRT(11) NBT 3.0 3.0 3.0 Microcrystalline cellulose 5 5 5 Mannitol 78.6 77.6 77.6 Crospovidone 5.0 5.0 5.0 Flavoring agent eucamentol 2 2 2 Sucralose 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 Magnesium stearate 1.0 - - Sodium stearyl fumarate - 2.0 - Compritol HD5 - - 2.0 Total number 100,0 100,0 100,0

Table 3E - Rapidly disintegrating tablet formulations. Amounts are in mg. RDT=rapidly disintegrating tablet.

Three rapidly disintegrating tablets BRT(12)-BRT(14) with nicotine are prepared as indicated in Table 3F.

In this example the following conditions apply. Punch used: 7.00 mm, round, shallow concave, B device. Tablet weight: 75.0 mg.

BRT(12) BRT(13) BRT(14) SmartEx QD 50 60.0 65.0 65.0 Nicotine Bitartrate (NBT) 3.0 3.0 3.0 Sodium carbonate anhydrous 5.0 - 5.0 Crospovidone (Kollidon CL-F, BASF) 5.0 5.0 - Peppermint powder 0.4 0.4 0.4 Sucralose 0.4 0.4 0.4 Aerosil 200 (silicon dioxide) 0.2 0.2 0.2 Magnesium stearate 1.0 1.0 1.0 Total number 75.0 75.0 75.0

Table 3F - Rapidly disintegrating tablet formulations. Amounts are in mg. RDT = rapid disintegrating tablet. RDT(13) was prepared similarly to RDT(12) but without the buffer. RDT(14) was prepared similarly to RDT(12) but without the disintegrant.

BRT(12)-BRT(13) were pressed to a hardness of 15-20 N. BRT(14) was pressed to a hardness of 25-35 N.

A sachet for oral use is prepared containing the powder composition, PPC 1, as shown in Table 3G. The sachet is manufactured as follows.

The nicotine-resin complex used in the present description is prepared by mixing water, nicotine, resin (Amberlite® IRP64) and glycerol. When a homogeneous solution is obtained and all the nicotine is bound to the ion exchange resin, the pressure is reduced and the resulting mixture is concentrated under vacuum at elevated temperature, providing the desired complex in powder form. The nicotine-resin complex is sieved.

In principle, any complex of cationic ion exchange resins (preferably a pharmaceutical grade non-ionic resin) can be used. The resin is capable of binding anionic molecules at the ion exchange sites.

The resulting nicotine-resin complex powder is mixed using a Turbula mixer for 6 minutes (speed 49 rpm) with the remaining ingredients to obtain the final powder composition.

The final powder composition is filled into a sachet (target content weight 400 mg powder per sachet). The next sachet used is one made from long-fiber paper.

The sachet material is a heat-sealable non-woven cellulose, such as long-fiber paper. Sachets that are not in the form of a non-woven cellulose fabric may also be used according to the invention.

The powder is filled into the sachet and held in the sachet by means of a seal.

When smaller amounts of additional humectants are included, other than, for example, sugar alcohols, these additional humectants are added in the same manner as magnesium stearate.

PPC 1 Amount of nicotine 3 mg Source material Content in mass percent NPR 4.75 Isomalt GalenIQ 720 45 Zerose TM Erythritol 40 Sodium carbonate anhydrous 2.50 Sodium bicarbonate 4.00 Flavoring agent 3.60 Acesulfame potassium 0.15 Total number 100

Table 3G - Nicotine sachets; NPR is nicotine polyacrylex resin, where the resin is Amberlite™ IRP64. Sachets contain 400 mg per piece.

A preparation of instant-dissolving sachets with residue containing nicotine polyacrylex resin (NPR) or nicotine bitartrate (NBT) containing PPC powder compositions 2-7 as indicated in Table 3H is obtained.

A preparation of residue-free, instant-dissolving sachets containing nicotine polyacrylex resin (NPR) or nicotine bitartrate (NBT) containing PPC 8-13 powder compositions as specified in Table 3I is obtained.

Sachets are obtained as follows.

For PPC 6 and 8-10, a method was used similar to that used for PPC 1.

For PPC 2-5, 7 and 11-13 the following method was used.

Nicotine bitartrate xH2O is mixed using a Turbula mixer for 6 minutes (speed 49 rpm) with the remaining ingredients to obtain the final powder composition.

The final powder composition is filled into a sachet (target content weight of 400 mg powder per sachet). The sachet material used is that of Example 2, made from long-fiber paper. The powder is filled into the sachet and retained in the sachet by means of a compactor.

The sachet material is a heat-sealable non-woven cellulose, such as long-fiber paper. Sachets that are not in the form of a non-woven cellulose fabric may also be used according to the invention.

The powder is filled into the sachet and held in the sachet by means of a seal.

When smaller amounts of additional humectants are included, other than, for example, sugar alcohols, these additional humectants are added in the same manner as magnesium stearate.

PPC 2 3 4 5 6 7 Amount of nicotine 3 mg 3 mg 3 mg 3 mg 3 mg 3 mg Source material Content in mass percent NPR - - - - 4.75 - NBT 2.14 2.14 2.14 2.14 - 2.14 Isomalt GalenIQ 720 67.7 - 67.7 - 62.6 67.7 Maltitol SweetPearl 300 DC - 67.7 - 65.2 - - Sodium carbonate 2.50 2.50 2.50 2.50 2.50 2.50 Sodium bicarbonate 4.00 4.00 4.00 4.00 4.00 4.00 Peppermint flavoring 2.50 2.50 2.50 2.50 2.50 - Menthol 1.00 1.00 1.00 - - - Eucalyptus flavor - - - 3.50 3.50 3.50 Acesulfame potassium 0.16 0.16 0.16 0.16 0.15 0.16 Dibasic calcium phosphate anhydrous. 20,00 20,00 - - - - Calcium carbonate DC - - 20,00 20,00 - - Mono-, diglyceride powder (emulsifier) - - - - 10.00 10.00 Hydrogenated vegetable oil (solid state) - - - - 10.00 10.00 Total number 100 100 100 100 100 100

Table 3H. Nicotine sachets; NPR is nicotine polyacrylex resin, where the resin is Amberlite™ IRP64. NBT is nicotine bitartrate. Sachets contain 400 mg per sachet.

PPC 8 9 10 11 12 13 Amount of nicotine 3 mg 3 mg 3 mg 3 mg 3 mg 3 mg Source material Content in mass percent NPR 4.75 4.75 4.75 - - - NBT - - - 2.14 2.14 2.14 Isomalt GalenIQ 720 - 85.1 - - 87.7 - Zerose TM Erythritol 85.1 - 87.7 - - Maltitol SweetPearl 300 DC - - 85.1 - - 87.7 Sodium carbonate anhydrous 2.50 2.50 - - - 2.50 Sodium bicarbonate 4.00 4.00 - - - 4.00 Effersoda - - 6.50 6.50 6.50 - Peppermint flavoring 2.50 2.50 2.50 - - - Menthol 1.00 1.00 1.00 - - - Eucalyptus flavor - - - 3.50 3.50 3.50 Acesulfame potassium 0.15 0.15 0.15 0.16 0.16 0.16 Total number 100 100 100 100 100 100

Table 3I. Nicotine sachets; NPR is nicotine polyacrylex resin, where the resin is Amberlite™ IRP64. NBT is nicotine bitartrate. Sachets contain 400 mg per sachet.

If additional magnesium stearate is added, it can be added to the complete powder mixture during the last few minutes of final mixing.

As described below, tablets according to the invention can be prepared from a wide range of different compositions.

As can be seen from Table 1, microcrystalline cellulose is used as a filler. Smaller amounts of filler such as microcrystalline cellulose can also be used. Examples of fillers used 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 tricalcium phosphates, cellulose polymers such as wood, starch polymers, fibers, and combinations thereof.

As can be seen from Table 1, mannitol is used as a bulk sweetener. Examples of bulk sweeteners used include sugar sweetener and/or sugar-free sweetener.

Bulk sweeteners can often support the flavor profile of a formulation.

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.

Sugar sweeteners typically include, but are not limited to, saccharide-containing components such as sucrose, dextrose, maltose, sucrose, lactose, sorbose, dextrin, trehalose, D-tagatose, invert sugar solids, 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.

As can be seen from Table 1 and 3A-3F, crospovidone, croscarmellose sodium, and sodium starch glycolate are used as disintegrants in rapidly disintegrating tablets. Examples of disintegrants used 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 superdisintegrants such as cross-linked cellulose (such as sodium carboxymethyl cellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural superdisintegrants, and calcium silicate, and combinations thereof.

As can be seen from Table 1 and 3A-3G, sucralose is used as a high intensity sweetener. High intensity sweeteners used 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, monelin, stevioside, and the like, alone or in combination.

As can be seen from Table 1 and 3A-3G, peppermint and menthol are used as flavoring agents. Flavors used include almond, almond amaretto, apple, bavarian cream, black cherry, black sesame seed, blueberry, brown sugar, bubble gum, toffee, cappuccino, caramel, caramel cappuccino, cheesecake (graham crust), hot cinnamon, cotton candy, circus cotton candy, clove, coconut, coffee, clear coffee, double chocolate, power beef, graham cracker, grape juice, green apple, Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada, 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, spearmint, strawberry, sweet cream, sweet tart, sweetener, toasted almond, tobacco, tobacco blend, vanilla ice cream, vanilla cake, vanilla bean, vanillin, waffle, Belgian waffle, watermelon, whipped cream, white chocolate, wintergreen, amaretto, banana cream, black walnut, blackberry, buttercream, cream rum, cherry, chocolate hazelnut, cinnamon roll, cola, peppermint cream, eggnog, english toffee, guava, lemonade, licorice, maple, mint chocolate chip, orange cream, peach, pina colada, pineapple, plum, pomegranate, praline and cream, red licorice, salted toffee, strawberry banana, strawberry kiwi, tropical punch, tutti-frutti, vanilla or any combination thereof.

According to an embodiment of the invention, the flavoring agent can be used as a taste masking agent for nicotine.

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

In some embodiments of the invention, the composition contains a pH regulating agent in an amount of from 2.7 to 5.7 wt.% of the said composition.

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

As can be seen from Table 1 and 3A-3G, sodium carbonate is used as a buffering agent. Buffering agents used include carbonate, including monocarbonate, bicarbonate, and sesquicarbonate, glycerinate, phosphate, glycerophosphate, alkali metal acetate, glyconate, or citrate, ammonium, tris buffer, amino acids, and mixtures thereof. Encapsulated buffer such as Effersoda may also be used.

In some embodiments, the composition comprises a buffering agent in an amount of from 2.7 to 5.7% by weight of the composition.

A buffering agent may be added to the formulation along with the water-soluble ingredients of the rapidly disintegrating tablet.

When a buffering agent is added to a rapidly disintegrating tablet as part of the water-soluble ingredients of the rapidly disintegrating tablet, a pH profile can be achieved in accordance with embodiments of the present invention.

A buffering agent in the tablet may be used to achieve desired pH values in the tablet recipient's saliva.

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.

The most suitable buffering agent according to preferred embodiments of the present invention is the sodium carbonate-sodium bicarbonate buffer system.

As can be seen from Table 1, silicon dioxide is used as a glidant. Other glidants used for the composition may also be used within the scope of the invention.

As can be seen from Table 1 and 3A-3G, magnesium stearate is used as a lubricant. Other lubricants used for the composition may also be used within the scope of the invention.

As can be seen from Table 3A-3F, ready-to-use systems can be used to prepare tablets. Typically, such ready-to-use systems can, for example, replace a filler, disintegrant, glidant, or the like with a separate 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).

In order to obtain a composition intended to release a nicotine content within a period of 90 seconds upon interaction with oral saliva and a composition intended to release a pH regulating agent content within a period of 60 seconds upon interaction with oral saliva, the range of parameters may be adjusted.

First, by changing the composition, the disintegration time can be changed. The use of ingredients with high solubility in water can help to reduce the disintegration time. A shorter disintegration time greatly contributes to the rapid release of nicotine, as well as the rapid release of the pH adjusting agent.

In particular, the inclusion of a disintegrant can significantly affect the disintegration time, depending on the overall composition. In addition, by changing the amount and type of disintegrant, the disintegration time can be further adjusted. For example, if a tablet having a lower disintegration time is desired, the percentage of disintegrant can be increased and/or the type of disintegrant can be at least partially replaced with a more effective disintegrant.

In addition, decreasing the particle size of the disintegrant tends to decrease the disintegration time, probably due to the increased surface area to volume ratio.

In addition, the compression force used in compressed tablets is significantly correlated with the obtained hardness, so that a higher compression force usually increases the hardness of the obtained tablet. By adjusting the hardness of the tablet, the disintegration time can also be influenced, so that a lower hardness usually gives a shorter disintegration time. In the present description, it has been observed for a number of compositions that by applying the correct compression force, a disintegration time of less than 60 seconds can be achieved when administered orally, whereas too much compression force can lead to a longer disintegration time, exceeding 60 seconds. In this regard, it should be noted that the threshold value of the 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 set leads to too slow disintegration, a further method of adjustment can be to replace the normal disintegrant with a superdisintegrant, i.e. one that promotes disintegration in a more effective way.

Increasing water solubility can also be accomplished by exchanging ingredients with low water solubility with ingredients with higher water solubility. For example, using sugar alcohols as fillers can be highly advantageous because sugar alcohols have higher water solubility than alternative fillers.

In addition, when the formulation is provided in tablet form, the use of sugar alcohols with lower compactibility results in a shorter disintegration time. Too low compactibility may reduce the mechanical strength of the tablet and lead to undesirably high abrasion and the risk of cracks, etc.

Further examples of parameters that can be adjusted to produce a composition designed to release nicotine content within a period of 90 seconds upon interaction with oral saliva and a composition designed to release pH-regulating agent content within a period of 60 seconds upon interaction with oral saliva include the size and shape of the tablet when the composition is provided in tablet form. The larger the tablet, the longer the disintegration time and, therefore, the release time of nicotine and pH-regulating agent.

For example, in such tablet embodiments, increasing the flatness (e.g., as measured by the diameter-to-height ratio) of a disk-shaped tablet typically increases the disintegration time by increasing the surface-to-volume ratio. As long as the tablet has satisfactory mechanical strength, the flatness can be increased.

In addition, in such embodiments of tablets, changing the cross-sectional profile from a convex-type tablet to a concave-shaped tablet reduces the disintegration time. It should be noted that this may reduce the mechanical strength of the tablet to some extent, however, provided that it is satisfactory, following a concave cross-section can help to increase disintegration and therefore reduce the disintegration time.

Furthermore, regardless of the use of tablets or powder formulations, when using binders, for example to obtain higher cohesiveness and mechanical strength of the tablet or formulation, the amount of such binders can be reduced as much as possible in order to obtain a higher disintegration rate and, consequently, a shorter disintegration time.

In addition, by adding a salivary secretion agent to the composition, it is possible to promote the increase of saliva in the vicinity of the composition, which again promotes the dissolution and disintegration of the composition to reduce the disintegration time.

Another parameter that can be adjusted is the form of nicotine used. If a shorter release time of nicotine is required, a form of nicotine that is rapidly released from any carrier can be used. Even faster is the use of nicotine without a carrier, such as nicotine free base or nicotine salt.

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

Typically, the formulation includes ingredients selected from the group consisting of bulk sweeteners, fillers, ready-to-use systems, flavors, dry binders, disintegrants, in the present description superdisintegrants, tabletting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffering agents, high intensity sweeteners, colors, glidants, lubricants, or any combination thereof. In the present description, tabletting aids are used for tablets, but not for other powder formulations. Absorption enhancers can include, for example, pH adjusting agents such as buffering agents and mucoadhesives.

In an embodiment of the invention, the tablet core is provided with an outer coating.

In an embodiment of the invention, said outer coating is selected from the group consisting of a hard coating, a soft coating, and an edible film coating, or any combination thereof.

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

According to an embodiment of the invention, an amount of dry binder is used to attach nicotine to the bulk sweetener.

According to an embodiment of the invention, said rapidly disintegrating tablet comprises one or more encapsulating delivery systems.

Example 3

pH in vivo

Rapidly disintegrating tablets are designed to have an in vivo pH higher than the pH of saliva between meals in the oral cavity. Therefore, the pH is measured in vivo as follows:

At least 6 patients chewed the unbuffered chewing base for 1 minute, after which the initial pH value in the saliva sample of each patient was measured using a suitable pH electrode system, for example, a PHW77-SS stainless steel electrode. Only patients having an initial pH in the saliva within the range of 6.7 to 7.3 after chewing the unbuffered chewing base for one minute were selected. These patients were thus classified as average patients.

One tablet is administered sublingually to at least six patients. The pH of the saliva of each of the six patients is then measured at specific time intervals. Each pH value is thus the arithmetic mean of six measurements taken on saliva samples from six patients.

The sample volume of individual saliva samples may vary, since the volume of saliva obtained may differ for each patient. This difference in sample volume does not have a significant effect on the pH measurements. In addition, it has been established through appropriate tests that the change in time between sample collections does not have a significant effect on the result. This means that the pH value measured after three minutes is not significantly affected by whether another saliva sample is collected from six patients, for example, after two minutes or not. In addition, it has been established through appropriate tests that the time from sample collection to the time of measurement is not critical for the measured value. However, in the present measurements, the pH values were measured in samples within a maximum of 15 minutes after sample collection.

The results are shown in Table 3J.

pH 10 sec 20 sec 90 sec In vivo DT (sec) BRT (12) (1 mg) 9.3 9.1 8.4 20 BRT (14) (1 mg) 7.4 7.2 7.6 210 BRT (13) (1 mg) 5.3 5.8 6.5 20 Sachet PPC(1) (3 mg) 7.1 7.3 7.3 n.d. Nicorette Microtab (2 mg) 6.7 6.8 6.8 ˃600 Nicotinell mint lozenge (2 mg) 6.9 7.1 7.2 ˃600 Nicotinell mint gum (2 mg) 7.2 7.4 7.6 n.d.

Table 3J. pH in vivo. Nicorette Microtab (2 mg), Nicotinell mint lozenge (2 mg), and Nicotinell mint gum (2 mg) were commercially available products.

As can be seen from Table 3J, the pH exceeds 7.5 for BRT 12 and 13. For BRT 12, this is even true after 10 and 20 seconds of exposure to oral saliva. BRT(13), prepared without any buffer, did not provide a pH above 7.5.

The required increase in salivary pH is at least 0.5-1.0 pH units. The standard nicotine mouth spray, Nicorette Microtab, Nicotinell mint lozenge and Nicotinell mint gum were used for comparison. The standard nicotine mouth spray also demonstrated rapid craving relief. The standard nicotine mouth spray increased the salivary pH to a maximum of 8.5 according to internal measurements. None of Nicorette Microtab and Nicotinell mint lozenge resulted in a pH above 7.2. Nicotinell mint gum did not result in a pH above 7.6.

The sample volume of individual saliva samples may vary because the volume of saliva obtained may differ for each patient. This difference in sample volume does not significantly affect the pH measurements.

It should be noted that the in vivo pH will differ from the in vitro pH due to the fact that acidic sodium bicarbonate is normally continuously formed in saliva, hence neutralizing the alkaline contribution of the buffer. Thus, the pH obtained in vivo will be lower than the in vitro pH, measured, for example, by dissolving a tablet in a beaker.

Example 4

Disintegration of nicotine tablets

The in vitro disintegration of the rapidly disintegrating tablets of Examples 1 and 2 was carried out in accordance with the European Pharmacopoeia 9.0, Section 2.9.1, Disintegration of Tablets and Capsules. As described in the Examples, each lot was manufactured in different sub-batches of tablets where the compression force varied and therefore the output parameters such as hardness and friability would also vary. These output parameters also have an effect on the in vitro disintegration. The results for Example 1 are shown in Table 4. The minimum and maximum value for the measured disintegration are given and this is more or less a function of the hardness.

Average in vitro disintegration (sec) Average hardness (H) Average abrasion (%) Min (sec) Max (sec) Min (N) Max (N) Min (%) Max (%) BRT(a) 21 24 14 63 0,0 0.3 BRT(b) 23 98 12 50 0,0 0.6 BRT(c) 29 177 14 55 0,0 0.5 BRT(d) 15 177 19 62 0,0 0,0 BRT(e) 13 175 15 45 0,0 0.2 BRT(f) 11 259 14 43 0,0 0.2

Table 4 - In vitro disintegration, hardness, abrasion. Time is presented in seconds.

The above table should be interpreted as shown in the following example. Looking at, for example, the BDT(a), the minimum mean disintegration time of 21 seconds corresponds to a tablet compressed hard enough to produce a cohesive tablet having a minimum mean hardness of 14 N and a friability of 0.3%. Similarly, the maximum mean disintegration time of 24 seconds corresponds to another tablet compressed harder to have a maximum mean hardness of 63 N. Thus, a tablet having an average friability of 0.0% BDT(a) corresponds to a tablet having an average hardness of 63 N. In other words, in Table 4, the BDT(a) refers to two different tablets compressed at two different pressures, with the relationship indicated above. That is, each line corresponds to two different tablets: one for the minimum values of disintegration time and hardness and the maximum value for friability, and the other for the maximum values of disintegration time and hardness and the minimum value for friability.

The results for example 2 are shown in Table 5.

Average in vitro disintegration (sec) Average hardness (H) Average abrasion (%) Min (sec) Max (sec) Min (N) Max (N) Min (%) Max (%) BRT(g) 120 210 17 22 N/A 0.5 BRT(h) 40 80 16 24 0.5 0.8 BRT(i) 10 46 17 22 0.3 0.3 BRT(j) 42 150 17 22 0.7 1.0 BRT(k) 45 201 17 22 0.6 0.9

Table 5 - In vitro disintegration, hardness, abrasion. Time is presented in seconds.

The above table should be interpreted as shown in the example below Table 4.

It can be seen that the in vitro disintegration can vary greatly between opened fast-disintegrating tablets. Thus, the desired disintegration profile can be used together with a high pH in vivo (as described in Example 3), due to which the nicotine can be used more efficiently. The most preferred in vitro disintegration profile is below 60 seconds, since it guarantees a high nicotine concentration in combination with a relatively high pH in vivo.

In vitro disintegration is a rapid method for determining the time and mechanism of action of a tablet. More preferably, in vivo disintegration is measured or combined. The in vivo disintegration time is the value for the actual disintegration of a sublingual tablet under the tongue. Tables 6 and 7 summarize the most important in vivo disintegration results.

Average disintegration in vivo (sec) Min (sec) Max (sec) BRT(a) 34 52 BRT(b) 18 27 BRT(c) 37 n.d. BRT(d) 42 n.d. BRT(e) 46 n.d.

Table 6 - In vivo disintegration. Time is presented in seconds.

Average disintegration in vivo (sec) Min (sec) Max (sec) BRT(g) 19 40 BRT(h) 13 48 BRT(i) 32 80 BRT(j) n.d. 56 BRT(k) n.d. 81

Table 7 - In vivo disintegration. Time is presented in seconds.

The above tables 6-7 should be interpreted as shown in the example below table 4.

As stated for the in vitro disintegration results above, the rate of disintegration in vivo may vary between the formulations disclosed. Disintegration time should be completed within 60 seconds of the onset of disintegration or preferably faster.

Since the dissolution of nicotine bitartrate is a relatively fast process, the time used to release the nicotine content can be taken as the disintegration time of the matrix (in this description, the tablet).

Example 5

Release and absorption of nicotine

Nicotine concentration measurements are carried out as follows:

One dose of the tablets from Examples 1 and 2 is administered sublingually to at least six patients. Saliva is collected at certain time intervals. The experiment is repeated. Thus, each nicotine concentration value is the arithmetic mean of 12 measurements, i.e., performed on saliva samples from six patients twice. The nicotine concentration in saliva is analyzed by HPLC after extraction into an appropriate buffer.

The results are shown in Tables 8A–8C.

Measuring time from initial interaction with oral saliva
[seconds] 10 20 90 Nicotine concentration [mg/ml] 2mg Nicotinell mint lozenge 0.06 0.05 0.10 1 mg BRT (12) 0.52 0.59 0.52 1 mg BRT (13) 0.74 0.66 0.66 1 mg BRT (14) 0.36 0.39 0.33 3 mg sachet PPC 1 0.04 0.07 0.17 Nicorette Microtab 2 mg 0.03 0.05 0.13 Nicotinell mint gum (2 mg) 0.02 0.04 0.18

Table 8A. Amount of nicotine in saliva. n.d. = not estimated.

Measuring time from initial interaction with oral saliva
[seconds] 10 20 90 Nicotine concentration [mg/ml] 2mg Nicotinell mint lozenge 1.90 1.91 1.85 1 mg BRT (12) No remainder No remainder No remainder 1 mg BRT (13) No remainder No remainder No remainder 1 mg BRT (14) n.d. n.d. No remainder 3 mg sachet PPC 1 n.d. n.d. 1.09 Nicorette Microtab 2 mg 1.90 1.87 1.77 Nicotinell mint gum (2 mg) 1.98 1.96 1.72

Table 8B. Amount of nicotine in residue. n.d. = not available (not estimated)

Measuring time from initial interaction with oral saliva
[seconds] 10 20 90 Nicotine absorption [wt.%] 2mg Nicotinell mint lozenge 2 2 3 1 mg BRT (12) 48 41 48 1 mg BRT (13) 26 34 35 1 mg BRT (14) n.d. n.d. 67 3 mg sachet PPC 1 n.d. n.d. 58 Nicorette Microtab 2 mg 4 4 5 Nicotinell mint gum (2 mg) 0 0 5

Table 8C. Nicotine absorption. n.d. = not estimated.

As can be seen from Table 8A-8C, the inventive compositions provided very high absorption, above 40% or even above 50%. In addition, since BRT 1 and 2 are comparable, only BRT 2 does not contain a buffer, the effect of the buffer inclusion can be observed. It is noted that BRT1 has a final absorption significantly higher than BRT2, which illustrates how the inclusion of a buffer increases the nicotine absorption. In addition, it is observed that the nicotine absorption is more or less constant at the time points of 10 seconds, 20 seconds and 90 seconds, illustrating how the disintegration time (approximately 10 seconds for BRT 1) is a limiting factor, and that the nicotine release time after disintegration, as well as the nicotine absorption time, are insignificant for the present compositions.

The tablets of Examples 1 and 2 are very suitable for the preparation of solid oral nicotine formulations for rapid onset of nicotine craving reduction, containing nicotine and a pH regulating agent, in which the formulation is designed to release the nicotine content over a period of 90 seconds upon interaction with saliva in the oral cavity and the formulation is designed to release the pH regulating agent content over a period of 60 seconds upon interaction with saliva in the oral cavity.

Example 6

Evaluation of rapidly disintegrating tablets - burning sensation

In general experiments, it was found that the nicotine fast-disintegrating tablets according to the invention lead to a high efficiency of nicotine absorption into the bloodstream for the patient taking the fast-disintegrating tablet. With such rapid integration, the high pH value in combination with the high concentration of nicotine, the patient swallows only a small portion of the nicotine instead of entering the bloodstream, thus leading to a rapid reduction in cravings.

When the pH in the oral cavity is high, nicotine is used very effectively. However, too high a pH in the saliva of patients taking a rapidly disintegrating tablet may be undesirable, since a highly alkaline pH leads to problems with irritation and burning of the sublingual tissue.

Therefore, the rapidly disintegrating tablets of the invention are indeed suitable in that they provide an effective use of nicotine and at the same time are pleasant for the patient, i.e. with clearly reduced undesirable side effects, in the present description in particular the so-called nicotine burning in the throat.

The burning sensation in the throat is assessed as described below.

Nicotine burn was assessed by a panel of 7 trained assessors. After calibration by chewing two standard nicotine gums of “known” burn intensity, each assessor rates the sensation of throat burning on a scale of 1 to 15, with 15 representing the most intense burning. Each assessor rates all samples twice. Ratings are recorded for the specified time periods. Averages are calculated.

Time [seconds] 145 295 505 Burning Index (1-15) BRT (12) 3.5 1.8 0.8 BRT (14) 6.6 4.5 2.7 Nicotinell mint
chewing gum (2 mg) 4.6 4.6 3.4 Nicotinell mint lozenge (2 mg) 4.8 4.9 4.2 Nicorette Microtab 2 mg 6.4 5.9 5.5

Table 9. Sensory assessment of burning sensation in the throat

Example 7 - Relieving Nicotine Cravings

Nicotine craving relief was studied using a panel of three subjects who rated all samples twice. Each subject reported the time from oral administration to craving relief, i.e., the sensation of nicotine reaching the head. The mean times for BRT (12) and BRT (14) and the three commercially available products are shown in Table 10.

Time before
weakening BRT (12) BRT (14) Nicotinell mint
chewing gum (2 mg) Nicotinell
mint candy (2 mg) Nicorette
Microtab 2 mg Average value 240 300 560 480 400

Table 10. Time before weakening.

As can be seen from Table 10, significantly faster attenuation was achieved compared to commercially available products.

Claims (37)

1. A compressed oral disintegrating nicotine tablet for rapid onset of nicotine craving reduction, comprising nicotine and a pH regulating agent, wherein the tablet is designed to release nicotine content over a period of 60 seconds upon interaction with oral saliva and the tablet is designed to release pH regulating agent content over a period of 60 seconds upon interaction with oral saliva, wherein the tablet contains mannitol in an amount greater than 40% by weight of the tablet, wherein the tablet contains nicotine in an amount of from 0.5 to 10 mg, wherein the pH regulating agent is an alkaline buffering agent, wherein the pH regulating agent is selected from the group consisting of monocarbonate, bicarbonate, sesquicarbonate and any combination thereof, and wherein the tablet contains a disintegrant in an amount of 1-10% by weight of the tablet, wherein the disintegrant is selected from the group consisting of crospovidone, sodium croscarmellose, sodium starch glycolate and any combination thereof. 2. A compressed orally disintegrating nicotine tablet according to claim 1, wherein the tablet is designed to release nicotine content over a period of from 5 to 60 seconds upon interaction with saliva in the oral cavity. 3. A compressed orally disintegrating nicotine tablet according to claim 1 or 2, wherein the tablet is designed to release nicotine content over a period of 10 to 40 seconds upon interaction with saliva in the oral cavity. 4. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 3, wherein the tablet contains said pH adjusting agent in an amount of at least 2.7% of the tablet. 5. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 4, wherein the tablet is designed to release the pH regulating agent content over a period of 40 seconds upon interaction with saliva in the oral cavity. 6. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 5, wherein the pH regulating agent content is released before the nicotine content. 7. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 6, in which at least 50% by weight of the pH adjusting agent content is released to 50% by weight of the nicotine content. 8. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 7, wherein the tablet is provided in a sublingual orally disintegrating tablet. 9. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 8, wherein the tablet is designed to disintegrate within a period of less than 60 seconds after oral administration. 10. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 9, wherein the tablet is designed to contain nicotine for dissolution in saliva within a period of less than 90 seconds after oral administration. 11. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 10, wherein said nicotine is provided in the form of a nicotine salt. 12. A compressed orally disintegrating nicotine tablet according to claim 11, wherein 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 hencitate, 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 their hydrates (e.g. nicotine zinc chloride monohydrate). 13. A compressed orally disintegrating nicotine tablet according to claim 11, wherein the nicotine salt comprises nicotine bitartrate. 14. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 10, wherein said nicotine is provided in the form of free base nicotine. 15. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 10, wherein said nicotine is provided in the form of a complex between nicotine and an ion exchange resin. 16. A compressed orally disintegrating nicotine tablet according to claim 15, wherein said complex between nicotine and an ion exchange resin is a nicotine polyacrylex resin (NPR). 17. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 10, wherein said nicotine is provided in combination with a fatty acid. 18. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 10, wherein said nicotine is provided in an ionic complex with at least one mucoadhesive water-soluble anionic polymer. 19. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 18, wherein said nicotine is provided in the form of synthetic nicotine. 20. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 19, wherein the tablet provides a peak nicotine concentration in saliva of greater than 0.3 mg/mL and a peak pH in saliva of greater than 8 within the first 120 seconds after oral administration. 21. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 20, wherein the tablet provides a peak nicotine concentration in saliva of greater than 0.5 mg/ml and a peak pH in saliva of greater than 8 within the first 120 seconds after oral administration. 22. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 21, wherein the tablet is designed to contain nicotine for dissolution in the saliva of the oral cavity within a period of less than 90 seconds after oral administration and in which at least 40% by weight of the nicotine is absorbed through the oral mucosa. 23. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 21, wherein the tablet is designed to contain nicotine for dissolution in the saliva of the oral cavity within a period of less than 90 seconds after oral administration and in which at least 50% by weight of the nicotine is absorbed through the oral mucosa. 24. A compressed orally disintegrating nicotine tablet according to any one of claims 1-23, wherein the tablet further comprises a disintegrant selected from the group consisting of 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 calcium silicate and combinations thereof. 25. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 24, wherein the disintegrant comprises cross-linked polyvinylpyrrolidone. 26. A compressed orally disintegrating nicotine tablet according to any one of claims 24, 25, wherein at least 50% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 50 micrometers. 27. A compressed orally disintegrating nicotine tablet according to any one of claims 24, 25, wherein at least 25% by weight of the cross-linked polyvinylpyrrolidone has a particle size of less than 15 micrometers. 28. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 27, wherein the tablet further comprises at least one polyol selected from sorbitol, erythritol, xylitol, maltitol, lactitol, isomalt and mixtures thereof. 29. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 28, wherein the tablet has a mass of from 25 to 200 mg, such as from 50 to 150 mg, such as 70 to 120 mg, such as about 75 mg or about 100 mg. 30. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 29, wherein the tablet further comprises sodium stearyl fumarate (SSF) as a glidant. 31. A compressed orally disintegrating nicotine tablet according to any one of claims 1-30, wherein the tablet contains microcrystalline cellulose in an amount of 1-10% by weight of the tablet. 32. A compressed orally disintegrating nicotine tablet according to any one of claims 1 to 31, wherein the composition further comprises an amount of an insoluble composition. 33. The compressed orally disintegrating nicotine tablet of claim 32, wherein the insoluble composition comprises at least one selected from dibasic calcium phosphate, calcium carbonate DC, mono-, diglyceride powder, hydrogenated vegetable oil and combinations thereof. 34. A compressed orally disintegrating nicotine tablet according to any one of claims 30 to 33, wherein the amount of insoluble composition is from 5 to 50% by weight of the tablet, such as from 10 to 30% by weight of the tablet. 35. A method for reducing craving for nicotine by administering an effective amount of said compressed orally disintegrating nicotine tablet according to any one of claims 1-34.