Fast dissolvable solid oral dosage form

Abstract

A dissolvable solid oral dosage form is disclosed, the dosage form comprising a first nicotine form and a second nicotine form, the dosage form having a disintegration time of no more than 10 minutes, wherein the first nicotine form and the second nicotine form are different, wherein the second nicotine form is a delayed nicotine form.

Description

[0001] FAST DISSOLVABLE SOLID ORAL DOSAGE FORM

[0002] FIELD OF INVENTION

[0003] The invention relates to a dissolvable solid oral dosage form according to the claims. Also, the invention relates to a dissolvable solid oral dosage form for use in alleviation of nicotine craving according to the claims. Furthermore, the invention relates to a method for treatment of nicotine craving according to the claims.

[0004] BACKGROUND

[0005] Nicotine-releasing tablets applied for the purpose of providing a release of nicotine in a user’s mouth over a certain period of time is well-known. Much effort has in prior art been put into emulating the nicotine release and oral perception of a cigarette when it is smoked by a user, which means that release profiles from nicotine tablets have been thoroughly investigated in prior art.

[0006] It is however an established fact that the one-to-one smoking-emulation is yet to be achieved with other means than a cigarette.

[0007] Furthermore, user perception of nicotine tablet may be improved, e.g. since release of nicotine is associated with undesirable irritation in the throat, a side effect known as nicotine burning or simply burning.

[0008] An example of an orally disintegrating nicotine tablet is known from PCT application WO 2019 / 110072 Al, to Fertin Pharma A / S, related to orally disintegrating tablets with disintegration within 60 second from oral administration.

[0009] SUMMARY

[0010] The invention relates to a dissolvable solid oral dosage form, the dosage form comprising a first nicotine form and a second nicotine form, the dosage form having a disintegration time of no more than 10 minutes, wherein the first nicotine form and the second nicotine form are different, wherein the second nicotine form is a delayed nicotine form.

[0011] One advantage of the invention may be that a fast nicotine release is combined with a sustained nicotine release. Many conventional nicotine products provide sustained nicotine release by slowly dissolving or otherwise slowly releasing nicotine from the from the nicotine dosage form upon administration to the oral cavity. However, the present invention advantageously facilitates a fast disintegration of the dosage form to give a fast release of the first nicotine form, while also providing sustained delivery of nicotine, such as a sustained release of nicotine extending beyond the disintegration time of the solid dosage form.

[0012] Another advantage of the invention may be that the so-called nicotine burning (i.e. throat irritation) is minimized. By providing nicotine in a fast-disintegrating dosage form, the dosage form may be disintegrated relatively fast, which may minimize nicotine burning, e.g. by reducing the saliva generation during use and thereby avoiding swallowing nicotine containing saliva. Thereby, nicotine burning may be significantly minimized, without having to decrease the nicotine dose. Conventionally, nicotine burning was managed by delaying the nicotine release, thereby lowering the oral nicotine concentration at any given moment. However, by providing a fast disintegrating nicotine dosage form, fast nicotine craving relief may be obtained while unexpectedly keeping nicotine burning low as well.

[0013] The sustained release of nicotine provided by the second nicotine form may facilitate keeping nicotine cravings in check over a longer period of time and thereby keeping the overall nicotine intake at a lower level for the user. In particular, the delay may be facilitated by at least a part of the second nicotine form being released after disintegration of the dosage form by the second nicotine form being provided as a delayed nicotine form. The delayed release of the second nicotine form may unexpectedly be achieved without compromising the fast nicotine craving relief and while also minimizing nicotine burning. Thus, the present invention unexpectedly facilitates a combination of minimized nicotine burning while at the same time achieving sustained nicotine release.

[0014] In the present context the term “delayed nicotine form” refers to nicotine forms which provide delayed release, in particular in comparison with the first nicotine form. In an embodiment of the invention, the delayed nicotine form refers to nicotine with release time of at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form. In an embodiment of the invention, the delayed nicotine form refers to nicotine selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, and any combination thereof. Also, in an embodiment the second nicotine form has a nicotine release time which is at least 1 minute longer than the first nicotine form, such as at least 3 minutes longer than the first nicotine form, such as at least 5 minutes longer than the first nicotine form.

[0015] 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 solid dosage form 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, encapsulated nicotine, nicotine sorbed to modified calcium carbonate, and nicotine-mucoadhesive complexes. Other nicotine forms, such nicotine salts, hereunder nicotine bitartrate, may readily dissolve upon disintegration of the matrix of the solid dosage form. Still, some nicotine forms may not require dissolving. This applies for e.g. nicotine free base, which is released upon disintegration of the solid dosage form.

[0016] It is noted within the present context that the term “dissolvable solid oral dosage form” refers to a dosage form for oral administration, e.g. for administration between the gum and lip or for administration on the tongue or sublingually under the tongue. The dosage form is overall dissolvable, particularly in saliva or water, in the sense that the main constituents of the dosage form are dissolvable. In some embodiments, the tablet comprises water-insoluble constituents in an amount of no more than 20% by weight of the tablet, such as no more than 15% by weight of the tablet, such as no more than 10% by weight of the tablet, such as no more than 5% by weight of the tablet. Such insoluble components may e.g. comprise ion exchange resin, insoluble cellulose fibers such as microcrystalline cellulose etc. For the avoidance of doubt, it is noted that the dosage form according to the present invention is not chewing gum tablet, i.e. the dosage form according to the present invention does not comprise gum base. Similarly, for the avoidance of doubt, it is noted that the dosage form is not an oral pouch. In an embodiment of the invention, the dosage form is orodispersible, e.g. in the sense of the European Pharmacopoeia 9.0.

[0017] In an embodiment of the invention, the dosage form is administered between the lip and gum, which is understood as positioning the dosage form in the oral vestibule such that it is in contact with a part of the gum, also known as gingiva. In this embodiment, the dosage form may be administered between the upper lip and gum or the lower lip and the gum. In an embodiment of the invention, the dosage form is administered between the upper lip and gum.

[0018] In an embodiment of the invention, the dosage form is administered between the gum and the lip extending corresponding to the incisor, canine, premolar, and molar teeth. Thus, in this embodiment, the dosage form would be positioned with one side of the dosage form being in contact with the lip and the opposite side of the dosage form being in contact with the gum opposite to the part of the lip in question.

[0019] In an embodiment of the invention, the dosage form is administered between the gum and the lip, the latter extending corresponding to the incisor and canine teeth. Thus, in this embodiment, the dosage form would be positioned with one side of the dosage form being in contact with the lip above these teeth and the opposite side of the dosage form being in contact with the gum opposite to the lip.

[0020] In an embodiment of the invention, the dosage form is administered on the tongue.

[0021] In an embodiment of the invention, the dosage form is administered sublingually, i.e. under the tongue.

[0022] As used herein, the term “dissolve” is the process where a solid substance enters a solvent (e.g. oral saliva) to yield a solution. Unless otherwise stated, dissolving implies a full dissolving of the compound in question.

[0023] As used herein, the term “disintegrate” refers to a reduction of a said object to components, fragments or particles. Disintegration may both refer to in vivo disintegration, the methods of which are defined herein, or in vitro disintegration. The in vitro measurements are carried out in accordance with European Pharmacopoeia 9.0, section 2.9.1, Disintegration of tablets and capsules.

[0024] In the present context, the term “disintegration time” refers to the time before the dosage form is fully disintegrated. It is noted that this may refer in vivo disintegration or in vitro disintegration. Also, it is noted that in vivo disintegration may refer to disintegration when administered orally, e.g. between gum and lip, on the tongue, or under the tongue (sublingually).

[0025] As used herein the term “water-soluble” refers to a relatively high water-solubility, for example a water-solubility of at least 1 gram of water-soluble composition or substance per 100 mL of water measured at 25 degrees Celsius, atmospheric pressure and pH of 7.0. Here, atmospheric pressure refers to a pressure of about 1 atmosphere, i.e. 101,325 Pascal (Pa) or a pressure within the range of 90,000 to 110,000 Pascal (Pa). In an embodiment, “water-soluble” refers to a water-solubility of at least 3 gram of water-soluble composition or substance per 100 mL of water measured as listed above, such as at least 5 gram of water-soluble composition or substance per 100 mL of water.

[0026] When referring to a “soluble” composition or substance, water-soluble is meant, unless otherwise stated.

[0027] Similarly, the term “water-insoluble” refers to a relatively low water-solubility, for example a water-solubility of less than 1 gram of water-soluble composition or substance per 100 mL of water measured at 25 degrees Celsius, atmospheric pressure and pH of 7.0. Here, atmospheric pressure refers to a pressure of about 1 atmosphere, i.e. 101,325 Pascal (Pa) or a pressure within the range of 90,000 to 110,000 Pascal (Pa).

[0028] When referring to a “insoluble” composition or substance, water-insoluble is meant, unless otherwise stated.

[0029] According to an advantageous embodiment of the invention, the dosage form has a disintegration time of no more than 8 minutes, such as no more than 6 minutes, such as no more than 4 minutes.

[0030] In an embodiment of the invention the dosage form has a disintegration of 2 to 10 minutes, such as 3 to 9 minutes, such as 4 to 8 minutes, such as 5 to 7 minutes.

[0031] According to an advantageous embodiment of the invention, the dosage form has a disintegration time of no more than 10 minutes when placed between the gum and lip, such as no more than 8 minutes, such as no more than 6 minutes, such as no more than 4 minutes.

[0032] In an embodiment of the invention the dosage form has a disintegration of 2 to 10 minutes when placed between the gum and lip, such as 3 to 9 minutes, such as 4 to 8 minutes, such as 5 to 7 minutes. According to an advantageous embodiment of the invention, the dosage form has a disintegration time of no more than 150 seconds when placed on the tongue, such as no more than 120 seconds, such as no more than 90 seconds.

[0033] In an embodiment of the invention the dosage form has a disintegration of 10 to 150 seconds when placed on the tongue, such as 20 to 120 seconds, such as 30 to 90 seconds.

[0034] According to an advantageous embodiment of the invention, the dosage form has an in vitro disintegration time of no more than 120 seconds, such as no more than 100 seconds, such as no more than 80 seconds, such as no more than 60 seconds, such as no more than 40 seconds.

[0035] In an embodiment of the invention, the dosage form has an in vitro disintegration time of 10 seconds to 120 seconds, such as 20 seconds to 100 seconds, such as 30 seconds to 80 seconds, such as 40 seconds to 60 seconds.

[0036] In an embodiment of the invention, the dosage form has an in vivo disintegration time of 2 to 10 minutes, such as 3 to 9 minutes, such as 4 to 8 minutes, such as 5 to 7 minutes.

[0037] According to an advantageous embodiment of the invention, the dosage form is a tablet.

[0038] According to an embodiment of the invention, the tablet is a disintegrating tablet.

[0039] In the context of the above embodiment, it is understood that a disintegrating tablet is a tablet that may disintegrate during use and may be provided as an orally disintegrating tablet or another type of disintegrating tablet. According to an advantageous embodiment of the invention, the dosage form is an orally disintegrating tablet.

[0040] It is noted that in the present context, the term “orally disintegrating nicotine tablet” or “orally disintegrating tablet” refers to a nicotine containing orally disintegrating tablet, also referred to as a nicotine ODT, i.e. a tablet that disintegrates relative fast. It is noted that orally disintegrating tablets, or ODTs, may sometimes be referred to as fast disintegrating tablets, or FDTs. In embodiments of the invention, the orally disintegrating nicotine tablet may thus disintegrate within 150 seconds, such as within 120 seconds, such as within 90 seconds upon oral administration, preferably when administered on the tongue. In embodiments of the invention, the orally disintegrating nicotine tablet may thus disintegrate within 150 seconds, such as within 120 seconds, such as within 90 seconds upon oral administration, preferably when administered under the tongue (sublingually). In an embodiment of the invention, the orally disintegrating nicotine tablet may thus disintegrate within 10 minutes upon oral administration, such as within 9 minutes upon oral administration, such as within 8 minutes upon oral administration, such as within 7 minutes upon oral administration, such as within 6 minutes upon oral administration, such as within 5 minutes upon oral administration, such as within 4 minutes upon oral administration, such as within 3 minutes upon oral administration, preferably when administered between the gum and the lip. In embodiments of the invention, the orally disintegrating nicotine tablet may disintegrate within 120 seconds in vitro, such as within 90 seconds in vitro, such as within 60 seconds in vitro, preferably when measuring vitro disintegration time in accordance with European Pharmacopoeia 9.0, section 2.9.1, Disintegration of tablets and capsules.

[0041] According to an embodiment of the invention, the in vivo disintegration time is measured by at least 6 trained assessors, the trained assessors abstaining from eating and drinking at least 30 minutes before initiation of any test, the tablet is weighted and placed in the mouth, on the tongue, where the in vivo disintegration time is registered as the time point where the tablet disintegration is substantially complete. During the test, the assessors refrained from chewing and did not substantially move the tablet from its initial position. It is noted that whereas the in vivo disintegration time is tested by placing the tablet on the tongue, as described above, the tablet may in some embodiments be intended for use as a sublingual tablet, i.e. below the tongue. Also, in some embodiments, the tablet may be intended to be used between the gum and lip. It is noted that the use of tablets between the gum and lip results in a longer disintegration time.

[0042] In an embodiment of the invention, trained assessors, e.g. for in vivo measurement of disintegration time, may be selected as described in the following. The trained assessors are selected based on the following criteria. First, the individuals chewed on a chewing gum base free of buffer for 1 minute, after which the initial pH in a sample from the saliva from each of the individuals is measured with a suitable pH-electrode system, e.g. a stainless steel electrode PHW77-SS. Only individuals having, after chewing on a chewing gum base free of buffer for one minute, an initial pH in the saliva inside the range from 6.7 and 7.3 are selected. These individuals thereby qualify as assessors. One dosage of the tablet is administered on the tongue to at least six assessors. Hereafter, disintegration time is evaluated by the six assessors. Each assessor evaluates each sample twice. Thus, each parameter evaluation is the arithmetic mean of 12 assessments performed on samples from six assessors. During the test, the assessors refrained from chewing and did not substantially move the tablet from its initial position.

[0043] According to an advantageous embodiment of the invention, the dosage form is a compressed tablet.

[0044] According to an embodiment of the invention, the tablet is composed of a plurality of compressed particles.

[0045] According to an embodiment of the invention, the tablet is compressed using a compression force of 1 to 35 kN, such as 2 to 30 kN, such as 2 - 20 kN The compression force used in compressed tablets correlate significantly with the obtained hardness, such that a high compression force typically increases the hardness of the obtained tablet. By adjusting the hardness of a tablet, 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 desired disintegration time can be achieved, whereas a too high compression force may result in a longer disintegration time above the desired disintegration time. 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 superdisintegrant, i.e. which facilitates disintegration in a more efficient way.

[0046] According to an advantageous embodiment of the invention, the dosage form is selected from the group consisting of an orally dissolving film, a solid gel, a compressed tablet (such as a compressed orally disintegrating tablet), a meltable tablet, a pastille, an effervescent tablet.

[0047] It is noted that in an embodiment of the invention, an orally dissolving film may also be referred to as an oral strip or an oral film strip.

[0048] According to an embodiment of the invention, the dosage form is an orally dissolving film.

[0049] According to an embodiment of the invention, the dosage form is a solid gel.

[0050] According to an embodiment of the invention, the dosage form is a compressed tablet.

[0051] According to an embodiment of the invention, the dosage form is a meltable tablet. According to an embodiment of the invention, the dosage form is a pastille.

[0052] According to an embodiment of the invention, the dosage form is an effervescent tablet.

[0053] According to an embodiment of the invention, the tablet is selected from the group consisting of an orally disintegrating tablet and an effervescent tablet.

[0054] According to an advantageous embodiment of the invention, the dosage form is an orally dissolving film.

[0055] According to an advantageous embodiment of the invention, the dosage form is an extruded dosage form.

[0056] In an embodiment of the invention, the extruded dosage form is selected from the group consisting of extruded orally dissolvable films, extruded pastilles, extruded melt tablets.

[0057] According to an advantageous embodiment of the invention, the dosage form is a cast dosage form.

[0058] In an embodiment of the invention, the cast dosage form is selected from the group consisting of cast orally dissolvable films, cast pastilles, cast melt tablets.

[0059] According to an advantageous embodiment of the invention, the dosage form is a cast orally dissolvable film.

[0060] According to an embodiment of the invention, the dosage form is an extruded orally dissolvable film. According to an advantageous embodiment of the invention, the first nicotine form is a fast nicotine form.

[0061] In the present context the term “fast nicotine form” refers to nicotine forms with fast release. In an embodiment of the invention, the fast nicotine form refers to nicotine which is released instantly or within seconds upon disintegration of the dosage form and exposure to oral saliva. In an embodiment of the invention, the fast nicotine form refers to nicotine free base and / or nicotine salt.

[0062] According to an advantageous embodiment of the invention, the first nicotine form comprises nicotine free base and / or nicotine salt.

[0063] In an embodiment of the invention, the first nicotine form is selected from the group consisting of nicotine free base, nicotine salt, and any combination thereof.

[0064] An advantage of the above embodiment may be that a fast craving relief of nicotine may be facilitated, e.g. due to a fast dissociation of the nicotine salt.

[0065] According to an advantageous embodiment of the invention, the first nicotine form comprises nicotine free base.

[0066] In an embodiment of the invention, the nicotine free base used as the first nicotine form is released relatively fast and may thus e.g. be mixed with a water-soluble component, such as sugar alcohol. In the present context, nicotine free base as the first nicotine form does not encompass encapsulated nicotine made using nicotine free base.

[0067] In the present context, nicotine salt as the first nicotine form does not encompass encapsulated nicotine made using nicotine salt.

[0068] In an embodiment of the invention, free base nicotine as the first nicotine form may be nicotine mixed with sugar alcohols. In an embodiment of the invention, the first nicotine form is nicotine free base.

[0069] According to an advantageous embodiment of the invention, the first nicotine form comprises nicotine salt.

[0070] According to an embodiment of the invention, the first nicotine form is nicotine salt.

[0071] According to an embodiment of the invention, the nicotine salt is selected from the group consisting of nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine bitartrate, nicotine chloride, nicotine citrate, nicotine fumarate, nicotine lactate, nicotine mucate, nicotine laurate, nicotine levulinate, nicotine malate, nicotine perchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate, nicotine succinate, nicotine sulfate, and any combination thereof.

[0072] It is understood that the nicotine salt may also be provided as a hydrated salt, or as a combination of hydrated and non-hydrated salt.

[0073] Nicotine chloride may e.g. be nicotine hydrochloride and / or nicotine dihydrochloride.

[0074] In an embodiment of the invention, the nicotine salt is selected from the list consisting of nicotine benzoate, nicotine monotartrate, nicotine bitartrate, nicotine hydrochloride, nicotine dihydrochloride, nicotine lactate, nicotine malate, nicotine pyruvate, nicotine succinate, and combinations thereof.

[0075] According to an advantageous embodiment of the invention, the first nicotine form comprises nicotine bitartrate.

[0076] The term NBT may be used as an abbreviation to denote nicotine bitartrate. An advantage of the above embodiment may be that a fast craving relief of nicotine may be facilitated, e.g. due to a fast dissociation of nicotine bitartrate.

[0077] In an embodiment of the invention, the first nicotine form is nicotine bitartrate.

[0078] In an embodiment of the invention, the first nicotine form is selected from the list consisting of nicotine free base and nicotine salts, or combinations thereof. It is noted that when nicotine free base and / or nicotine salt is used, it is implied that the nicotine is provided without a carrier unless explicitly specified otherwise.

[0079] It is noted that when referring to nicotine salts as the first nicotine form or part thereof, these are nicotine salts that are considered water-soluble as defined herein.

[0080] According to an advantageous embodiment of the invention, the second nicotine form comprises a carrier.

[0081] The above mentioned carrier may e.g. be selected from the group consisting of mucoadhesive, ion-exchange resin, encapsulation agents, calcium carbonate, cellulose such as microcrystalline cellulose, and any combination thereof.

[0082] According to an advantageous embodiment of the invention, the second nicotine form comprises a natural carrier.

[0083] The above mentioned natural carrier may e.g. be selected from the group consisting of mucoadhesive, natural encapsulation agents, calcium carbonate, cellulose such as microcrystalline cellulose, and any combination thereof.

[0084] It is noted that the term “natural carrier” may sometimes also be referred to as “natural origin carrier” or “carrier of natural origin”. As natural carriers refer to carriers of natural origin, natural carriers do not include carriers of synthetic origin, such as e.g. polacrilex resin. Additionally, it is noted that the term “natural encapsulation agents” refer to encapsulation of natural origin.

[0085] According to an advantageous embodiment of the invention, the second nicotine form comprises at least one selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, nicotine sorbed to calcium carbonate, nicotine bound to oleic acid, nicotine sorbed on cellulose, such as microcrystalline cellulose, and any combination thereof.

[0086] In an embodiment of the invention, the second nicotine form is selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, nicotine sorbed to calcium carbonate, nicotine bound to oleic acid, nicotine sorbed on cellulose, such as microcrystalline cellulose, and any combination thereof.

[0087] According to an advantageous embodiment of the invention, the second nicotine form comprises at least one selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, and any combination thereof.

[0088] In an embodiment of the invention, the second nicotine form is selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, and any combination thereof.

[0089] In an embodiment of the invention, the second nicotine form comprises at least one selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, and any combination thereof. In an embodiment of the invention, the second nicotine form comprises at least one selected from the group consisting of a nicotine-mucoadhesive complex, encapsulated nicotine, and any combination thereof.

[0090] In an embodiment of the invention, the second nicotine form comprises at least one selected from the group consisting of nicotine bound to an ion exchange resin, encapsulated nicotine, and any combination thereof.

[0091] According to an advantageous embodiment of the invention, the second nicotine form comprises a nicotine-mucoadhesive complex.

[0092] An advantage of the above embodiment may be that the uptake of nicotine may be facilitated by the use of nicotine-mucoadhesive complex. The mucoadhesive may provide for a prolonged retention time in the oral cavity and specifically at or near the oral mucosa, thereby facilitating uptake of the nicotine. Also, when nicotine is absorbed, it will not contribute to the unintended side effect of nicotine burning in the throat, i.e. irritation of the mucosa in the throat. Nicotine burning in the throat occurs when unabsorbed nicotine is swallowed and thereby comes into contact with the throat, where it induces nicotine burning.

[0093] In an embodiment of the invention, the nicotine-mucoadhesive complex comprises nicotine provided in ionic complex with at least one mucoadhesive water-soluble anionic polymer.

[0094] In an embodiment of the invention, said nicotine-mucoadhesive complex is nicotine provided in ionic complex with at least one mucoadhesive water-soluble anionic polymer.

[0095] Preparation of nicotine in ionic complex with at least one mucoadhesive water-soluble anionic polymer is described in international patent application WO 2018 / 113916 Al, which is hereby incorporated by reference. According to an advantageous embodiment of the invention, the nicotine- mucoadhesive complex comprises nicotine bound to a water-soluble anionic mucoadhesive polymer

[0096] According to an advantageous embodiment of the invention, the at least one water- soluble anionic mucoadhesive polymer is weakly acidic.

[0097] According to an advantageous embodiment of the invention, the at least one water- soluble anionic mucoadhesive polymer comprises carboxylic functional groups.

[0098] According to an advantageous embodiment of the invention, the at least one water- soluble anionic mucoadhesive polymer is selected from sulfonated polysaccharides and / or anionic polysaccharides and / or polyacrylic acid.

[0099] According to an advantageous embodiment of the invention, the at least one water- soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, gellan gum, carbomer, carboxymethyl cellulose, and any combination thereof.

[0100] According to an advantageous embodiment of the invention, the at least one water- soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethyl cellulose, and any combination thereof.

[0101] In an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, gellan gum, and any combination thereof. In an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, and any combination thereof.

[0102] In an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of carrageenan, gellan gum, and any combination thereof.

[0103] In an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, gellan gum, and any combination thereof.

[0104] According to an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is xanthan gum.

[0105] According to an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is carrageenan.

[0106] According to an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is gellan gum.

[0107] According to an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is carbomer.

[0108] According to an embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is carboxymethyl cellulose.

[0109] According to an advantageous embodiment of the invention, the at least one water- soluble anionic mucoadhesive polymer has an average molecular weight (mw) of at least 50 kDa, such as at least 75 kDa, such as at least 100 kDa, such as at least 150 kDa, such as at least 200 kDa, such as at least 250 kDa. In an embodiment of the invention the at least one water-soluble anionic mucoadhesive polymer has an average molecular weight (mw) of 50 to 800 kDa, such as 100 to 700 kDa, such as 150 to 600 kDa, such as 200 to 500 kDa, such as 300 to 400 kDa.

[0110] According to an advantageous embodiment of the invention, the second nicotine form comprises nicotine bound to an ion exchange resin, such as nicotine polacrilex resin.

[0111] In an embodiment of the invention, the second nicotine form is nicotine bound to an ion exchange resin, such as nicotine polacrilex resin.

[0112] In an embodiment of the invention, the second nicotine form comprises nicotine polacrilex resin.

[0113] In an embodiment of the invention, the second nicotine form is nicotine polacrilex resin.

[0114] As used herein, the term ”NPR” refers to nicotine bound to polacrilex resin.

[0115] In an embodiment of the invention, the encapsulated nicotine may be made using nicotine selected from the group consisting of free base nicotine, nicotine salt, nicotine bound to an ion exchange resin, and any combination thereof.

[0116] In an embodiment of the invention, the encapsulated nicotine may comprise one or more polymers selected from the list consisting of poly(lactic-co-glycolic acid) (PLGA), chitosan, alginate, polyglycolide, polylactic acid (PLA), polyvinyl acetate (PVAc), starch, and any combination thereof.

[0117] In an embodiment of the invention, the encapsulated nicotine may comprise one or more polymers selected from the list consisting of poly(lactic-co-glycolic acid) (PLGA), chitosan, alginate, polyglycolide, polylactic acid (PLA), polyvinyl acetate (PVAc), and any combination thereof. In an embodiment of the invention, the encapsulated nicotine comprises one or more polymers selected from the list consisting of chitosan, alginate, starch and any combination thereof.

[0118] In an embodiment of the invention, the encapsulated nicotine comprises alginate.

[0119] In an embodiment of the invention, the encapsulated nicotine may comprise selfemulsifying systems, such as self-emulsifying systems comprising one or more surfactants. Self-emulsifying systems may also be referred to as SEDDS (selfemulsifying drug delivery systems).

[0120] In an embodiment of the invention, embodiment of the invention, the second nicotine form comprises nicotine formulated as co-crystals. Co-crystals may be obtained by crystalizing nicotine together with suitable crystalizing agents.

[0121] In an embodiment of the invention, the dosage form is free of nicotine polacrilex resin.

[0122] In an embodiment of the invention, the dosage form is free of ion exchange resin.

[0123] In an embodiment of the invention, the dosage form is free of synthetic ion exchange resin.

[0124] In an embodiment of the invention, the dosage form is free of nicotine bound to ion exchange resins.

[0125] In an embodiment of the invention, the dosage form is free of nicotine bound to synthetic ion exchange resins. According to an advantageous embodiment of the invention, the dosage form comprises nicotine in an amount of at least 0.2 mg, such as at least 0.5 mg, such as at least 1.0 mg.

[0126] In an embodiment of the invention, the dosage form comprises nicotine in an amount of 0.2 mg to 12.0 mg, such as 0.2 mg to 10.0 mg, such as 0.2 mg to 8.0 mg, such as 0.2 mg to 6.0 mg, such as 0.2 mg to 4.0 mg, such as 0.5 to 4.0 mg, such as 1.0 to 4.0 mg.

[0127] In an embodiment of the invention, the dosage form comprises nicotine in an amount of 0.2 mg to 12.0 mg, such as 0.2 mg to 10.0 mg, such as 0.5 mg to 8.0 mg, such as 0.5 mg to 6.0 mg, such as 1.0 mg to 4.0 mg, such as 1.0 to 3.0 mg, such as 1.0 to 2.0 mg.

[0128] According to an advantageous embodiment of the invention, the dosage form comprises nicotine in an amount of at least 0.2% by weight of the dosage form, such as at least 0.3% by weight of the dosage form, such as at least 0.5% by weight of the dosage form.

[0129] In an embodiment of the invention, the dosage form comprises nicotine in an amount of 0.2 to 5% by weight of the dosage form, such as 0.3 to 3% by weight of the dosage form, such as 0.5 to 2% by weight of the dosage form.

[0130] According to an advantageous embodiment of the invention, the dosage form comprises the first nicotine form in an amount of at least 0.1 mg, such as at least 0.3 mg, such as at least 0.5 mg.

[0131] In an embodiment of the invention, the dosage form comprises the first nicotine form in an amount of 0.1 mg to 6.0 mg, such as 0.2 mg to 5.0 mg, such as 0.25 mg to 4.0 mg, such as 0.3 mg to 3.0 mg, such as 0.4 mg to 4.0 mg, such as 0.5 to 1.5 mg, such as 1.0 to 2.0 mg. According to an advantageous embodiment of the invention, the dosage form comprises the second nicotine form in an amount of at least 0.1 mg, such as at least 0.3 mg, such as at least 0.5 mg.

[0132] In an embodiment of the invention, the dosage form comprises the second nicotine form in an amount of 0.1 mg to 6.0 mg, such as 0.2 mg to 5.0 mg, such as 0.25 mg to 4.0 mg, such as 0.3 mg to 3.0 mg, such as 0.4 mg to 4.0 mg, such as 0.5 to 1.5 mg, such as 1.0 to 2.0 mg.

[0133] In an embodiment of the invention, the first nicotine form and / or the second nicotine form comprises synthetic nicotine.

[0134] In an embodiment of the invention, the first nicotine form and / or the second nicotine form consists of synthetic nicotine.

[0135] According to an advantageous embodiment of the invention, the second nicotine form has a release time of at least 1 minute after disintegration of the dosage form, such as at least 2 minutes after disintegration of the dosage form, such as at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form, such as at least 10 minutes after disintegration of the dosage form.

[0136] It is noted that the “release time” refers to the time for a complete release of nicotine.

[0137] According to an advantageous embodiment of the invention, the second nicotine form is characterized by having a slower release rate of 70% by weight of the nicotine from the second nicotine form than the release rate of 70% by weight of nicotine from the first nicotine form, when measured according to USP 29 requirements for nicotine release from nicotine polacrilex. According to the above embodiment, the first nicotine form releases 70% by weight of its nicotine within a first time period when measured according to USP 29, the second nicotine form releases 70% by weight of its nicotine within a second time period when measured according to USP 29 requirements for nicotine release from nicotine polacrilex, wherein the second time period is longer than the first time period.

[0138] According to an advantageous embodiment of the invention, the second nicotine form is characterized by releasing 70% by weight of the nicotine from the second nicotine form within a period of time, which is longer than the period of time for releasing 70% by weight of nicotine release from nicotine polacrilex, when measured according to USP 29 requirements for nicotine release from nicotine polacrilex.

[0139] It is noted that when referring to the USP 29 requirements for nicotine release from nicotine polacrilex, the relevant parameters of USP 29 should of course be translated to the specific nicotine form in question.

[0140] According to an advantageous embodiment of the invention, the second nicotine form is characterized by less than 70% by weight release of the nicotine from the second nicotine form within a period of time of 10 minutes when measured according to USP 29 requirements for nicotine release from nicotine polacrilex.

[0141] In an embodiment of the invention, the release time of the delayed nicotine form is at least 5 minutes from start of disintegration of the dosage form, such as at least 7 minutes from start of disintegration of the dosage form, such as at least 10 minutes from start of disintegration of the dosage form, such as at least 12 minutes from start of disintegration of the dosage form, such as at least 15 minutes from start of disintegration of the dosage form, such as at least 20 minutes from start of disintegration of the dosage form, such as at least 25 minutes from start of disintegration of the dosage form, such as at least 30 minutes from start of disintegration of the dosage form. It is noted that the start of disintegration of the dosage form may be oral administration in vivo release time, or may be from start of in vitro disintegration test as described herein.

[0142] In an embodiment of the invention the second nicotine form has a release time of 1 to 20 minutes after disintegration of the dosage form, such as 2 to 18 minutes after disintegration of the dosage form, such as 3 to 16 minutes after disintegration of the dosage form, such as 4 to 14 minutes after disintegration of the dosage form, such as 5 to 12 minutes after disintegration of the dosage form, such as 6 to 10 minutes after disintegration of the dosage form, such as 7 to 9 minutes after disintegration of the dosage form.

[0143] According to an advantageous embodiment of the invention, the dosage form comprises disintegrant.

[0144] According to an advantageous embodiment of the invention, the dosage form comprises said disintegrant in an amount of at least 0.5% by weight of the dosage form, such as at least 1% by weight of the dosage form, such as at least 2% by weight of the dosage form, such as at least 3% by weight of the dosage form, such as at least 5% by weight of the dosage form.

[0145] According to an embodiment of the invention, the dosage form comprises disintegrant in an amount of 0.5 to 15% by weight of the dosage form, such as 1 to 15% by weight of the dosage form, such as 2 to 14% by weight of the dosage form, such as 3 to 12% by weight of the dosage form, such as 5 to 10% by weight of the dosage form.

[0146] According to an advantageous embodiment of the invention, said disintegrant is selected from the list consisting of starch, pregelatinized starch, calcium silicate, crosslinked cellulose, crosslinked polyvinyl pyrrolidone, crosslinked starch, crosslinked alginate, and combinations thereof. In the present context the terms “crosslinked alginate” and “crosslinked salt of alginic acid” are used interchangeably.

[0147] According to an embodiment of the invention, the disintegrant is selected from the list consisting of starch, pregelatinized starch, cellulose, calcium silicate, crosslinked cellulose, crosslinked polyvinyl pyrrolidone, crosslinked starch, crosslinked alginate, and combinations thereof.

[0148] According to an advantageous embodiment of the invention, said disintegrant comprises pregelatinized starch.

[0149] According to an advantageous embodiment of the invention, said disintegrant consists of pregelatinized starch.

[0150] It is understood that some disintegrants are referred to as superdisintegrants.

[0151] According to an advantageous embodiment of the invention, the disintegrant comprises a superdisintegrant.

[0152] According to an advantageous embodiment of the invention, the dosage form comprises superdisintegrant in an amount of at least 0.5% by weight of the dosage form, such as at least 1% by weight of the dosage form, such as at least 2% by weight of the dosage form, such as at least 3% by weight of the dosage form, such as at least 5% by weight of the dosage form.

[0153] According to an embodiment of the invention, the dosage form comprises superdisintegrant in an amount of 0.5 to 15% by weight of the dosage form, such as 1 to 15% by weight of the dosage form, such as 2 to 14% by weight of the dosage form, such as 3 to 12% by weight of the dosage form, such as 5 to 10% by weight of the dosage form. In some embodiments, the disintegrant may comprise combination of regular disintegrant and superdisintegrant.

[0154] In an embodiment of the invention, the disintegrant consists of superdisintegrant.

[0155] According to an advantageous embodiment of the invention, the superdisintegrant is selected from the group consisting of crosslinked cellulose, crosslinked polyvinyl pyrrolidone, crosslinked starch, crosslinked alginate, and any combinations thereof.

[0156] According to an advantageous embodiment of the invention, the disintegrant is a super disintegrant selected from the group consisting of crosslinked cellulose, crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, and any combinations thereof.

[0157] According to an advantageous embodiment of the invention, the disintegrant is a super disintegrant selected from the group consisting of crosslinked polyvinyl pyrrolidone, croscarmellose, sodium starch glycolate, and any combinations thereof.

[0158] Examples of crosslinked cellulose super disintegrants include structure and brands names such as cross-linked sodium carboxymethylcellulose, Croscarmellose®, Ac-Di- Sol®, Solutab® etc.

[0159] Examples of crosslinked polyvinyl pyrrolidone (PVP) super disintegrants include structure and brands names such as Kollidon®, Polyplasdone®, polyplasdone XL®, Kollidon CL® etc. Crosslinked polyvinyl pyrrolidone (PVP) disintegrant is also sometimes referred to as crospovidone.

[0160] Examples of crosslinked starch super disintegrants include structure and brands names such as sodium starch glycolate, Glycolys®, Explotab®, Primogel®, Vivastar®, Tablo® etc. In an embodiment of the invention, the disintegrant comprises cross-linked polyvinylpyrrolidone.

[0161] In an embodiment of the invention, at least 50% by weight of the cross-linked polyvinylpyrrolidone has a particle size below 50 micrometers, such as 50 to 100% by weight of the cross-linked polyvinylpyrrolidone has a particle size below 50 micrometers.

[0162] In an embodiment of the invention, at least 25% by weight of the cross-linked polyvinylpyrrolidone has a particle size below 15 micrometers, such as 25 to 100% by weight of the cross-linked polyvinylpyrrolidone has a particle size below 15 micrometers.

[0163] In an embodiment of the invention, ready to use systems may be used. 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 SmartExlOO (Shin Etsu / Harke Pharma).

[0164] Thus, in the above embodiment, ready to use systems may be included as a convenient way of including e.g. both sugar alcohol and disintegrant.

[0165] According to an embodiment of the invention, the dosage form further comprises dissolution modifiers in an amount of at most 2% by weight of the dosage form, such as at most 1% by weight of the dosage form, such as at most 0.5% by weight of the dosage form, such as at most 0.25% by weight of the dosage form, such as at most 0.1% by weight of the dosage form.

[0166] It is noted that certain dissolution modifiers may somewhat overlap with mucoadhesives. However, in the present context it is understood that when referring to dissolution modifiers, these are added separately from nicotine, i.e. dissolution modifiers do not include any nicotine-mucoadhesive complexes.

[0167] According to an embodiment of the invention, the dissolution modifiers are selected from the group consisting of xanthan gum, guar gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, monovalent alginate, pullulan, tragacanth gum, gum karaya, fenugreek gum, cassia gum, carrageenan, agar, alginic acid and monovalent salts thereof, and any combination thereof.

[0168] It is noted that in the present context the terms “monovalent alginate”, “monovalent salt of alginate” and “monovalent salt of alginic acid” are used interchangeably. It is further noted that in the present context dissolution modifiers may comprise noncrosslinked alginates, whereas dissolution modifiers do not comprise crosslinked alginates.

[0169] An advantage of the above embodiment may be that the small amount of dissolution modifiers may improve the mouthfeel.

[0170] According to an embodiment of the invention, the dissolution modifiers are selected from the group consisting of xanthan gum, guar gum, and any combinations thereof.

[0171] An advantage of the above embodiment may be that the small amount of dissolution modifiers may improve the mouthfeel.

[0172] In an embodiment of the invention, the dissolution modifier comprises xanthan gum.

[0173] In an embodiment of the invention, the dissolution modifier comprises guar gum.

[0174] According to an embodiment of the invention, the dosage form is free of dissolution modifiers. It is noted that the dissolution modifiers of the above embodiment does not refer to nicotine-mucoadhesive complexes, and thus the second nicotine form may comprise nicotine-mucoadhesive complex also in the above embodiment. In an embodiment of the invention, the dissolution modifier(s), if any, are added separately from the second nicotine form. Thus, the dissolution modifier does not include any nicotine- mucoadhesive complexes.

[0175] In an embodiment of the invention, the dosage form is substantially free of dissolution modifiers, such as free of dissolution modifiers.

[0176] In an embodiment of the invention, the dosage form is free of xanthan gum.

[0177] Thus, according to an embodiment of the invention, the dosage form is not an adhering dosage form, e.g. by only including a minor amount of mucoadhesive, such as no more than 10% by weight of the dosage form, such as no more than 5% by weight of the dosage form, such as no more than 2% by weight of the dosage form, such as no more than 1% by weight of the dosage form.

[0178] According to an advantageous embodiment of the invention, the dosage form comprises at least one sugar alcohol.

[0179] According to an advantageous embodiment of the invention, the dosage form comprises the at least one sugar alcohol sugar alcohol in an amount of at least 40% by weight of the dosage form, such as at least 50% by weight of the dosage form, such as at least 60% by weight of the dosage form, such as at least 70% by weight of the dosage form, such as at least 80% by weight of the dosage form.

[0180] It is noted that the above-mentioned embodiment may be particularly relevant e.g. for tablets and when using sugar alcohols that are solid at 25 degrees Celsius, and / or sugar alcohols comprising at least 4 carbon atoms, in particular sugar alcohols selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

[0181] In an embodiment of the invention, the dosage form comprises the at least one sugar alcohol in an amount of 40 to 95% by weight of the dosage form, such as 50 to 95% by weight of the dosage form, such as 60 to 90% by weight of the dosage form, such as 70 to 90% by weight of the dosage form, such as 80 to 90% by weight of the dosage form.

[0182] According to an advantageous embodiment of the invention, the dosage form comprises the at least one sugar alcohol sugar alcohol in an amount of at least 5% by weight of the dosage form, such as at least 10% by weight of the dosage form, such as at least 20% by weight of the dosage form, such as at least 30% by weight of the dosage form, such as at least 40% by weight of the dosage form.

[0183] It is noted that the above-mentioned embodiment may be particularly relevant e.g. for tablets and when using sugar alcohols that are solid at 25 degrees Celsius, and / or sugar alcohols comprising at least 4 carbon atoms, in particular sugar alcohols selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

[0184] In an embodiment of the invention, the dosage form comprises the at least one sugar alcohol in an amount of 5 to 50% by weight of the dosage form, such as 10 to 45% by weight of the dosage form, such as 15 to 40% by weight of the dosage form, such as 20 to 35% by weight of the dosage form, such as 25 to 30% by weight of the dosage form.

[0185] According to an advantageous embodiment of the invention, the at least one sugar alcohol comprises sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof. In an embodiment of the invention, the sugar alcohol is a solid sugar alcohol at 25 degrees Celsius.

[0186] The solid sugar alcohols have a desirable compressibility; hence the use of solid sugar alcohols is desirable when forming compressed dosage forms.

[0187] It is noted that sugar alcohols, also sometimes referred to as polyols, are different from sugars.

[0188] According to an embodiment of the invention, the sugar alcohol is selected from sugar alcohols comprising at least 4 carbon atoms, such as 4 to 16 carbon atoms, such as 5 to 12 carbon atoms.

[0189] In an embodiment of the invention, the dosage form is free of sugar alcohols comprising no more than three carbons. Examples of sugar alcohols comprising no more than three carbons include glycerol, propylene glycol, and ethylene glycol.

[0190] It is noted that such sugar alcohols comprising no more than three carbons may in some embodiments be relevant to include as plasticizers.

[0191] In an embodiment, the dosage form is free of glycerol.

[0192] According to an advantageous embodiment of the invention, the at least one sugar alcohol comprises sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

[0193] Thus, in the above embodiment, the at least one sugar alcohol may include mixtures of different types of sugar alcohols. In an embodiment of the invention, the at least one sugar alcohol is selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

[0194] In an embodiment of the invention, the at least one sugar alcohol is selected from the group consisting of xylitol, maltitol, mannitol, isomalt, sorbitol, and any combination thereof.

[0195] In an embodiment of the invention, the at least one sugar alcohol is selected from the group consisting of xylitol, mannitol, isomalt, sorbitol and any combination thereof.

[0196] In an embodiment of the invention, the at least one sugar alcohol is selected from the group consisting of mannitol, isomalt, sorbitol and any combination thereof.

[0197] In an embodiment of the invention, the at least one sugar alcohol comprises or consists of mannitol.

[0198] In an embodiment of the invention, the at least one sugar alcohol comprises or consists of isomalt.

[0199] In an embodiment of the invention, the at least one sugar alcohol comprises or consists of sorbitol.

[0200] In an embodiment of the invention, the dosage form comprises at least one sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof in an amount of at least 40% by weight of the dosage form, such as at least 50% by weight of the dosage form, such as at least 60% by weight of the dosage form, such as at least 70% by weight of the dosage form, such as at least 80% by weight of the dosage form. According to the above embodiment, the dosage form may comprise further sugar alcohols not selected from said group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

[0201] According to an advantageous embodiment of the invention, the dosage form comprises at least one film forming agent.

[0202] Film forming agents may be especially advantageous when the dosage form is an orally dissolving film.

[0203] According to an advantageous embodiment of the invention, the dosage form comprises the at least one film forming agent in an amount of at least 40% by weight of the dosage form, such as at least 50% by weight of the dosage form, such as at least 60% by weight of the dosage form.

[0204] According to an advantageous embodiment of the invention, the at least one film forming agent comprises at least one water-soluble polymer.

[0205] According to an advantageous embodiment of the invention, the at least one film forming agent comprises at least one selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), pullulan, alginate, pectin, gelatin, carrageenan, xanthan gum, locust bean gum, starch, modified starch, gum arabic, guar gum, agar gum, methyl cellulose, carboxy methylcellulose (CMC), and any combination thereof.

[0206] It is noted that certain film forming agents may somewhat overlap with mucoadhesives. However, in the present context it is understood that when referring to film forming agents, these are added separately from nicotine, i.e. film forming agents do not include any nicotine-mucoadhesive complexes. According to an advantageous embodiment of the invention, the dosage form comprises at least one plasticizer.

[0207] Plasticizers may be especially advantageous when the dosage form is an orally dissolving film.

[0208] According to an advantageous embodiment of the invention, the dosage form comprises the least one plasticizer in an amount of 2 to 10% by weight of the dosage form.

[0209] According to an advantageous embodiment of the invention, the at least one plasticizer is selected from the group consisting of glycerin, propylene glycol, ethylene glycol, polyethylene glycol, tributyl citrate, triethyl citrate, triacetin, glycerol triacetate, and any combination thereof.

[0210] Within the present context, the term plasticizer does not refer to any of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, or lactitol.

[0211] According to an advantageous embodiment of the invention, the dosage form comprises a pH regulating agent.

[0212] According to an advantageous embodiment of the invention, the pH regulating agent is an alkaline pH regulating agent, such as an alkaline buffering agent.

[0213] In an embodiment of the invention, the pH regulating agent is free of acidic pH regulating agent.

[0214] In an embodiment of the invention, the pH regulating agent is a buffering agent.

[0215] According to an advantageous embodiment of the invention, the pH regulating agent comprises pH regulating agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, di-alkali hydrogen phosphate, tri-alkali phosphate, or any combination thereof.

[0216] According to an advantageous embodiment of the invention, the pH regulating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or any combination thereof.

[0217] According to an advantageous embodiment of the invention, the pH regulating agent comprises or consists of sodium carbonate.

[0218] In an embodiment of the invention, the pH regulating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

[0219] In an embodiment of the invention, the pH regulating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, or any combination thereof.

[0220] Combinations of a carbonate and a bicarbonate may be especially advantageous. Such combination may e.g. be a sodium carbonate - sodium bicarbonate buffer system, e.g. sodium carbonate and sodium bicarbonate in a weight-ratio between 5: 1 and 1 : 1, preferably in a weight-ratio between 4.1 : 1 and 1.5: 1.

[0221] An advantage of the above embodiment may be an increased uptake of nicotine in the oral cavity.

[0222] In an embodiment of the invention, the pH regulating agent is selected from the group consisting of trometamol, amino acids, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

[0223] In an embodiment of the invention, the pH regulating agent is selected from the group consisting of trometamol, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

[0224] In an embodiment of the invention, the pH regulating agent comprises di-alkali hydrogen phosphate and / or tri-alkali phosphate, such as disodium phosphate, dipotassium phosphate, trisodium phosphate and / or tripotassium phosphate.

[0225] Trometamol and phosphate buffers have a desirable relative neutral taste, hence the use of these pH regulating agents may be found not compromise the taste and mouthfeel of the dosage form.

[0226] In an embodiment of the invention, the pH regulating agent comprises trometamol.

[0227] In an embodiment of the invention, the pH regulating agent consists of trometamol.

[0228] In the present context the term trometamol refers to (tri s(hydroxymethyl)aminom ethane), also sometimes referred to as tris buffer.

[0229] In an embodiment of the invention, the pH regulating agent comprises amino acid.

[0230] In an embodiment of the invention, the pH regulating agent consists of amino acid.

[0231] According to an advantageous embodiment of the invention, the dosage form comprises the pH regulating agent in an amount of at least 0.2% by weight of the dosage form, such as at least 0.5% by weight of the dosage form, such as at least 1% by weight of the dosage form, such as at least 2% by weight of the dosage form. In an embodiment of the invention, the dosage form comprises the pH regulating agent in an amount of 0.2 to 10% by weight of the dosage form, such as 0.5 to 8% by weight of the dosage form, such as 1 to 6% by weight of the dosage form, such as 2 to 4% by weight of the dosage form.

[0232] In an embodiment of the invention, the dosage form comprises the pH regulating agent in an amount of at most 2% by weight of the dosage form, such as at most 1.5% by weight of the dosage form, such as at most 1% by weight of the dosage form, such as at most 0.5% by weight of the dosage form, such as at most 0.2% by weight of the dosage form, such as at most 0.1% % by weight of the dosage form.

[0233] According to an advantageous embodiment of the invention, the dosage form is free of effervescent agents.

[0234] An advantage of the above embodiment may be an improved user experience. Often, inclusion of effervescent agents may lead to tingling sensations, which may be rather undesirable, in particular if the dosage form is administered between the gum and the lip.

[0235] A further advantage may be that using effervescent agents may lead to the oral pH value being below the optimum range for efficient nicotine absorption over the mucous membrane. Avoiding the use of effervescent agents may therefore facilitate improved nicotine absorption.

[0236] In an embodiment of the invention, the dosage form is substantially free from pH regulating agent.

[0237] In an embodiment of the invention, the dosage form is free from pH regulating agent.

[0238] In an embodiment of the invention, the dosage form is substantially free from alkaline pH regulating agent. In an embodiment of the invention, the dosage form is free from alkaline pH regulating agent.

[0239] According to an advantageous embodiment of the invention, the dosage form has a weight of no more than 1000 mg, such as no more than 900 mg, such as no more than 800 mg, such as no more than 700 mg, such as no more than 600 mg, such as no more than 500 mg, such as no more than 400 mg, such as no more than 300 mg, such as no more than 200 mg, such as no more than 150 mg, such as no more than 120 mg, such as no more than 100 mg, such as no more than 50mg.

[0240] An advantage of the above embodiment may be that that the size provides a discreet method for delivering nicotine.

[0241] In an embodiment of the invention, the dosage form has a weight of 20 to 1000 mg, such as 20 to 900 mg, such as 20 to 800 mg, such as 20 to 700 mg, such as 25 to 600 mg, such as 25 to 500 mg, such as 25 to 400 mg, such as 25 to 300 mg, such as 25 to 200mg, such as 50 to 150 mg, such as 70-120mg, such as about 75 mg or about 100 mg, or such as 25 to 50 mg.

[0242] According to an advantageous embodiment of the invention, dosage form has a weight of more than 20 mg, such as more than 30 mg, such as more than 40 mg, such as more than 50 mg, such as more than 60 mg, such as more than 70 mg, such as more than 80 mg.

[0243] In an embodiment of the invention dosage form has a weight of 20-200 mg, such as 30-180 mg, such as 40-160 mg, such as 50-140 mg, such as 60-120 mg, such as 80- 100 mg.

[0244] According to an advantageous embodiment of the invention, the dosage form is a one- layer dosage form. One advantage of the above embodiment may be that it is very simple, since any complicating layers or modules are avoided without compromising the presence of both the first and the second nicotine form.

[0245] One advantage of the above embodiment may be that it ensures simultaneous release of the first and second nicotine form from the dosage form. That is, in the above embodiment the contribution from the first and second nicotine form to the total nicotine amount available to the user is exclusively controlled by the difference in nicotine release profiles between the first and second nicotine forms.

[0246] According to an advantageous embodiment of the invention, the dosage form comprises at least one module, and wherein the at least one module comprises at least part of the first nicotine form and at least part of the second nicotine form.

[0247] According to an advantageous embodiment of the invention, the dosage form comprises at least one module, and wherein the at least one module comprises the first nicotine form and the second nicotine form.

[0248] An advantage of the above embodiment may be that release from the dosage form of the two nicotine forms is synchronized in way, in the sense that they are associated with the same module of the dosage form and that their nicotine release is therefore more reliably determinable from the nicotine form itself.

[0249] In an embodiment of the invention, any further module except the at least one module is free of nicotine.

[0250] In an embodiment of the invention, the first nicotine form and the second nicotine form are provided in the same module. It is noted that this may apply both to single-module dosage forms and to multi-module dosage forms, where the first nicotine form and the second nicotine form are provided in the same module. In the latter case, any further module is free of the first nicotine form and free of the second nicotine form, such as free of nicotine.

[0251] In an embodiment of the invention, the dosage form comprises at least one module, wherein the at least one module comprises the first nicotine form and the second nicotine form.

[0252] In an embodiment of the invention, the dosage form is provided as a single-module dosage form, which comprises the first nicotine form and the second nicotine form.

[0253] In an embodiment of the invention, the dosage form is provided as a multi-module dosage form, where the first nicotine form and the second nicotine form are provided in the same module.

[0254] In an embodiment of the invention, the dosage form consists of one module.

[0255] According to an advantageous embodiment of the invention, the dosage form is a multi-layer dosage form, such as a two-layer dosage form or a three-layer dosage form.

[0256] According to an embodiment of the invention, the dosage form is a two-layer dosage form.

[0257] According to an embodiment of the invention, the dosage form is a two-layer tablet.

[0258] According to an embodiment of the invention, the dosage form is a three-layer tablet.

[0259] According to an embodiment of the invention, the dosage form is a three-layer dosage form.

[0260] According to an embodiment of the invention, the dosage form is a multilayer dosage form comprising a first layer and a second layer. According to an embodiment of the invention, the layers are fused by compression.

[0261] According to an embodiment of the invention, the first and the second layers are fused by compression.

[0262] In the present context the term layer refers to a module of the dosage form composing a significant part of the dosage form, such as e.g. at least 20% by weight of the dosage form, such as at least 30% by weight of the dosage form, such as at least 40% by weight of the dosage form.

[0263] In an embodiment of the invention, the dosage form is a multilayer dosage form. The multilayer dosage form may comprise three or more layers.

[0264] According to an advantageous embodiment of the invention, the dosage form comprises flavor.

[0265] According to an advantageous embodiment of the invention, the dosage form comprises flavor in an amount of at least 0.1% by weight of the dosage form, such as at least 0.25% by weight of the dosage form, such as at least 0.5% by weight of the dosage form, such as at least 1.0% by weight of the dosage form, such as at least 1.5% by weight of the dosage form, such as at least 2.0% by weight of the dosage form, such as at least 2.5% by weight of the dosage form, such as at least 3.0% by weight of the dosage form.

[0266] In an embodiment of the invention the dosage form comprises flavor in an amount of 0.1 to 8% by weight of the dosage form, such as 0.25 to 8% by weight of the dosage form, such as 0.5 to 8% by weight of the dosage form, such as 1 to 7% by weight of the dosage form, such as 2 to 6% by weight of the dosage form, such as 3 to 5 % by weight of the dosage form. In an embodiment of the invention, the dosage form comprises flavor in an amount of more than 3% by weight of the dosage form, such as more than 5.0% by weight of the dosage form, such as more than 7.5% by weight of the dosage form, such as more than 10.0% by weight of the dosage form, such as more than 12.5% by weight of the dosage form, such as more than 15.0% by weight of the dosage form, such as more than 17.5% by weight of the dosage form, such as more than 20.0% by weight of the dosage form.

[0267] In an embodiment of the invention the dosage form comprises flavor in an amount of 3 to 45% by weight of the dosage form, such as 5 to 40% by weight of the dosage form, such as 10 to 35% by weight of the dosage form, such as 15 to 30% by weight of the dosage form, such as 20 to 25% by weight of the dosage form.

[0268] In an embodiment of the invention the dosage form comprises flavor in an amount of more than 0.3% by weight of the dosage form, such as at least 0.35% by weight of the dosage form, such as at least 0.4% by weight of the dosage form.

[0269] According to an embodiment of the invention, the dosage form comprises flavor in an amount of no more than 5% by weight of the dosage form, such as no more than 4% by weight of the dosage form, such as no more than 3% by weight of the dosage form, such as no more than 2% by weight of the dosage form, such as no more than 1.0% by weight of the dosage form, such as no more than 0.5% by weight of the dosage form, such as no more than 0.25% by weight of the dosage form, such as no more than 0.1% by weight of the dosage form.

[0270] In an embodiment of the invention, the dosage form comprises one or more flavors. In an embodiment of the invention, one or more flavors are selected from peppermint, menthol, 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 firutti, vanilla, or any combination thereof.

[0271] In an embodiment of the invention, the one or more flavors comprises menthol.

[0272] In an embodiment of the invention, the one or more flavors comprises peppermint.

[0273] According to an embodiment of the invention, flavor may be used as taste masking for the nicotine.

[0274] According to an advantageous embodiment of the invention, the dosage from is free of flavor.

[0275] According to an advantageous embodiment of the invention, the dosage form comprises high intensity sweetener.

[0276] In an embodiment of the invention, the high intensity sweetener is selected from sucralose, aspartame, salts of acesulfame, such as acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside and the like, alone or in combination. According to an advantageous embodiment of the invention, the dosage form comprises high intensity sweetener in an amount of at least 0.01% by weight of the dosage form, such as at least 0.1% by weight of the dosage form, such as at least 0.2% by weight of the dosage form, such as at least 0.3% by weight of the dosage form, such as at least 0.5% by weight of the dosage form, such as at least 0.75% by weight of the dosage form.

[0277] In an embodiment of the invention the dosage form comprises high intensity sweetener in an amount of 0.01 to 1% by weight of the dosage form, such as 0.1 to 0.9% by weight of the dosage form, such as 0.2 to 0.8% by weight of the dosage form, such as 0.3 to 0.7% by weight of the dosage form, such as 0.4 to 0.6% by weight of the dosage form.

[0278] In an embodiment of the invention the dosage form comprises high intensity sweetener in an amount of more than 0.3% by weight of the dosage form, such as at least 0.35% by weight of the dosage form, such as at least 0.4% by weight of the dosage form.

[0279] In an embodiment of the invention the dosage form comprises high intensity sweetener in an amount of no more than 1% by weight of the dosage form, such as no more than 0.8% by weight of the dosage form, such as no more than 0.6% by weight of the dosage form, such as no more than 0.4% by weight of the dosage form, such as no more than 0.2% by weight of the dosage form, such as no more than 0.1% by weight of the dosage form, such as no more than 0.01% by weight of the dosage form.

[0280] According to an advantageous embodiment of the invention, the dosage form is free of high intensity sweetener.

[0281] According to an advantageous embodiment of the invention, dosage form induces a nicotine effect, which is perceived after disintegration of the dosage form. In an embodiment of the invention, the nicotine effect may be quantified by the change of pulse rate.

[0282] In the above embodiment the change of pulse rate is understood to be the average change of pulse rate relative to the average pulse rate at rest and before initiating use of the nicotine tablet for a test person.

[0283] According to an advantageous embodiment of the invention, the nicotine effect is perceived at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form, such as at least 10 minutes after disintegration of the dosage form, such as at least 15 minutes after disintegration of the dosage form, such as at least 20 minutes after disintegration of the dosage form.

[0284] According to an advantageous embodiment of the invention, dosage form induces a nicotine craving relief, which is perceived after disintegration of the dosage form.

[0285] According to an advantageous embodiment of the invention, the nicotine craving relief is perceived at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form, such as at least 10 minutes after disintegration of the dosage form, such as at least 15 minutes after disintegration of the dosage form, such as at least 20 minutes after disintegration of the dosage form.

[0286] According to an advantageous embodiment of the invention, at least part of the second nicotine form is released after disintegration of the dosage form, such as at least 50% by weight of the second nicotine form.

[0287] According to an advantageous embodiment of the invention, the dosage form reduces nicotine burning.

[0288] The invention further relates to a dissolvable solid oral dosage form according to the invention or any of its embodiments for use in alleviation of nicotine craving. According to an advantageous embodiment of the invention, the dosage form is administered between the gum and the lip.

[0289] According to an advantageous embodiment of the invention, the dosage form is administered orally, such as on the tongue or sublingually.

[0290] In an embodiment of the invention, the dosage form is administered on the tongue.

[0291] In an embodiment of the invention, the dosage form is administered sublingually.

[0292] The invention further relates to a method for treatment of nicotine craving, the method comprising the steps of administering a therapeutically effective amount of nicotine, wherein the nicotine is provided in a dissolvable solid dosage form comprising a first nicotine form and a second nicotine form, wherein the dosage form has a disintegration time of no more than 10 minutes, wherein the first nicotine form and the second nicotine form are different, wherein the second nicotine form is a delayed nicotine form.

[0293] In an embodiment of the invention, the method utilizes the dissolvable solid dosage form according to the invention or any of its embodiments.

[0294] The invention further relates to a dissolvable solid oral dosage form, the dosage form comprising a first nicotine form and a second nicotine form, the dosage form having a disintegration time of no more than 12 minutes, wherein the first nicotine form and the second nicotine form are different, wherein the second nicotine form is a delayed nicotine form.

[0295] In an embodiment of the invention, the tablet described above may further be limited by any embodiments described herein. FIGURES

[0296] The invention will now be described with reference to the figures, where Figure 1 illustrates the effect on pulse rate of an example of an orally disintegrating nicotine tablet used according to the invention.

[0297] DETAILED DESCRIPTION

[0298] As used herein, the terms ’’disintegrant” refers to an ingredient facilitating disintegration of a disintegrating dosage form , when the disintegrating dosage form comes into contact with saliva. Disintegrants usable within the scope of the invention may include starch, pregelatinized starch, modified starch (including potato starch, maize starch, starch 1500, sodium starch glycolate and starch derivatives), crosslinked alginates, and superdisintegrants, such as crosslinked cellulose (such as sodium carboxy methyl cellulose), crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, crosslinked alginic acid, natural superdisintegrants, and calcium silicate. Disintegrants may often be considered as measure promoting the break-up of the dosage form into smaller fragments upon administration to allow the onset of drug dissolution and eventual absorption.

[0299] Hence, for the avoidance of doubt it is noted that the terms “dissolve”, “disintegrate” and “disintegrating dosage form” according to the present invention, does not include a chewing gum tablet comprising gum base and also not a pouched product comprising a water insoluble pouch membrane. Pouch membrane may also be referred to as fleece.

[0300] Further, for the avoidance of doubt it is noted that the term “solid” according to the present invention, does not include a liquid dosage form such as a spray.

[0301] As used herein, the term ’’nicotine” refers to nicotine in any form, including free base nicotine, 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 of microbial origin, or starch microspheres, nicotine bound to CaCO3, and mixtures thereof. Thus, when referring to nicotine amounts, the amounts refers to the amount of pure nicotine. Thus, when measuring the concentration of nicotine added as nicotine salt, it is the mass of the equivalent amount of pure nicotine, not the mass of the salt, that is relevant. Nicotine also covers nicotine not obtained from tobacco, often referred to as synthetic nicotine. An alternative to nicotine may be 6-methyl nicotine.

[0302] As used herein, the term ’’nicotine salt” refers to nicotine in ionized form bonded electrostatically to a counterion.

[0303] As used herein, the term ”NBT” refers to nicotine bitartrate and hydrates thereof.

[0304] As used herein, the term ”%” and “percent” refers to percent by weight, unless otherwise is stated.

[0305] 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 acids and bases, including acidic buffering agents and alkaline buffering agents. On the other hand, pH regulating agents does not include substances and compositions that can only affect the pH by dilution. Furthermore, pH regulating agents does not include e.g. flavoring, fillers, etc. In an advantageous embodiment of the invention, the pH regulating agent is alkaline.

[0306] As used herein, the term “buffering agent” is used interchangeably with “buffer” and refers to agents for obtaining a buffer solution. Buffering agents may include alkaline buffering agents, i.e. for obtaining a buffer solution with an alkaline pH.

[0307] In an embodiment of the invention, the dosage form comprises a filler. In an embodiment of the invention, the filler is selected form the group consisting of microcrystalline cellulose, magnesium- and calcium carbonate, sodium sulphate, ground limestone, silicate compounds such as magnesium- and aluminum silicate, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, fibers and combinations thereof. In an embodiment of the invention, the dosage form comprises a bulk sweetener. In an embodiment of the invention, the bulk sweetener comprises or consists of sugar sweetener and / or sugarless sweetener.

[0308] The bulk sweeteners may often support the flavor profile of the formulation, and may also be included as filler material.

[0309] In an embodiment of the invention, the sugar sweetener is selected from 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. These sugar sweeteners may also be included as a humectant.

[0310] In an embodiment of the invention, the sugarless sweeteners are selected from sugar alcohols (also referred to as polyols), such as sorbitol, erythritol, xylitol, maltitol, mannitol, lactitol, and isomalt. Sugar alcohols with four or more carbons and / or which are solid at 25 degrees Celsius are usable especially for tablets.

[0311] In an embodiment of the invention, the pH regulating agent is a buffering agent. In an embodiment of the invention, the buffering agent is sodium carbonate. In an embodiment of the invention, the buffering agents is selected from carbonate, including monocarbonate, bicarbonate and sesquicarbonate, glycerinate, phosphate, glycerophosphate, acetate, glyconate or citrate of an alkali metal, ammonium, tris buffer, amino acids and mixtures thereof. Encapsulated buffer, such as Effersoda may also be used.

[0312] Buffering agent in the dosage form may be used to obtain the desired pH-values in the saliva of a dosage form user. In some embodiments, the buffering agent comprises sodium carbonate and sodium bicarbonate, e.g. in a weight-ratio between 5: 1 and 2.5: 1, preferably in a weight-ratio between 4.1 : 1 and 3.5: 1.

[0313] A suitable buffering agent according to embodiments of the present invention is the sodium carbonate - sodium bicarbonate buffer system.

[0314] In an embodiment of the invention, silicon dioxide is used as a glidant. Other glidants usable for the formulation may also be used within the scope of the invention.

[0315] In an embodiment of the invention, ready to use systems may be used. 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 SmartExlOO (Shin Etsu / Harke Pharma).

[0316] In order to obtain a fast disintegrating dosage form, such as a dissolvable solid oral dosage form with a disintegration time of no more than 10 minutes, or such as an orally disintegrating tablet disintegrating within 60 seconds from oral administration on the tongue, or a disintegrating tablet disintegrating within 60 seconds in vitro, a range of parameters can be adjusted.

[0317] First, by varying the composition, the disintegration time can be altered. Using ingredients with a high water-solubility may facilitate a lowered disintegration time.

[0318] Particularly, by varying the amount and type of the disintegrant may significantly influence the disintegration time, the disintegration time may be further adjusted. For example, if a dosage form 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. In this respect, superdisintegrants are generally considered more effective disintegrants than disintegrants not being superdisintegrants.

[0319] Additionally, including a dissolution modifier may influence the disintegration time, by varying the amount and type of the dissolution modifier. For example, if a shorter disintegration time is desired, the content of dissolution modifier may be decreased (or even eliminated) and / or the type of dissolution modifier may be at least partly exchanged for a dissolution modifier less effective in delaying dissolution.

[0320] Also, decreasing the particle size of the disintegrant tends to lower the disintegration time, likely due to an increased surface area to volume ratio.

[0321] 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.

[0322] Moreover, using sugar alcohols with a lower compactibility leads to lower disintegration time for compressed tablets. Too low compactibility may compromise the mechanical strength of the dosage form and lead to undesirably high friability and risk of cracks etc.

[0323] Further examples of parameters that may be adjusted in order to adjust the disintegration time include size and shape of the dosage form. The larger the dosage form, the longer the disintegration time and thus release of the contents of the dosage form, such as release of nicotine.

[0324] Further, increasing the flatness (e.g. quantified by a diameter to height ratio) for e.g. a disc-shaped tablet typically increases disintegration time by increasing the surface-to- volume. As long as e.g. the tablet has a satisfactory mechanical strength, flatness may be increased. E.g. for tablets, modifying the cross-sectional profile from a convex type 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.

[0325] Furthermore, by adding a salivation agent to the dosage form, an increased amount of saliva in the vicinity of the dosage form may be facilitated, which again supports the dissolving and disintegration of the dosage form to reduce the disintegration time. Thus, sweeteners, in particular sugar alcohols, may be advantageous in this respect.

[0326] According to an advantageous embodiment of the invention, the dosage form comprises a lubricant, such as sodium stearyl fumarate (SSF) or magnesium stearate.

[0327] 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.

[0328] According to an advantageous embodiment of the invention, the dosage form comprises binder.

[0329] When using binders, e.g. to obtain a higher cohesiveness and mechanical strength of the tablet, the amount of such binders may be decreased as much as possible to obtain a higher disintegration rate and thus a shorter disintegration time.

[0330] According to an embodiment of the invention the dosage form is disc shaped.

[0331] Thus, a wide range of parameters may be adjusted to obtain the desired disintegration time of the dosage form. According to an embodiment of the invention, the oral dosage form is an orally dissolving film, such as a fast dissolving film.

[0332] A fast-dissolving film formulation typically comprises a film forming agents (sometimes referred to as a polymeric base), a plasticizer, nicotine, and optional excipients such as bulk sweeteners (typically sugar alcohols), flavors, and stabilizers.

[0333] In this context, the sugar alcohols usable as bulk sweeteners are typically those solid at 25 degrees Celsius and / or which comprise at least four carbons, in particular sugar alcohols selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

[0334] Suitable film forming agents include hydrocolloids such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), pullulan, alginate, pectin, gelatin, carrageenan, xanthan gum, locust bean gum, starch, modified starch, gum arabic, guar gum, agar gum, methyl cellulose, carboxy methylcellulose (CMC), polyvinyl alcohol (PVA), and sodium carboxymethylcellulose (NaCMC). The film forming agent is typically present in an amount ranging from 40% to 80% by weight of the dry film.

[0335] The plasticizer, such as glycerin, propylene glycol, ethylene glycol, polyethylene glycol, tributyl citrate, triethyl citrate, triacetin, glycerol triacetate, or combinations thereof, may be incorporated to improve film flexibility and prevent brittleness. The plasticizer may typically be included in an amount ranging from 1 to 20% by weight of the dry film, such as 2-10% by weight of the dry film. In some embodiments, no plasticizer is included.

[0336] The disintegration time of the film may be adjusted by considering several different factors. Increasing the concentration of hydrophilic polymers, such as HPMC or PVA, can enhance water uptake and accelerate disintegration. Including a superdisintegrant like crospovidone or croscarmellose sodium can further facilitate rapid film breakup. The selection of plasticizers can also play a role, as lower molecular weight plasticizers, such as glycerin, tend to promote faster dissolution compared to higher molecular weight alternatives. Additionally, reducing film thickness and incorporating porosity-enhancing agents, such as effervescent components (e.g. citric acid and sodium bicarbonate), can improve the dissolution rate of the film.

[0337] Additional excipients may be included, such as high intensity sweeteners and / or flavors. Other optional components, such as surfactants or stabilizers, may be added in small amounts (e.g. 0.1% to 5%) to enhance the properties of the film.

[0338] The orally dissolving films may be manufactured as follows. First, the film forming agent is dispersed in a solvent system, typically water or a water-alcohol mixture, under continuous stirring until a homogeneous solution is obtained. The plasticizer, if any, is then added to the mixture to enhance film flexibility. When using nicotine in water-soluble form, the nicotine may be dissolved directly into the polymeric solution to ensure homogeneous dispersion and prevent aggregation.

[0339] Then, the formulation is subjected to continuous mixing to ensure uniform dispersion of all components. High-shear mixing may be employed for homogeneity enhancement. Excipients such as sweeteners and flavors can be added at this stage, e.g. to improve palatability.

[0340] Then, the homogeneous mixture may be cast onto a non-stick substrate, such as a Teflon-coated plate or a polyethylene terephthalate (PET) film. The thickness of the film is controlled using e.g. a slot die coating technique, typically maintaining a film thickness in the range of 50 to 500 micrometers.

[0341] Finally, the cast film is subjected to controlled drying conditions to remove the solvent and achieve the desired mechanical properties. Drying may e.g. be performed at temperatures ranging from 30°C to 80°C, depending on the solvent system and polymer type. This step ensures rapid moisture evaporation while preventing thermal degradation of nicotine. Once dried, the film can be cut into individual dosage units using precision cutting tools such as rotary cutters or die punches.

[0342] Extruded films may be manufactured as follows: First, the ingredients are blended in dry form to ensure uniform distribution. The dry blend is then fed into an extruder, where it is heated and processed under controlled temperature and shear conditions to form a homogenous molten mixture.

[0343] The molten mass is then extruded through a flat die to form a continuous sheet of film. The thickness of the film is controlled by adjusting the die gap and extrusion speed. The extruded film is subsequently cooled and solidified using a series of rollers to achieve the desired mechanical properties.

[0344] Thus, the orally dissolving films may be manufactured in various ways as illustrated above.

[0345] According to an embodiment of the invention, the dosage form is a non-chewable dosage form, such as a non-chewable tablet.

[0346] It is noted that that the dosage form of the above embodiment is non-chewable in the sense that it is not intended for chewing. More specifically, chewing gum and dosage forms denoted as chewable tablets are not included in the dosage form of the above embodiment.

[0347] EXAMPLES

[0348] Example 1

[0349] Preparation of mucoadhesive-nicotine particles.

[0350] Aqua purificata (10 ml) was placed in a plastic beaker with a screw cap. A water- soluble anionic mucoadhesive polymer was slowly added to the water and the plastic beaker was closed with the cap before the dispersion was stirred at approximately 100°C for 6 h. Nicotine of purity 99% was added, and the gel mixture was vortexed. Afterwards it was vigorously stirred for 1 h between 60°C and 80°C. Precipitation was performed by pipetting 2 ml of the polymer gel with a positive displacement pipette into 30 ml isopropyl alcohol (IP A) under stirring conditions. The supernatant was poured off and discarded. Residual water and IPA were evaporated from the precipitate until the structure of the product was substantially solid. The product was comminuted into given average particles dimensions.

[0351] Nicotine was loaded to carrageenan in a 4: 1 weight ratio between carrageenan and nicotine. In this example, r-Carrageenan was used, with the trade name Gelcarin GP 379 NF from FMC. The average particle size of the carrageenan-ni cotine particles was approx.100 microns.

[0352] Example 2:

[0353] Preparation of one layer compressed tablets

[0354] Raw materials are weighed from bags or buckets into separate weighing containers. All excipients are sifted through an 800 micrometer sieve into a stainless steel or plastic bin in the following order:

[0355] • Half the filler / sugar alcohol

[0356] • The API and all other excipients, except lubricant (if any)

[0357] • The remaining half of the filler / sugar alcohol

[0358] These are mixed in a Turbula mixer for 4 - 10 minutes at 25 RPM. Then lubricant, for example magnesium stearate is sifted through an 800 micrometer sieve into the mixing bin, and the lubrication is conducted by additional mixing for 1 - 2 minutes at 25 RPM. The fill level of the mixing bin is kept between 40% and 70%, according to standardized practice. The lubricated powder blend is transferred to the hopper of a tableting machine.

[0359] The orally disintegrating tablets are manufactured on a lab scale machine, for example RIVA Piccola bi-layer tablet press, which is also suitable for preparation of one layer tablets. The tablet machine is commissioned by adjusting the fill depth and compression force so the weight and hardness of the tablets match the acceptance criteria. A pre-compression force could be included to avoid capping.

[0360] Table 1 : Suggested start up parameters. *The design of punches is not fixed. As the curvature impacts thickness, the thickness is not a fixed target at this time of development.

[0361] The acceptance criteria for friability should be fulfilled so packaging of the resulting orally disintegrating tablets is possible, but in this embodiment, the sugar alcohol and / or filler should have relatively good compressibility and still have fast disintegration.

[0362] The fast disintegrating tablets according to the invention may comprise coloring agents. According to an embodiment of the invention, the fast disintegrating tablets may comprise color agents and whiteners such as FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide and combinations thereof. Example 3:

[0363] Preparation of tablets comprising a first and a second modules.

[0364] The composition of second module, i.e. a module that is different in composition from the fast disintegrating tablet module, is prepared by pouring about half the sugar alcohol into a mixing bowl, followed by the other ingredients except lubricant, and finally the remaining sugar alcohol. The ingredients are tumbled / mixed with a mixer (Turbula or Duma) for 4-10 min at 49 rpm.

[0365] Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

[0366] The composition of first module, i.e. the fast disintegrating tablet 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.

[0367] Lubricant is added and the ingredients are further mixed for 1-2 min at 49 rpm.

[0368] The lubricated powder blends are sequentially transferred to the hopper of a tableting machine.

[0369] The second module is then compressed at a compression force of about 3-8 kN, after which the first module is fused by compression to the second module at a compression force of about 20-30 kN. Punch used unless otherwise specified: 12.00 mm, circular, shallow concave, B tooling.

[0370] The tablets are manufactured on a lab scale machine, for example RIVA Piccola bilayer 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.

[0371] Example 4: Tablet compositions, one layer tablets

[0372] Example 4A: Tablets were prepared according to example 2, unless otherwise specified.

[0373] In this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Tablet weight: 200.0 mg. Table 2: Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). MCC = microcrystalline cellulose. HIS = High intensity sweeteners. Nicotine Carragenan = nicotine-mucoadhesivee (carrageenan) complex made according to example 1, which has a 1 :4 loading of nicotine. The 1stnicotine dose refers to the dose of the first nicotine form, here NBT. The 2ndnicotine dose refers to the dose of the second nicotine form, here Nicotine Carrageenan.

[0374] 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.

[0375] In the above examples a peppermint flavor in powder form was used. A mixture of peppermint and menthol may also be used. Of course, other flavors as described herein may be used as well, in combination with menthol and / or peppermint or replacing these. The flavor may be liquid or powdered or a combination, i.e. a liquid flavor and a powdered flavor is added.

[0376] In the above magnesium stearate is used as lubricant. Other lubricants, such as sodium stearyl fumerate may also be usable within the scope of the invention.

[0377] Sodium carbonate is used as the alkaline pH regulating agent. 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.

[0378] Example 4B:

[0379] Tablets were prepared according to example 2, unless otherwise specified.

[0380] In this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Tablet weight: 150.0 mg.

[0381]

[0382] Table 3: Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). MCC = microcrystalline cellulose. HIS = High intensity sweeteners. Nicotine Carrageenan = nicotine-mucoadhesive (carrageenan) complex made according to example 1, which has a 1 :4 loading of nicotine. The 1stnicotine dose refers to the dose of the first nicotine form, here NBT. The 2ndnicotine dose refers to the dose of the second nicotine form, here Nicotine Carrageenan.

[0383] Alternative ingredients as described in relation to ODF1-ODF7 of table 2 may also be applied for ODF10-ODF15.

[0384] Example 4C:

[0385] Tablets were prepared according to example 2, unless otherwise specified.

[0386] In this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Tablet weight: 75.0 mg.

[0387] Table 4. Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). MCC = microcrystalline cellulose. Nicotine Carrageenan = nicotine-mucoadhesive (carrageenan) complex made according to example 1, which has a 1 :4 loading of nicotine. The 1stnicotine dose refers to the dose of the first nicotine form, here NBT. The 2ndnicotine dose refers to the dose of the second nicotine form, here Nicotine Carrageenan.

[0388] Alternative ingredients as described in relation to 0DF1-0DF7 of table 2 and ODFIO- 0DF15 of table 3, may also be applied for ODF20-ODF26.

[0389] Example 4D:

[0390] Tablets were prepared according to example 2, unless otherwise specified. In this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. The given tablet weight is described in the table below.

[0391] Table 5: Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). MCC = microcrystalline cellulose. HIS = High intensity sweeteners. Nicotine Carrageenan = nicotine-mucoadhesive (carrageenan) complex made according to example 1, which has a 1 :4 loading of nicotine. *Weight percent of encapsulated nicotine corresponds only to the amount of NBT used to make the encapsulated nicotine. The amount of encapsulation material applied is included in the amount of tablet filler material, in this case sorbitol. The 1stnicotine dose refers to the dose of the first nicotine form, here NBT. The 2ndnicotine dose refers to the dose of the second nicotine form, here Nicotine Carrageenan or Encapsulated nicotine.

[0392] Alternative ingredients as described in relation to ODF1-ODF26 of tables 2-4 may also be applied for ODF30-ODF34.

[0393] Example 4E:

[0394] Tablets were prepared according to example 2, unless otherwise specified. In this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

[0395] Table 6. Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). MCC = microcrystalline cellulose. NPR = nicotine polacrilex resin (nicotine content of 16% by weight). HIS = High intensity sweeteners. Nicotine Xanthan, Nicotine Carbomer = nicotine-mucoadhesive (xanthan / carbomer) complex made according to example 1, which has a 1 :4 loading of nicotine. The 1stnicotine dose refers to the dose of the first nicotine form, here NBT or Nicotine free base. The 2ndnicotine dose refers to the dose of the second nicotine form, here Nicotine-Xanthan, Nicotine-Carbomer, or NPR.

[0396] * Free base nicotine is included as a premix with a fraction of the sugar alcohol, in this case mannitol

[0397] Alternative ingredients as described in relation to ODF1-ODF34 of tables 2-5 may also be applied for ODF41-ODF45.

[0398] Example 4F:

[0399] Tablets ODF50-ODF55 were prepared according to example 3.

[0400] For tablets ODF50-ODF53 of this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Total tablet weight of 300.0 mg, with each layer being 150 mg.

[0401] For tablets ODF54-ODF55 of this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Weight of 1stlayer: 100.0 mg. Weight of 2ndlayer: 300.0 mg. Tablet weight: 400.0 mg.

[0402]

[0403] Table 7. Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). MCC = microcrystalline cellulose. HIS = High intensity sweeteners. Nicotine Carrageenan = nicotine-mucoadhesive (carrageenan) complex made according to example 1, which has a 1 :4 loading of nicotine. NBT is the 1stnicotine form, Nicotine Carrageenan is the 2ndnicotine form. NPR = nicotine polacrilex resin (nicotine content of 16% by weight).

[0404] Alternative ingredients as described in relation to ODF1-ODF45 of tables 2-6 may also be applied for ODF50-ODF55.

[0405] Example 4G: Tablets were prepared according to example 2.

[0406] In this example, the following conditions were applied. Punch used: 7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

[0407] Table 7A. Composition of tablets. NBT = nicotine bi-tartrate (nicotine content of 32.38% by weight). NPR = nicotine polacrilex resin (nicotine content of 16% by weight). MCC = microcrystalline cellulose. Alternative ingredients as described in relation to ODF1-ODF53 of tables 2-7 may also be applied for ODF60-ODF64.

[0408] Example 5 - Film Casting: The film forming agent (e.g. HPC or HPMC) was dissolved in water together with plasticizer and sugar alcohol. Then, the nicotine forms were added to the solution together with remaining ingredients. The obtained mixture was heated to dissolve all solids and obtain a second mixture for casting. The obtained second mixture was cast on a plate and allowed to dry to obtain a mucoadhesive film strip.

[0409] Example 6 - Film Extrusion Thin strips can also be formed by a hot melt extrusion process whereby ingredients are combined in, or prior to introduction to, an extruder which heats and mixes the ingredients and melt extrudes a laminar composition, which is then calendered and cut / punched to provide thin film strips of desired thickness. An extrusion temperature of 55 degrees Celsius and a screw speed of 125 RPM was used.

[0410] Example 7:

[0411] Films were prepared as indicated in the below table. The weight of the films is 50 mg.

[0412] by weight). HIS = High intensity sweeteners. Nicotine Carrageenan = nicotine- mucoadhesive (carrageenan) complex, which has a 1 :4 loading of nicotine. PEO = Polyethylene oxide. HPMC = Hydroxypropyl methylcellulose. MCC = Microcrystalline cellulose. PEG 400 = Polyethylene glycol 400. The 1stnicotine dose refers to the dose of the first nicotine form, here NBT. The 2ndnicotine dose refers to the dose of the second nicotine form, here Nicotine Carrageenan. Example 8: Evaluation

[0413] The produced tablets of the invention were evaluated and found highly suitable as delivery vehicles of nicotine in that they provide a favorable release of nicotine and at the same time are pleasant to the user, e.g. with respect to an acceptable nicotine burning while providing a lasting (i.e. a long-lasting) perceived effect of nicotine.

[0414] Example 9: Nicotine effect

[0415] Nicotine effect was evaluated using a panel of three users evaluating all samples twice. The tablets were administered under the lip, specifically at the position between the upper lip and gum.

[0416] Each user assessed the nicotine effect, i.e. the perceived effect of nicotine stimulating the body. All users agreed that while the nicotine effect from the comparative tablet Cl started to decrease after peaking at about 7 minutes, inventive tablet ODF34 provided a perceived, significant nicotine effect continuing for an extended time which was only perceived as decreasing after about 25 minutes. The users noted a relatively sharp decline in perceived effect from the comparative tablet Cl quickly after it was disintegrated, the perceived effect from the inventive tablet ODF34 was clearly felt for a significant period of time after the tablet was disintegrated.

[0417] Also, as an additional measure of the nicotine effect, the difference in pulse rate during and after administration was noted relative to the pulse rate at rest before administration. Higher difference in pulse rate thus corresponds to higher effect of nicotine. Difference in pulse rates relative to the pulse rate at rest is noted in below table 9.

[0418] Table 9. Difference in pulse rate relative to pulse rate at rest.

[0419] As observed from table 9 and shown in figure 1, administration between the upper lip and gum of inventive tablet ODF34 resulted in a sustained nicotine effect lasting throughout the measured 25 minutes, whereas the nicotine experience duration was much shorter for the comparative Cl tablet.

Claims

CLAIMS1. A dissolvable solid oral dosage form, the dosage form comprising a first nicotine form and a second nicotine form, the dosage form having a disintegration time of no more than 10 minutes, wherein the first nicotine form and the second nicotine form are different, wherein the second nicotine form is a delayed nicotine form.

2. The dissolvable solid oral dosage form according to claim 1, wherein the dosage form has a disintegration time of no more than 8 minutes, such as no more than 6 minutes, such as no more than 4 minutes.

3. The dissolvable solid oral dosage form according to claim 1 or 2, wherein the dosage form has a disintegration time of no more than 10 minutes when placed between the gum and lip, such as no more than 8 minutes, such as no more than 6 minutes, such as no more than 4 minutes.

4. The dissolvable solid oral dosage form according to any of claims 1-3, wherein the dosage form has a disintegration time of no more than 150 seconds when placed on the tongue, such as no more than 120 seconds, such as no more than 90 seconds.

5. The dissolvable solid oral dosage form according to any of claims 1-4, wherein the dosage form has an in vitro disintegration time of no more than 120 seconds, such as no more than 100 seconds, such as no more than 80 seconds, such as no more than 60 second, such as no more than 40 seconds.

6. The dissolvable solid oral dosage form according to any of claims 1-5, wherein the dosage form is a tablet.

7. The dissolvable solid oral dosage form according to any of claims 1-6, wherein the dosage form is an orally disintegrating tablet.

8. The dissolvable solid oral dosage form according to any of claims 1-7, wherein the dosage form is a compressed tablet.

9. The dissolvable solid oral dosage form according to any of claims 1-6, wherein the dosage form is selected from the group consisting of an orally dissolving film, a solid gel, a compressed tablet (such as a compressed orally disintegrating tablet), a meltable tablet, a pastille, an effervescent tablet.

10. The dissolvable solid oral dosage form according to any of claims 1-9, wherein the dosage form is an orally dissolving film.

11. The dissolvable solid oral dosage form according to any of claims 1-10, wherein the dosage form is an extruded dosage form.

12. The dissolvable solid oral dosage form according to any of claims 1-11, wherein the dosage form is a cast dosage form.

13. The dissolvable solid oral dosage form according to any of claims 1-12, wherein the dosage form is a cast orally dissolvable film.

14. The dissolvable solid oral dosage form according to any of claims 1-13, wherein the first nicotine form is a fast nicotine form.

15. The dissolvable solid oral dosage form according to any of claims 1-14, wherein the first nicotine form comprises nicotine free base and / or nicotine salt.

16. The dissolvable solid oral dosage form according to any of claims 1-15, wherein the first nicotine form comprises nicotine free base.

17. The dissolvable solid oral dosage form according to any of claims -16, wherein the first nicotine form comprises nicotine salt.

18. The dissolvable solid oral dosage form according to any of claims -17, wherein the second nicotine form comprises a carrier.

19. The dissolvable solid oral dosage form according to any of claims -18, wherein the second nicotine form comprises a natural carrier.

20. The dissolvable solid oral dosage form according to any of claims 1-19, wherein the second nicotine form comprises at least one selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, nicotine sorbed to calcium carbonate, nicotine bound to oleic acid, nicotine sorbed on cellulose, such as microcrystalline cellulose, and any combination thereof.

21. The dissolvable solid oral dosage form according to any of claims 1-20, wherein the second nicotine form comprises at least one selected from the group consisting of a nicotine-mucoadhesive complex, nicotine bound to an ion exchange resin, encapsulated nicotine, and any combination thereof.

22. The dissolvable solid oral dosage form according to any of claims 1-21, wherein the second nicotine form comprises a nicotine-mucoadhesive complex.

23. The dissolvable solid oral dosage form according to claim 21 or 22, wherein the nicotine-mucoadhesive complex comprises nicotine bound to a water-soluble anionic mucoadhesive polymer.

24. The dissolvable solid oral dosage form according to claim 23, wherein the at least one water-soluble anionic mucoadhesive polymer is weakly acidic.

25. The dissolvable solid oral dosage form according to any of claims 23-24, wherein the at least one water-soluble anionic mucoadhesive polymer comprises carboxylic functional groups.

26. The dissolvable solid oral dosage form according to any of claims 23-25, wherein the at least one water-soluble anionic mucoadhesive polymer is selected from sulfonated polysaccharides and / or anionic polysaccharides and / or polyacrylic acid.

27. The dissolvable solid oral dosage form according to any of claims 23-26, wherein the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, gellan gum, carbomer, carboxymethyl cellulose, and any combination thereof.

28. The dissolvable solid oral dosage form according to any of claims 23-27, wherein the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethyl cellulose, and any combination thereof.

29. The dissolvable solid oral dosage form according to any of claims 23-28, wherein the at least one water-soluble anionic mucoadhesive polymer has an average molecular weight (mw) of at least 50 kDa, such as at least 75 kDa, such as at least 100 kDa, such as at least 150 kDa, such as at least 200 kDa, such as at least 250 kDa.

30. The dissolvable solid oral dosage form according to any of claims 1-29, wherein the second nicotine form comprises nicotine bound to an ion exchange resin, such as nicotine polacrilex resin.

31. The dissolvable solid oral dosage form according to any of claims 1-30, wherein the dosage form comprises nicotine in an amount of at least 0.2 mg, such as at least 0.5 mg, such as at least 1.0 mg.

32. The dissolvable solid oral dosage form according to any of claims 1-31, wherein the dosage form comprises nicotine in an amount of at least 0.2% by weight of the dosage form, such as at least 0.3% by weight of the dosage form, such as at least 0.5% by weight of the dosage form.

33. The dissolvable solid oral dosage form according to any of claims 1-32, wherein the dosage form comprises the first nicotine form in an amount of at least 0.1 mg, such as at least 0.3 mg, such as at least 0.5 mg.

34. The dissolvable solid oral dosage form according to any of claims 1-33, wherein the dosage form comprises the second nicotine form in an amount of at least 0.1 mg, such as at least 0.3 mg, such as at least 0.5 mg.

35. The dissolvable solid oral dosage form according to any of claims 1-34, wherein the second nicotine form has a release time of at least 1 minute after disintegration of the dosage form, such as at least 2 minutes after disintegration of the dosage form, such as at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form, such as at least 10 minutes after disintegration of the dosage form.

36. The dissolvable solid oral dosage form according to any of claims 1-35, wherein the second nicotine form is characterized by having a slower release rate of 70% by weight of the nicotine from the second nicotine form than the release rate of 70% by weight of nicotine from the first nicotine form when measured according to USP 29 requirements for nicotine release from nicotine polacrilex.

37. The dissolvable solid oral dosage form according to any of claims 1-36, wherein the second nicotine form is characterized by releasing 70% by weight of the nicotine from the second nicotine form within a period of time, which is longer than the period of time for releasing 70% by weight of nicotine release from nicotine polacrilex, whenmeasured according to USP 29 requirements for nicotine release from nicotine polacrilex.

38. The dissolvable solid oral dosage form according to any of claims 1-37, wherein the second nicotine form is characterized by less than 70% by weight release of the nicotine from the second nicotine form within a period of time of 10 minutes when measured according to USP 29 requirements for nicotine release from nicotine polacrilex.

39. The dissolvable solid oral dosage form according to any of claims 1-38, wherein the dosage form comprises disintegrant.

40. The dissolvable solid oral dosage form according to claim 39, wherein the dosage form comprises said disintegrant in an amount of at least 0.5% by weight of the dosage form, such as at least 1% by weight of the dosage form, such as at least 2% by weight of the dosage form, such as at least 3% by weight of the dosage form, such as at least 5% by weight of the dosage form.

41. The dissolvable solid oral dosage form according to claim 39 or 40, wherein said disintegrant is selected from the list consisting of starch, pregelatinized starch, calcium silicate, crosslinked cellulose, crosslinked polyvinyl pyrrolidone, crosslinked starch, crosslinked alginate, and combinations thereof.

42. The dissolvable solid oral dosage form according to any of claims 39-41, wherein said disintegrant comprises pregelatinized starch.

43. The dissolvable solid oral dosage form according to any of claims 39-42, wherein said disintegrant consists of pregelatinized starch.

44. The dissolvable solid oral dosage form according to any of claims 39-43, wherein the disintegrant comprises a superdisintegrant.

45. The dissolvable solid oral dosage form according to any of claims 1-44, wherein the dosage form comprises superdisintegrant in an amount of at least 0.5% by weight of the dosage form, such as at least 1% by weight of the dosage form, such as at least 2% by weight of the dosage form, such as at least 3% by weight of the dosage form, such as at least 5% by weight of the dosage form.

46. The dissolvable solid oral dosage form according to claim 44 or 45, wherein the superdisintegrant is selected from the group consisting of crosslinked cellulose, crosslinked polyvinyl pyrrolidone, crosslinked starch, crosslinked alginate, and any combinations thereof.

47. The dissolvable solid oral dosage form according to any of claims 39-46, wherein the disintegrant is a super disintegrant selected from the group consisting of crosslinked cellulose, crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, and any combinations thereof.

48. The dissolvable solid oral dosage form according to any of claims 39-47, wherein the disintegrant is a super disintegrant selected from the group consisting of crosslinked polyvinyl pyrrolidone, croscarmellose, sodium starch glycolate, and any combinations thereof.

49. The dissolvable solid oral dosage form according to any of claims 1-48, wherein the dosage form comprises at least one sugar alcohol.

50. The dissolvable solid oral dosage form according to claim 49, wherein the dosage form comprises the at least one sugar alcohol sugar alcohol in an amount of at least 40% by weight of the dosage form, such as at least 50% by weight of the dosage form, such as at least 60% by weight of the dosage form, such as at least 70% by weight of the dosage form, such as at least 80% by weight of the dosage form.

51. The dissolvable solid oral dosage form according to claim 49 or 50, wherein the dosage form comprises the at least one sugar alcohol sugar alcohol in an amount of at least 5% by weight of the dosage form, such as at least 10% by weight of the dosage form, such as at least 20% by weight of the dosage form, such as at least 30% by weight of the dosage form, such as at least 40% by weight of the dosage form.

52. The dissolvable solid oral dosage form according to any of claims 49-51, wherein the at least one sugar alcohol comprises sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol and any combination thereof.

53. The dissolvable solid oral dosage form according to any of claims 1-52, wherein the dosage form comprises at least one film forming agent.

54. The dissolvable solid oral dosage form according to claim 53, wherein the dosage form comprises the at least one film forming agent in an amount of at least 40% by weight of the dosage form, such as at least 50% by weight of the dosage form, such as at least 60% by weight of the dosage form.

55. The dissolvable solid oral dosage form according to claim 53 or 54, wherein the at least one film forming agent comprises at least one water-soluble polymer.

56. The dissolvable solid oral dosage form according to any of claims 53-55, wherein the at least one film forming agent comprises at least one selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), pullulan, alginate, pectin, gelatin, carrageenan, xanthan gum, locust bean gum, starch, modified starch, gum arabic, guar gum, agar gum, methyl cellulose, carboxy methylcellulose (CMC), and any combination thereof.

57. The dissolvable solid oral dosage form according to any of claims 1-56, wherein the dosage form comprises at least one plasticizer.

58. The dissolvable solid oral dosage form according to claim 57, wherein the dosage form comprises the least one plasticizer in an amount of 2 to 10% by weight of the dosage form.

59. The dissolvable solid oral dosage form according to claim 57 or 58, wherein the at least one plasticizer is selected from the group consisting of glycerin, propylene glycol, ethylene glycol, polyethylene glycol, tributyl citrate, triethyl citrate, triacetin, glycerol triacetate, and any combination thereof.

60. The dissolvable solid oral dosage form according to any of claims 1-59, wherein the dosage form comprises a pH regulating agent.

61. The dissolvable solid oral dosage form according to claim 60, wherein the pH regulating agent is an alkaline pH regulating agent, such as an alkaline buffering agent.

62. The dissolvable solid oral dosage form according to claim 60 or 61, wherein the pH regulating agent comprises pH regulating agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, di-alkali hydrogen phosphate, tri-alkali phosphate, or any combination thereof.

63. The dissolvable solid oral dosage form according to any of claims 60-62, wherein the pH regulating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or any combination thereof.

64. The dissolvable solid oral dosage form according to any of claims 60-63, wherein the pH regulating agent comprises or consists of sodium carbonate.

65. The dissolvable solid oral dosage form according to any of claims 60-64, wherein the dosage form comprises the pH regulating agent in an amount of at least 0.2% by weight of the dosage form, such as at least 0.5% by weight of the dosage form, such as at least 1% by weight of the dosage form, such as at least 2% by weight of the dosage form.

66. The dissolvable solid oral dosage form according to any of claims 1-65, wherein the dosage form is free of effervescent agents.

67. The dissolvable solid oral dosage form according to any of claims 1-66, wherein the dosage form has a weight of no more than 1000 mg, such as no more than 900 mg, such as no more than 800 mg, such as no more than 700 mg, such as no more than 600 mg, such as no more than 500 mg, such as no more than 400 mg, such as no more than 300 mg, such as no more than 200 mg, such as no more than 150 mg, such as no more than 120 mg, such as no more than 100 mg, such as no more than 50mg.

68. The dissolvable solid oral dosage form according to any of claims 1-67, wherein dosage form has a weight of more than 20 mg, such as more than 30 mg, such as more than 40 mg, such as more than 50 mg, such as more than 60 mg, such as more than 70 mg, such as more than 80 mg.

69. The dissolvable solid oral dosage form according to any of claims 1-68, wherein the dosage form is a one-layer dosage form.

70. The dissolvable solid oral dosage form according to any of claims 1-69, wherein the dosage form comprises at least one module, and wherein the at least one module comprises at least part of the first nicotine form and at least part of the second nicotine form.

71. The dissolvable solid oral dosage form according to any of claims 1-70, wherein the dosage form comprises at least one module, and wherein the at least one module comprises the first nicotine form and the second nicotine form.

72. The dissolvable solid oral dosage form according to any of claims 1-71, wherein the dosage form is a multi-layer dosage form, such as a two-layer dosage form or a three-layer dosage form.

73. The dissolvable solid oral dosage form according to any of claims 1-72, wherein the dosage form comprises flavor.

74. The dissolvable solid oral dosage form according to any of claims 1-73, wherein the dosage form comprises flavor in an amount of at least 0.1% by weight of the dosage form, such as at least 0.25% by weight of the dosage form, such as at least 0.5% by weight of the dosage form, such as at least 1.0% by weight of the dosage form, such as at least 1.5% by weight of the dosage form, such as at least 2.0% by weight of the dosage form, such as at least 2.5% by weight of the dosage form, such as at least 3.0% by weight of the dosage form.

75. The dissolvable solid oral dosage form according to any of claims 1-74, wherein the dosage from is free of flavor.

76. The dissolvable solid oral dosage form according to any of claims 1-75, wherein the dosage form comprises high intensity sweetener.

77. The dissolvable solid oral dosage form according to any of claims 1-76, wherein the dosage form comprises high intensity sweetener in an amount of at least 0.01% by weight of the dosage form, such as at least 0.1% by weight of the dosage form, such as at least 0.2% by weight of the dosage form, such as at least 0.3% by weight of the dosage form, such as at least 0.5% by weight of the dosage form, such as at least 0.75% by weight of the dosage form.

78. The dissolvable solid oral dosage form according to any of claims 1-77, wherein the dosage form is free of high intensity sweetener.

79. The dissolvable solid oral dosage form according to any of claims 1-78, wherein dosage form induces a nicotine effect, which is perceived after disintegration of the dosage form.

80. The dissolvable solid oral dosage form according to claim 79, wherein the nicotine effect is perceived at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form.

81. The dissolvable solid oral dosage form according to any of claims 1-80, wherein dosage form induces a nicotine craving relief, which is perceived after disintegration of the dosage form.

82. The dissolvable solid oral dosage form according to claim 81, wherein the nicotine craving relief is perceived at least 3 minutes after disintegration of the dosage form, such as at least 5 minutes after disintegration of the dosage form.

83. The dissolvable solid oral dosage form according to any of claims 1-82, wherein at least part of the second nicotine form is released after disintegration of the dosage form, such as at least 50% by weight of the second nicotine form.

84. The dissolvable solid oral dosage form according to any of claims 1-83, wherein the dosage form reduces nicotine burning.

85. The dissolvable solid oral dosage form according to any of claims 1-84 for use in alleviation of nicotine craving.

86. The dissolvable solid oral dosage form according for use according to claim 85, wherein the dosage form is administered between the gum and the lip.

87. The dissolvable solid oral dosage form according for use according to claim 85, wherein the dosage form is administered orally, such as on the tongue or sublingually.

88. A method for treatment of nicotine craving, the method comprising the step of administering a therapeutically effective amount of nicotine, wherein the nicotine is provided in a dissolvable solid dosage form comprising a first nicotine form and a second nicotine form, wherein the dosage form has a disintegration time of no more than 10 minutes, wherein the first nicotine form and the second nicotine form are different, wherein the second nicotine form is a delayed nicotine form.

89. The method according to claim 88, wherein the dissolvable solid dosage form according to any of claims 1-87 is used.

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