Patent ID: 12194149

DETAILED DESCRIPTION

As used herein the term “water-dissolvable nicotine tablet” refers to a compressed tablet that overall is dissolvable in water. While the nicotine lozenge of the invention comprises dissolvable FDT module, it also comprises dissolvable lozenge module. Thus, the nicotine tablet of course does not comprise e.g. chewing gum modules that does not dissolve in water. Furthermore, the nicotine tablet is water-dissolvable in the sense that it disintegrates and that main constituents dissolve in water. The nicotine tablet of the invention is a compressed tablet, formed by compression of at least a first powdered composition and a second powdered composition to give the first and second compressed modules, respectively.

The water-dissolvable nicotine tablet may comprise some amounts of water-insoluble material, such as no more than 10% by weight of the tablet of e.g. MCC. Thus, the majority of the water-dissolvable nicotine tablet is comprised of water-soluble material, such as more than 90% by weight of the tablet.

The nicotine tablet may disintegrate and dissolve within a period of at least 2 minutes upon oral administration, such as at least 3 minutes, such as at least 4 minutes, such as at least 5 minutes.

As used herein, the term “FDT-module” (Fast Disintegrating Tablet-module) refers a module having the characteristics of a so-called fast disintegrating tablet. Fast disintegrating tablets, also sometimes referred to as orally disintegrating tablets (ODT), generally exhibits rapid oral disintegration with no need for chewing or drinking liquids to ingest these products.

FDT-modules of the invention exhibits fast disintegration, typically below 60 seconds from placing it in the mouth, or even faster such as 30 seconds from placing it in the mouth. In some embodiments of the invention, the FDT-modules disintegrates within 30 seconds, such as within 20 seconds, such as within 15 seconds.

As used herein the term “lozenge-module” refers to a module imparting lozenge properties, i.e. a module that dissolve or disintegrate over minutes in the mouth, whereby its constituents are released, e.g. acidic pH regulating agents, flavor, etc. depending on the specific embodiment. For example, the lozenge-module may disintegrate and dissolve within a period of at least 2 minutes upon oral administration, such as at least 3 minutes, such as at least 4 minutes, such as at least 5 minutes.

As used herein, the term “disintegrate” refers to a reduction of an object to components, fragments or particles. Disintegration time may be measured in vitro or in vivo. Unless otherwise stated, the in vitro measurements are carried out in accordance with European Pharmacopeia 9.0, section 2.9.1, Disintegration of tablets and capsules. In vivo measurements are carried out as described in example 3B.

As used herein, the term “dissolve” is the process where a solid substance enters a solvent (oral saliva) to yield a solution. Unless otherwise stated, dissolving implies a full dissolving of the compound in question.

As used herein, the term “disintegrant” refers to an ingredient facilitating disintegration of an FDT-module, when the FDT-module comes into contact with saliva. Disintegrants may often be considered as measure promoting the break-up of the module into smaller fragments upon administration to facilitate nicotine release and eventual absorption.

As used herein, the term “binder” refers to an ingredient promoting cohesiveness to the powder composition during tablet production and thereby facilitating production of modules and thereby nicotine tablets with a desirable mechanical strength.

In preferred embodiments of the invention, the second compressed module comprises binder.

As used herein, the term “nicotine” refers to nicotine in any form, including free base nicotine; nicotine salts; nicotine bound to a carrier, such as nicotine bound to ion exchange resins, nicotine bound to zeolites; nicotine bound to fibres or microspheres, nicotine bound to CaCO3, nicotine bound to sugar alcohol; and mixtures thereof. Bound is here to be understood as nicotine being ionically bound, adsorbed or absorbed onto the carrier, depending on the type of carrier.

When referring to nicotine amounts in milligram, the amounts are to be understood as the nicotine dose, i.e. the amounts refers to the amount of pure nicotine.

When referring to nicotine amounts in weight percent, the amount are to be understood as the actual amount of the nicotine source in relation to the specified term, such as the first compressed module or the nicotine tablet. I.e. a first compressed module of 75 mg comprising nicotine bitartrate in an amount of 4% by weight of the first compressed module, refers to a first compressed module comprising 3 mg of nicotine bitartrate (i.e. 1 mg of pure nicotine).

Nicotine also covers nicotine not obtained from tobacco, often referred to as synthetic nicotine.

Nicotine is included in the first compressed module. In embodiments nicotine is included in the first compressed module but not in the second compressed module.

As used herein the term “free-base nicotine” refers to non-protonated form of nicotine. Free-base nicotine may be provided as a liquid or as mixed with an amount of ion exchange resin; water-soluble compositions, such as sugar alcohols or water-soluble fibers; or water-insoluble fibers; or modified calcium carbonate. While free-base nicotine includes both free-base nicotine extracted from tobacco as well as synthetically manufactured free-base nicotine, the free-base nicotine is not provided in the form of tobacco or powdered tobacco.

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

As used herein, the term “NBT” refers to nicotine bitartrate and hydrates thereof.

As used herein, the term “%” and “percent” refers to percent by weight, unless otherwise is stated.

As used herein, the term “release of nicotine” refers to the nicotine being made bioavailable, i.e. available for absorption over the mucous membrane in the oral cavity. While some forms of nicotine require dissolution for being bioavailable, other forms may be readily absorbed into the body without dissolution. For example, in order for the nicotine to be bioavailable, the matrix of the tablet should be disintegrated. Some forms of nicotine require the nicotine to further be released from e.g. a carrier, e.g. nicotine from a nicotine-ion exchange resin such as nicotine polacrilex. Other nicotine forms, such nicotine salts, hereunder nicotine bitartrate, may readily dissolve upon disintegration of the matrix of the tablet. Still, some nicotine forms may not require dissolving. This applies for e.g. nicotine free base, which is released upon disintegration of the solid formulation matrix.

As used herein, the term “pH regulating agent” refers to agents, which active adjust and regulates the pH value of the solution to which they have been added or are to be added. Thus, pH regulating agents may be acidic or alkaline.

An acidic pH regulating agent, when added to water having a pH of 7.0 at a temperature of 25 degrees Celsius will induce a pH below 7.5, whereas an alkaline pH regulating agent, when added to water having a pH of 7.0 will induce a pH above 7.5.

When more than one pH regulating agents are included in the same module, these form a combined pH regulating agent. The combined pH regulating agent is an acidic pH regulating agent when inducing a pH below 7.5 when added to water having a pH of 7.0 measured at a temperature of 25 degrees Celsius, atmospheric pressure, or an alkaline pH regulating agent when inducing a pH above 7.5 when added to water having a pH of 7.0 measured at a temperature of 25 degrees Celsius, atmospheric pressure.

In other words, an acidic pH regulating agent can in some embodiments e.g. be an acidic buffering system comprising a combination of pH regulating agents, as long as the buffering system induces a pH below 7.5 when added to water having a pH of 7.0 measured at a temperature of 25 degrees Celsius, atmospheric pressure.

On the other hand, pH regulating agents does not including substances and compositions that can only affect the pH by dilution. Furthermore, pH regulating agents does not include e.g. flavors, fillers, etc.

In some preferred embodiments, the acidic pH regulating agent, when added to water having a pH of 7.0 will induce a pH below 7.0 when measured at 25 degrees Celsius and atmospheric pressure.

As used herein, a “molar ratio” refers to the ratio of the molar content of the first component divided by the molar content of the second component.

The relative content between the first component and the second component may also be presented as equivalents of the first component relative to the second component.

Thus, a second compressed module comprising acidic pH regulating agent in a molar ratio of 1.0 relative to the amount of nicotine in the first compressed module, may also be presented as a nicotine tablet comprising 1.0 eq. of acidic pH regulating agent relative to the amount of nicotine in the first compressed module, i.e. a nicotine tablet comprising 1.0 eq. of acidic pH regulating agent and 1.0 eq. of nicotine in the first compressed module.

When referring to amounts of an ingredient by terms such as “less than”, “no more than”, this generally refers to the particular ingredient being absent or present in a range from trace amounts to the specified maximum amount.

As used herein the term “flavor” is understood as having its ordinary meaning within the art. Flavor includes liquid and powdered flavors. Thus, flavors do of course not include sweeteners (such as sugar, sugar alcohols and high intensity sweeteners), or acids providing pure acidity/sourness, nor compounds providing pure saltiness (e.g. NaCl) or pure bitterness. The flavors can be natural or synthetic flavors.

Typically, the nicotine tablet may comprises of ingredients selected from the group consisting of fillers, flavors, binders, disintegrants, hereunder super disintegrants, emulsifiers, antioxidants, pH regulating agents hereunder alkaline and acidic pH regulating agents, high intensity sweeteners, colors, glidants, lubricants, or any combination thereof.

In an advantageous embodiment of the invention, the tablet comprises bulk sweetener as filler ingredient.

In an advantageous embodiment of the invention, the first compressed module comprises bulk sweetener as filler ingredient.

In an advantageous embodiment of the invention, the second compressed module comprises bulk sweetener as filler ingredient.

In an advantageous embodiment of the invention, the first and second compressed module comprise bulk sweetener as filler ingredient.

In embodiments where the nicotine tablet comprises bulk sweeteners, different bulk sweeteners may be used. Bulk sweeteners include sugar sweetener and/or sugarless sweetener.

Sugar sweeteners generally include, but are not limited to saccharide-containing components, such as sucrose, dextrose, maltose, saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, and the like, alone or in combination.

Sugarless sweeteners generally include, but are not limited to sugar alcohols (also sometimes referred to as polyols) such as xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol and lactitol.

Combinations of sugar and/or non-sugar sweeteners may be used in the nicotine tablet.

The bulk sweeteners may often support the flavor profile of the nicotine tablet.

In embodiment of the invention, bulk sweeteners may be supplemented with other usable fillers including as examples, magnesium and calcium carbonate, sodium sulphate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, fibers, plant fibers, such as wheat fiber, oat fiber, pea fiber, and combinations thereof.

High intensity artificial sweetening agents can also be used in combination with the above bulk sweeteners. For example, high intensity sweeteners include, but are not limited to sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside (natural intensity sweetener) and the like, alone or in combination.

Usage level of the artificial sweetener will vary considerably and will depend on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavor used and cost considerations. Thus, the active level of artificial sweetener may vary from about 0.001 to about 8% by weight (such as from about 0.02 to about 8% by weight).

In embodiments where the nicotine tablet comprises flavor, different flavors may be used.

Usable flavors including as examples almond, almond amaretto, apple, Bavarian cream, black cherry, black sesame seed, blueberry, brown sugar, bubblegum, butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake (graham crust), cinnamon redhots, cotton candy, circus cotton candy, clove, coconut, coffee, clear coffee, double chocolate, energy cow, 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 tarts, sweetener, toasted almond, tobacco, tobacco blend, vanilla bean ice cream, vanilla cupcake, vanilla swirl, vanillin, waffle, Belgian waffle, watermelon, whipped cream, white chocolate, wintergreen, amaretto, banana cream, black walnut, blackberry, butter, butter rum, cherry, chocolate hazelnut, cinnamon roll, cola, creme de menthe, eggnog, English toffee, guava, lemonade, licorice, maple, mint chocolate chip, orange cream, peach, pina colada, pineapple, plum, pomegranate, pralines and cream, red licorice, salt water taffy, strawberry banana, strawberry, kiwi, tropical punch, tutti frutti, vanilla, or any combination thereof.

According to an embodiment of the invention, flavor may be used as taste masking for the nicotine and/or taste masking of the alkaline pH regulating agent.

In an embodiment of the invention the nicotine tablet comprises glidant. Silicon dioxide may be used as a glidant. Other glidants usable for the tablet may also be used within the scope of the invention.

In an embodiment of the invention the nicotine tablet comprises lubricant. Magnesium stearate and/or sodium stearyl fumarate may be used as a lubricant. Other lubricants usable for the tablet may also be used within the scope of the invention.

Ready to use systems may be used within the scope of the invention. Typically, such ready-to-use systems may e.g. replace filler, disintegrant, glidant or similar with a single powder mix. Suitable ready-to-use systems for the purpose, but not limited to, include 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). Using a ready to use systems comprising a disintegrant may be especially advantageous.

In order to obtain an FDT-module being designed for disintegrating within a period of 60 second upon oral administration, a range of parameters can be adjusted.

First, by varying the composition, the disintegration time can be altered. Using ingredients with a high water-solubility may facilitate a lowered disintegration time.

Particularly, including a disintegrant may significantly influence the disintegration time, subject to the total composition of the first compressed module. Also, by varying the amount and type of the disintegrant, the disintegration time may be further adjusted. For example, if the first compressed module having a lower disintegration time is desired, the percentage content of disintegrant may be increased and/or the type of disintegrant may be at least partly exchanged for a more effective disintegrant, such as a super disintegrant.

It is noted, that some ingredients have a dual function, such as some ingredients may be used as disintegrants in one contexts and as binders in another context. For example, some disintegrants may have binding properties or visa versa. Hence, the list of binders may have overlap with the list of disintegrants.

In some embodiments, the disintegrant may comprise a combination of regular disintegrant and super-disintegrant, where the regular disintegrant may contribute with some disintegrating properties upon oral administration and desirable binding properties during production, and the super disintegrant ensures a fast disintegration upon oral administration.

Also, decreasing the particle size of the disintegrant tends to lower the disintegration time, likely due to an increased surface area to volume ratio.

Furthermore, the compression force used to press the first compressed module correlate significantly with the obtained hardness of the first compressed module, such that a high compression force typically increases the hardness of the obtained first compressed module. By adjusting the hardness of a first compressed module, the disintegration time may also be influenced, such that a lowered hardness typically gives a shorter disintegration time. Here it has been observed for a number of compositions that by applying the correct compression force a disintegration time below 60 seconds upon oral administration can be achieved, whereas a too high compression force may result in a longer disintegration time above 60 seconds. In this regard it is noted that the threshold compression force may vary significantly, depending on other parameters, such as overall composition, content and type of disintegrant, etc. When, for example, a certain setup results in a too slow disintegration, a further way of adjusting may be to replace a regular disintegrant with a super disintegrant, i.e. which facilitates disintegration in a more efficient way.

Increasing the water-solubility may also be facilitated by exchanging ingredients with low water-solubility with ingredients having higher water-solubility. For example, using sugar alcohols as fillers may be very advantageous insofar that the sugar alcohols have a higher water solubility than alternative fillers.

Moreover, using sugar alcohols with a lower compact ability leads to lower disintegration time. Too low compact ability may compromise the mechanical strength of the first compressed module and the second compressed module and lead to undesirably high friability and risk of cracks etc.

Another examples of parameters that may be adjusted in order to obtain a first compressed module being designed for disintegrating within a period of 60 second upon oral administration include the overall design of the tablet. In some embodiments, such as a tablet comprising a second compressed module being a core and a first compressed module being a surrounding compressed coating, the first compressed module will have a higher exposed surface area compared to a layered tablet design. Increased exposed surface area may decrease disintegration time.

Further examples of parameters that may be adjusted in order to obtain a first compressed module being designed for disintegrating within a period of 60 second upon oral administration include size and shape of the first compressed module and overall tablet. The larger volume of the first compressed module, the longer the disintegration time and thus release time of the nicotine and alkaline pH regulating agent.

For example, increasing the flatness of a layered tablet (e.g. quantified by a diameter to height ratio) for e.g. a disc-shaped tablet typically decreases disintegration time by increasing the surface-to-volume. As long as the tablet has a satisfactory mechanical strength, flatness may be increased.

Also, modifying the cross-sectional profile from a convex type nicotine tablet to a concave shaped tablet lowers the disintegration time. It is noted that this may to some degree lower the mechanical strength of the tablet, however, as long as it is satisfactory, pursuing the concave cross-section may help to increase disintegration and thus lower the disintegration time.

Further, the type and amount of lubricant, if any, may be adjusted to optimize disintegration time. For example, using Sodium stearyl fumarate (SSF) typically leads to a lower disintegration time compared to when using magnesium stearate MgSt.

Thus, a wide range of parameters may be adjusted when designing the first compressed module with a disintegration time of 60 second upon oral administration.

The same parameter may be adjusted when designing the second compressed module to have a disintegration time of at least 2 minutes upon oral administration, such as at least 3 minutes, such as at least 4 minutes, such as at least 5 minutes.

The disintegration time of the second compressed module equals the disintegration time of the nicotine tablet, since the first compressed module is designed to disintegrate within 60 seconds from oral administration.

In an embodiment of the invention the second compressed module of the nicotine tablet comprises binders.

It is noted, that some ingredients have a dual function such as some ingredients may be used as disintegrants in one contexts and as binders in another context. For example, some disintegrants may have binding properties or visa versa. Hence, the list of binders may have overlap with the list of disintegrants.

In an advantageous embodiment of the invention, the second compressed module comprises a binder.

Usable binders include any of, but are not limited to polysaccharides and modified polysaccharides, such as acacia gum, agar, carrageenan, chitosan, inulin, xanthan gum, tragacanth, pullulan, guar gum, pectin, chitin; alginic acid or a salt thereof; carbomer; cellulose; copovidone; gelatin; polycarbophil or a salt thereof; microcrystalline cellulose; polyvinyl alcohol; starch; pregelatinated starch; modified cellulose such as carboxymethylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropylmethyl cellulose; polyethylene glycol; polyethylene oxide; and mixtures thereof.

In one embodiment, the binder included within the second compressed module of the tablets of the present invention may be selected from the group consisting of alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum, microcrystalline cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and mixtures thereof.

In one embodiment, the binder included within the second compressed module of the tablets of the present invention may be selected from the group consisting of alginic acid or a salt thereof, polycarbophil or a salt thereof, xanthan gum, and mixtures thereof.

In one embodiment, the binder included within the second compressed module of the tablets of the present invention may be selected from the group consisting of microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, or a mixture thereof.

In some embodiments, the first compressed module comprises binder.

Also, when using binders, e.g. to obtain a higher cohesiveness and mechanical strength of a compressed module, the amount of such binders may be adjusted as to obtain a higher or lower disintegration rate and thus a longer or shorter disintegration time.

In some embodiments, the first compressed module comprises binder and super-disintegrant.

Binder may advantageously be included in the first compressed module, whereby a desirable cohesiveness during tableting is achieved. By also including super-disintegrant in the module, a desirable low disintegration time of the module may be obtained.

EXAMPLES

Example 1A: Preparation of Tablets Comprising a Second Module being a Tablet Core Fully Surrounded by a First Module

The composition of second module is prepared by pouring about half of the filler into a mixing bowl, followed by the remaining ingredients except lubricant, and finally the remaining filler. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm. Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The composition of first module is prepared by pouring all the ingredients except lubricant, into a mixing bowl. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm.

Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The lubricated powder blends are sequentially transferred to the hopper of a tableting machine.

The composition of the second module is compressed at a compression force of approximately 3 kN to form the tablet core.

The tablet core, i.e. the compressed second module, is transferred to a second compression device, whereafter the composition of the first module is press coated around the core.

The composition is compressed at a compression force of about 15-20 kN to form a first compressed module surrounding the second module.

The fast disintegrating tablets are manufactured on a rotary press machine, for example Manestry DryCota tablet press. The tablet machine is commissioned by adjusting the fill depth and compression force so the weight and hardness of nicotine tablets match the acceptance criteria.

Example 1B: Preparation of Tablets Comprising a Second Module being a Tablet Core Partly Surrounded by a First Module

The composition of second module is prepared by pouring about half of the filler into a mixing bowl, followed by the remaining ingredients except lubricant, and finally the remaining filler. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm.

Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The composition of first module is prepared by pouring all the ingredients except lubricant, into a mixing bowl. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm.

Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The lubricated powder blends are sequentially transferred to the hopper of a tableting machine.

The composition of the second module is compressed at a compression force of approximately 3 kN to form second modules.

The composition of the first module is transferred to the tableting machine, the second module is placed in the punch cylinder, and the first composition is compressed and fused by compression to the second module at a compression force of about 15-20 kN to form a first compressed module partially surrounding the second module.

The tablet machine is commissioned by adjusting the fill depth and compression force so the weight and hardness of nicotine tablets match the acceptance criteria.

Example 1C

Preparation of Tablets Comprising a First and a Second Module being Tablet Layers

The composition of second module is prepared by pouring about half of the filler into a mixing bowl, followed by the remaining ingredients except lubricant, and finally the remaining filler. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm.

Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The composition of first module is prepared by pouring all the ingredients except lubricant, into a mixing bowl. The ingredients are tumbled/mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm.

Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

The lubricated powder blends are sequentially transferred to the hopper of a tableting machine.

The second module is then compressed at a compression force of about 3-6 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN. Punch used unless otherwise specified: 10.00 mm, circular, shallow concave, D tooling.

The fast disintegrating tablets are manufactured on a lab scale machine, for example RIVA Piccola tablet press. The tablet machine is commissioned by adjusting the fill depth and compression force so the weight and hardness of tablets match the acceptance criteria. A pre-compression force could be included to avoid capping.

Example 2: Tablet Compositions

Example 2A

450 mg nicotine tablets were made each with 350 mg second module and 100 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 1Compositions of first and second compressed modules.NT1NT2NT3NT4NT5NT6NT7NT8C1Nicotine dose0.51.01.52.02.53.04.05.01.0(mg)Acidic pH3.53.53.53.53.53.53.53.50regulatingagent [eq]*Raw materialContent in weight percent of 1stmodule1stmoduleMannitol78.076.575.073.572.070.567.564.576.5Disintegrant151515151515151515Sodium555555555carbonateNBT1.53.04.56.07.5912.015.03.0MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRaw materialContent in weight percent of 2ndmodule2ndmoduleMannitol97.6597.0596.4595.8595.2594.6593.4592.2598.25Citric acid0.61.21.82.43.03.64.86.0—Flavor111111111HIS0.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Mannitol may be used as the sugar alcohol in first module and second module. Other usable sugar alcohols for use in second module may include xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol or any combination thereof. Of these erythritol, isomalt, sorbitol, xylitol, or any combination thereof are particularly preferred. Other usable sugar alcohols for use in first module may include xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol or any combination thereof. Of these xylitol, erythritol, isomalt, or any combination thereof, are particularly preferred.

The disintegrant in the amount in first module may e.g. be a starch disintegrant. Examples of other usable disintegrates include pregelatinated starch, cellulose, modified cellulose, microcrystalline cellulose, alginates, ion-exchange resin, calcium silicate, and combinations thereof. Alternatively, super-disintegrants such as crosslinked cellulose, crosslinked polyvinyl pyrrolidone, crosslinked starch, crosslinked alginic acid, and combinations thereof, could have been used, although the amount of super-disintegrant used might advantageously have been reduced.

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

Fruit flavors, and mixtures thereof, menthol, peppermint, and mixtures thereof, may be used in the above formulations as flavors. Other flavors may also be used within the scope of the invention.

Sodium carbonate is used as the alkaline pH regulating agent in the first module. Further usable alkaline pH regulating agents include sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

Citric acid is used as the acidic pH regulating agent in the second module. Further usable acidic pH regulating agents include phosphoric acid, monosodium dihydrogen phosphate, monopotassium dihydrogen phosphate, monosodium dihydrogen citrate, monopotassium dihydrogen citrate, disodium hydrogen citrate, dipotassium hydrogen citrate, malic acid, monosodium malate, monopotassium malate, succinic acid, monosodium succinate, monopotassium succinate, tartaric acid, monosodium tartrate, monopotassium tartrate, acetic acid, sorbic acid, benzoic acid, formic acid, and combinations thereof.

In the above MgSt (Magnesium stearate) is used as lubricant. Other lubricants, such as sodium stearyl fumerate may also be usable within the scope of the invention.

C1 is a comparative example not comprising acidic pH regulating agent in the second compressed module.

Examples 2B

450 mg nicotine tablets were made each with 350 mg second module and 100 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-kN.

TABLE 2Compositions of first and second modules.NTNTNTNTNTNTNTNT1112131415161718C2Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH3.53.53.53.53.53.53.53.53.5regulatingagent [eq]*Raw materialContent in weight percent of 1stmodule1stmoduleMannitol90.589.587.585.583.581.579.577.591.5Super-12468101214—disintegrantSodium555555555carbonateNBT3.03.03.03.03.03.03.03.03.0MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRaw materialContent in weight percent of 2ndmodule2ndmoduleMannitol97.0597.0597.0597.0597.0597.0597.0597.0597.05Citric acid1.21.21.21.21.21.21.21.21.2Flavor111111111HIS0.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

In NT11-NT18, Crosslinked polyvinyl pyrrolidone, here Crospovidone®, Kollidon CL-F is used as a super disintegrant. Alternative super disintegrants may e.g. include crosslinked cellulose (such as Croscarmellose®), crosslinked starch (such as sodium starch glycolate) and crosslinked alginic acid (such as Alginic acid NF®).

C2 is a comparative example not comprising disintegrant in the first compressed module.

Alternative ingredients as described in relation to NT1-NT8 may also be applied for NT11-NT18.

Example 2C

450 mg nicotine tablets were made each with 350 mg second module and 100 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 3Compositions of first and second compressed modules.NTNTNTNTNTNTNTNTNTNT21222324252627282930Nicotine1.01.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH0.51.02.04.05.03.55.07.511.515.0regulatingagent[eq]*RawContent in weight percent of 1stmodulematerial1stmoduleMannitol86.586.586.586.586.586.586.586.586.586.5Super-5555555555disintegrantSodium5555555555carbonateNBT3.03.03.03.03.03.03.03.03.03.0MgSt0.50.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial2ndmoduleMannitol98.2397.9197.5796.9096.5597.4797.1396.5695.6793.15Citric acid0.020.340.681.351.70————5.1Mono—————0.530.741.061.70—sodiumdihydrogenphosphateDisodium—————0.250.380.630.88—hydrogenphosphateFlavor1111111111HIS0.250.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent(s) in the second module is presented as equivalents relative to the nicotine in the first module. Where the acidic pH regulating agent is mixture of pH regulating agents, the molar ratio refers to the total molar amount of acidic pH regulating agent(s) relative to the molar amount of nicotine in the first compressed module. Super disintegrant is used in the first compressed module. The super-disintegrant used may e.g. be crosslinked polyvinyl pyrrolidone, such as Crosspovidone ®. Other usable super-disintegrants, such as crosslinked cellulose, crosslinked starch, crosslinked alginic acid, and combinations thereof could have been applied.

Sodium carbonate is used as the alkaline pH regulating agent in the first module. Further usable alkaline pH regulating agents include sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

Citric acid is used as the acidic pH regulating agent in the second module of NT21-25 and NT30. Further usable acidic pH regulating agents include phosphoric acid, monosodium dihydrogen phosphate, monopotassium dihydrogen phosphate, monosodium dihydrogen citrate, monopotassium dihydrogen citrate, disodium hydrogen citrate, dipotassium hydrogen citrate, malic acid, monosodium malate, monopotassium malate, succinic acid, monosodium succinate, monopotassium succinate, tartaric acid, monosodium tartrate, monopotassium tartrate, acetic acid, sorbic acid, benzoic acid, formic acid, and combinations thereof.

Monosodium dihydrogen phosphate-disodium hydrogen phosphate mixture is used as the acidic pH regulating system in the second module of NT26-29. Further usable acidic pH regulating agents include phosphoric acid, monosodium dihydrogen phosphate, monopotassium dihydrogen phosphate, citric acid, monosodium dihydrogen citrate, monopotassium dihydrogen citrate, disodium hydrogen citrate, dipotassium hydrogen citrate, malic acid, monosodium malate, succinate, tartaric acid, monosodium tartrate, monopotassium tartrate, acetic acid, sorbic acid, benzoic acid, formic acid, and combinations thereof.

Alternative ingredients as described in relation to NT1-NT8 may also be applied for NT21-NT30.

Example 2D—Varying Acidic pH Regulating Agent and Equivalents Used

300 mg nicotine tablets were made each with 225 mg second module and 75 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 4Compositions of first and second modules.NTNTNTNTNTNTNTNTNT313233343536373839Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH2.02.02.02.02.02.01.03.05.0regulatingagent[eq]*RawContent in weight percent of 1stmodulematerial 1stmoduleMannitol85.485.485.485.485.485.485.485.485.4Super-555555555disintegrantSodium555555555carbonateNBT4.14.14.14.14.14.14.14.14.1MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial2ndmoduleMannitol96.8597.5197.3997.6096.3997.9297.8897.1596.41Disodium1.4————————hydrogencitrateMalic acid—0.74————0.371.101.84Mono-——0.86——————sodiummalateSuccinic———0.65—————acidTartaric————1.86————acidAcetic acid—————0.33———Flavor111111111HIS0.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Alternative ingredients as described in relation to NT1-NT30 may also be applied for NT31-NT39.

Example 2E

300 mg nicotine tablets were made each with 225 mg second module and 75 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 5Compositions of first and second compressed modules.NTNTNTNTNTNTNTNTNT414243444546474849C3Nicotine1.01.01.01.01.01.01.01.01.01.0tdose (mg)Acidic pH2.02.02.02.02.02.02.02.02.02.0regu-latingagent [eq]*Raw materialContent in weight percent of 1stmodule1stmoduleMannitol86.484.486.484.485.485.485.485.485.490.4Super-5555555555disintegrantSodium34.534.5——————carbonateSodium11.511.5——————bicarbonateTrometamol————55————Disodium——————5———hydrogenphosphatePotassium———————55—carbonateNBT4.14.14.14.14.14.14.14.14.14.1MgSt0.50.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100100moduleRaw materialContent in weight percent of 2ndmodule2ndmoduleMannitol97.2097.2097.5197.5197.2097.5197.2097.2097.5197.20Citric acid1.051.05——1.051.051.051.05Malic acid——0.740.740.740.74—Fruit flavor1111111111HIS0.250.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Fruit flavors have been used in NT41-49 and C3.

C3 is a comparative example not comprising alkaline pH regulating agent in the first compressed module.

Alternative ingredients as described in relation to NT1-NT39 may also be applied for NT41-NT49.

Example 2F

300 mg nicotine tablets were made each with 225 mg second module and 75 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 6Compositions of first and second modules.NTNTNTNTNTNTNTNTNT515253545556575859Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH2.02.02.02.02.02.02.02.02.0regulatingagent [eq]*RawContent in weight percent of 1stmodulematerial 1stmoduleMannitol86.1576.1566.1556.1546.1536.15—56.1585.15Xylitol———————30.00—Erythritol—10.0020.0030.0040.0050.0086.15——Super-555555555disintegrantSodium344444443carbonateSodium1———————1bicarbonateHIS0.250.250.250.250.250.250.250.250.25Flavor————————1.0NBT4.14.14.14.14.14.14.14.14.1MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial 2ndmoduleMannitol97.20————50.0050.0050.00—Isomalt—97.20———47.20——50.00Sorbitol——97.20———47.20—47.20Xylitol———97.20———47.20—Erythritol————97.20————Citric acid1.051.051.051.051.051.051.051.051.05Flavor111111111HIS0.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Alternative ingredients as described in relation to NT1-NT49 may also be applied for NT51-NT59.

Example 2G

300 mg nicotine tablets were made each with 225 mg second module and 75 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-kN.

TABLE 7Compositions of first and second compressed modules.NTNTNTNTNTNTNTNTNT616263646566676869Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH2.02.02.02.02.02.02.02.02.0regulatingagent [eq]*RawContent in weight percent of 1stmodulematerial 1stmoduleMannitol84.1583.1583.1583.1583.1583.1583.1583.1583.15crosslinked8.08.08.0———8.08.08.0polyvinylpyrrolidonecrosslinked———8.0—————cellulosecrosslinked————8.0————starchcrosslinked—————8.0———alginic acidSodium344444444carbonateHIS0.250.250.250.250.250.250.250.250.25NBT4.14.14.14.14.14.14.14.14.1MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial 2ndmoduleMannitol92.2093.2095.2095.2095.2095.2092.2092.2092.20MCC5.04.02.02.02.02.0———Sodium——————5.0——alginateCalcium———————5.0—polycarbophilXanthan gum————————5.0Citric acid1.051.051.051.051.051.051.051.051.05Flavor111111111HIS0.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Alternative ingredients as described in relation to NT1-NT59 may also be applied for NT61-NT69.

Example 2H

300 mg nicotine tablets were made each with 225 mg second module and 75 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-kN.

TABLE 8Compositions of first and second modules.NTNTNTNTNTNTNTNTNT717273747576777879Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH2.02.02.02.02.02.02.02.02.0regulatingagent [eq]*RawContent in weight percent of 1stmodulematerial 1stmoduleMannitol81.4083.9086.9081.4083.9086.9081.4083.9086.90crosslinked10.07.55.0——————polyvinylpyrrolidonecrosslinked———10.07.55.0———cellulosecrosslinked——————10.07.55.0starchSodium444444444carbonateNBT4.14.14.14.14.14.14.14.14.1MgSt0.50.5—0.50.5—0.50.5—Total 1st100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial 2ndmoduleMannitol90.9590.9590.9590.9590.9590.9590.9590.9590.95MCC4.04.04.04.04.04.04.04.04.0Citric acid1.051.051.051.051.051.051.051.051.05Flavor2.72.72.72.72.72.72.72.72.7HIS0.30.30.30.30.30.30.30.30.3MgSt1.01.01.01.01.01.01.01.01.0Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Alternative ingredients as described in relation to NT1-NT69 may also be applied for NT71-NT79.

Example 2I—Nicotine Sources and Glidant

500 mg nicotine tablets were made each with 350 mg second module and 150 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN

TABLE 9Compositions of first and second modules.NTNTNTNTNTNTNTNTNT818283848586878889Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH3.53.53.53.53.53.53.53.53.5regulatingagent [eq]*RawContent in weight percent of 1stmodulematerial 1stmoduleMannitol88.8387.5087.5087.5087.50——85.9055.90Erythritol—————87.5087.50—30Super5.05.05.05.05.05.05.05.05.0disintegrantSodium5.05.05.05.05.05.05.05.05.0carbonateNBT———————2.12.1Nicotine0.67————————free baseNicotine-—2.0———————calciumcarbonate**Nicotine-——2.0——2.0———MCC**Nicotine-———2.0—————solublefiber**Nicotine-————2.0—2.0——sugaralcohol**MgSt0.50.50.50.50.50.50.5——Sodium———————2.02.0stearylfumerateTotal 1st100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial 2ndmoduleMannitol90.8090.8090.8090.8090.8090.8090.8040.8090.80Isomalt———————50.00—MCC3.03.03.03.03.03.03.03.03.0Citric acid1.21.21.21.21.21.21.21.21.2Flavor3.63.63.63.63.63.63.63.63.6HIS0.40.40.40.40.40.40.40.40.4MgSt1.01.01.01.01.01.01.01.01.0Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.**free nicotine base sorbed onto carrier in a weight ratio of 1:2

Alternative ingredients as described in relation to NT1-NT79 may also be applied for NT81-NT89.

Example 2J

500 mg nicotine tablets were made each with 350 mg second module and 150 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 10ACompositions of first and second compressed modules.NTNTNTNTNTNTNTNT9192939495969798C4Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH3.53.53.53.53.53.53.53.53.5regulatingagent [eq]*RawContent in weight percent of 1stmodulematerial 1stmoduleMannitol87.1587.1587.1587.1587.1587.1587.1587.1587.15Super5.05.05.05.05.05.05.05.05.0disintegrantSodium5.05.05.05.05.05.05.05.05.0carbonateHIS0.250.250.250.250.250.250.250.250.25NBT2.12.12.12.12.12.12.12.12.1MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRawContent in weight percent of 2ndmodulematerial 2ndmoduleMannitol95.5595.9295.0595.4294.0594.4293.0593.4294.25MCC2.02.02.02.02.02.02.02.02.0Citric acid1.2—1.2—1.2—1.2——Malic acid—0.83—0.83—0.83—0.83—Fruit flavor0.50.51.01.02.02.03.03.03.0HIS0.250.250.250.250.250.250.250.250.25MgSt0.50.50.50.50.50.50.50.50.5Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module.

Alternative ingredients as described in relation to NT1-NT89 may also be applied for NT91-NT98.

Example 2K

300 mg nicotine tablets were made each with 200 mg second module and 100 mg first module. The tablets were prepared according to example 1C, i.e. a layered design. However, the tablets could alternatively have been prepared according to example 1A or 1B.

Punch used: 10.00 mm, circular, shallow concave, D tooling.

The second compressed module is compressed at a compression force of about 3 kN, after which the first module is fused by compression to the second module at a compression force of about 15-20 kN.

TABLE 10BCompositions of first and second compressed modules.NTNTNTNTNTNTNTNT101102103104105106107108C5Nicotine1.01.01.01.01.01.01.01.01.0dose (mg)Acidic pH5.13.40.855.13.63.43.43.4—regulatingagent [eq]*materialRawContent in weight percent of 1stmodulematerial 1stmoduleMannitol80.480.480.480.480.480.480.480.480.4Super8.08.08.08.08.08.08.08.08.0disintegrantSodium5.05.05.05.05.05.05.05.05.0carbonateMCC3.03.03.03.03.03.03.03.03.0NBT3.13.13.13.13.13.13.13.13.1MgSt0.50.50.50.50.50.50.50.50.5Total 1st100100100100100100100100100moduleRawmaterial 2ndContent in weight percent of 2ndmodulemoduleMannitol89.990.992.488.990.2390.990.990.992.9Blue color0.10.10.10.10.10.10.10.10.1MCC2.52.52.52.52.52.52.52.52.5Citric acid3.02.00.5——2.02.02.0—NaH2PO4———2.672.67————Na2HPO4———1.33—————Fruit flavor2.02.02.02.02.02.02.02.02.0HIS1.51.51.51.51.51.51.51.51.5MgSt1.01.01.01.01.01.01.01.01.0Total 2nd100100100100100100100100100moduleNBT = Nicotine bi-tartrate (nicotine content of 32.38% by weight).NaH2PO4= Mono sodium dihydrogen phosphate.Na2HPO4= Di-sodium hydrogen phosphate.HIS = high intensity sweetener.*The amount of acidic pH regulating agent in the second module is presented as equivalents relative to the nicotine in the first module. Where the acidic pH regulating agent is mixture of pH regulating agents, the molar ratio refers to the total molar amount of acidic pH regulating agent(s) relative to the molar amount of nicotine in the first compressed module.

Alternative ingredients as described in relation to NT1-NT98 may also be applied for NT101-NT108.

For the samples 106, 107 and 108 the compression force was adjusted to provide nicotine tablets with different hardness (breaking force):

TABLE 10CNicotine tablets with differenthardness (breaking force).SampleHardness, N1066510785108105

Example 3A: In Vivo Disintegration Time of First Compressed Module

The in vivo disintegration time of the first compressed module may be determined using a coloring agent. Nicotine tablets were prepared by adding a coloring agent to the second compressed module, whereby at two-colored tablet is obtained.

A sample tablet comprising a colored second compressed module was tested in a test panel of 8 test persons. Test subjects abstain from eating and drinking at least 30 minutes before initiation of any test. The test person was a healthy person appointed on an objective basis according to specified requirements.

For testing the tablet was placed in the mouth, between the tongue and the palate.

The tablet was visually inspected for every 5 seconds, to determine the time where the un-colored, white first compressed module has fully disintegrated, i.e. the time where no white color is observed at the residual tablet.

TABLE 11in vivo disintegration of first compressed module.NT102NT103NT104C5Acidic pHCitric acidCitric acidMonosodiumNoneregulating[3.4 eq.][0.85 eq.]dihydrogenagent [eq.]phosphate-disodiumhydrogenphosphatemixture[5.1 eq.]Time pointsWhite rWhiteWhiteWhite0++++5 sec.++++10 sec.++++15 sec.−−−−20 sec.−−−−

Conclusion: the first disintegrating modules were found to have desirable low disintegration time of below 15 seconds.

Example 3B: In Vivo Disintegration Time of Nicotine Tablet

A sample tablet was tested in a test panel of 8 test persons. Test subjects abstain from eating and drinking at least 30 minutes before initiation of any test. The test person was a healthy person appointed on an objective basis according to specified requirements.

The test persons were instructed to swallow saliva after 1 minute and not before that time point.

The test persons report the time, where they sense full disintegration of the tablet. The average disintegration time reported by the test persons is calculated for each tablet.

TABLE 12Ain vivo disintegration time of nicotine tablets.NT102NT103NT104C5Acidic pHCitric acidCitric acidMonosodiumNoneregulating[3.4 eq.][0.85 eq.]dihydrogenagent [eq.]phosphate-disodiumhydrogenphosphatemixture[5.1 eq.]Average4 min. 0 sec.4 min. 25 sec.4 min. 5 sec.4 min.disintegration10 sec.time

Conclusion: the tested tablets were all found to have a disintegration time of below 5 min.

In vivo disintegration time was also tested for nicotine tablets of samples 106, 107 and 108 with different hardness (breaking force):

TABLE 12BIn vivo disintegration time of Nicotine tabletswith different hardness (breaking force).AveragedisintegrationSampleHardness, Ntime, [m:ss]106653:00107854:001081054:50

Example 3C: In Vivo Testing of Release of pH Regulating Agents

A sample tablet was tested in a test panel of 8 test persons. Test subjects abstain from eating and drinking at least 30 minutes before initiation of any test. The test person was a healthy person appointed on an objective basis according to specified requirements.

For testing the tablet was placed in the mouth, between the tongue and the palate. The test persons were instructed to swallow saliva after pH measurement performed at 1 minute, and not before that time point.

After 0, 0.5, 1, 2, 3 and 5 minutes, the saliva pH was measured at desired time points (15, 30, 45 second, 1, 1.5, 2, 3, 4 and 5 minutes). The saliva pH was measured directly in the oral saliva using standard pH strips.

The average saliva pH of the test persons is calculated at the different time.

Applying the method outlined above, an in vivo pH profile was obtained for selected samples.

NT102NT103NT104C5Acidic pHCitric acidCitric acidMonosodiumNoneregulating[3.4 eq.][0.85 eq.]dihydrogenagent [eq.]phosphate-disodiumhydrogenphosphatemixture[5.1 eq.]Time pointsSaliva pHSaliva pHSaliva pHSaliva pH06.86.86.86.815 sec.1010109.530 sec.9.09.59.59.045 sec.8.78.18.78.71 min.8.38.18.38.31 min. 30 sec.7.3<6.57.47.92 min.6.8<6.57.47.73 min.6.8<6.57.17.74 min.6.8<6.57.17.75 min.6.86.87.47.1

Conclusion: The test demonstrates that tablets comprising an alkaling pH regulating agent in the first compressed module and comprising an acidic pH regulating agent in the second compressed module provide a desirable pH profile, i.e. a desirable pH above 7.5 during the initial time of use followed by a reduction in pH to below 7.5.

Example 3D: Evaluation of Burning Sensation in the Oral Cavity and Throat

Nicotine burning was evaluated by a test panel of 10 trained assessors. At first calibration of nicotine burning was made by means of placing a representative standard nicotine tablet in the mouth, between the tongue and the palate and sucking it to complete disintegration. For this purpose tablets corresponding to the first module of sample C5 were used. Then, each assessor evaluates the burning sensation in the oral cavity and in the throat on a scale from 1 to 15, where is the most intense burning. Each assessor evaluates all samples twice. The evaluations are noted for the time periods indicated. Average values are calculated.

NT102C5Acidic pH3.4noneregulatingagent [eq.]Burning score (1-15)Time pointsOralThroatOralThroat1 min.5.73.86.53.82 min.4.53.85.75.23 min.2.43.53.64.94 min.1.22.42.03.75 min.0.42.51.03.66 min.0.42.10.73.38 min.0.11.60.22.210 min.0.11.20.11.5

Conclusion: The test demonstrates that the tablet comprising an acidic pH regulating agent in the second compressed module is given a significant lower burning score at all time points compared to a comparative tablet not comprising acidic pH regulating agent. The tablets comprising an acidic pH regulating agent in the second compressed module were given a lower burning score both in relation to burning sensation in the oral cavity and in the throat.