Ion exchange compositions having water-soluble mucoadhesive polymers

Abstract

The present invention relates to an oral tablet for oral mucosal delivery of a biologically active compound, the tablet comprising: a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet; and an ion exchange composition comprising a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound.

Description

[Technical Field]

[0001] The present invention relates to the field of ion exchange compositions for loading cationic biologically active compounds. In particular, the present invention relates to ion exchange compositions based on particles of water-soluble anionic mucoadhesive polymers. [Background technology]

[0002] Ion exchange resins have been used in the field of oral delivery to obtain controlled release and delivery of biologically active compounds such as nicotine. The purpose of the ion exchange resins was to stabilize the biologically active compound while ensuring controlled release of the biologically active compound, such as nicotine, upon oral administration. Harmful effects of the biologically active compound, such as throat irritation, can be reduced in this way, while the biologically active compound can be delivered over an extended period of time to users in need of relief due to their increasing craving.

[0003] Nicotine is a well-known and well-characterized alkaloid that can be isolated from the dried leaves of Nicotiana tabacum. Its many commercial uses include its usefulness as a fumigant and insecticide. It has therapeutic value in the treatment of smoking withdrawal syndrome. This treatment is based on the fact that administration of nicotine to the body is easily achieved by smoking, for example, from cigarettes, pipes, or cigars. Smokers experience a satisfying sensation from such administration.

[0004] U.S. Patent No. 3,901,248 discloses a chewable smoking replacement composition comprising a chewing gum base and a nicotine / cation exchange resin complex dispersed therein. Chewing such a composition releases a small, reduced amount of nicotine into the mouth within the first few minutes of chewing. This composition is only moderately effective at eliciting the pleasant smoking sensation typically desired by people undergoing treatment incorporating such chewing gum. However, while the composition may generally have fewer adverse effects, such as throat irritation, its extended release properties result in a large amount of nicotine being swallowed by the user, and therefore, the bioavailability of the nicotine present in the formulation may be relatively low. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 3,901,248 Summary of the Invention [Problem to be solved by the invention]

[0006] While prior art ion exchange resins generally comply with stability requirements and have been used in nicotine products for decades, there remains a need in the art for ion exchange compositions suitable for use in oral mucosal delivery of biologically active compounds that do not suffer from the drawbacks of the prior art. In particular, there is a need in the art for ion exchange compositions that provide improved bioavailability of biologically active compounds such as nicotine. [Means for solving the problem]

[0007] The present invention relates to an oral tablet for oral mucosal delivery of a biologically active compound, the tablet comprising: a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet; and an ion exchange composition comprising a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound.

[0008] Generally, unlike conventional ion exchange resins, the ion exchange compositions of the present invention are associated with mucoadhesive properties. Thus, when the ion exchange compositions of the present invention are administered, they tend to adhere to mucosal surfaces, where biologically active compounds can be delivered directly to the oral mucosa and absorbed into the bloodstream. This feature of the ion exchange compositions can address various problems in the prior art.

[0009] One of the problems that can be solved by the present invention is improved bioavailability of biologically active compounds, i.e., the content of biologically active compounds in oral formulations that becomes available for transport across the oral mucosa. In other words, the present invention helps to solve the problem of maximizing the availability of active compounds available for absorption, avoiding that much of the biologically active compound is swallowed during use.

[0010] As a result, by maximizing the use of biologically active compounds, certain side effects of biologically active compounds can be avoided. For example, the harmful effects of nicotine can be avoided or at least reduced. It is known that swallowing large amounts of nicotine can cause throat irritation and discomfort to users. Therefore, according to the present invention, by optimizing the bioavailability of biologically active compounds, harmful side effects can be improved.

[0011] Another result of the present invention is that a higher content of biologically active compound can be used in oral formulations as a result of less significant adverse side effects. In the same context, this also provides the option of formulating with a lower content of biologically active compound while still obtaining the same or similar pharmacological effect of the biologically active compound due to its higher bioavailability.

[0012] Importantly, the ion exchange compositions of the present invention comprise a plurality of particles, allowing the biologically active compound to adhere to the mucosal surface, where it can be delivered directly to the oral mucosa and protected until it is absorbed into the bloodstream. This route of targeting the biologically active compound as part of a particle to the site of action has at least two associated advantages. First, less waste of the biologically active compound can be achieved. Second, higher bioavailability can be achieved. In this regard, it has been observed that administration of water-soluble anionic mucoadhesive polymers without formulation into particles according to the present invention results in lower bioavailability and a higher degree of adverse effects.

[0013] Surprisingly, it has been found that the significant adhesion of particles of at least one water-soluble anionic mucoadhesive polymer according to the present invention is associated with a higher concentration of biologically active compounds in distinct regions of the oral mucosa.Thus, when the particles of the present invention are attached to the oral mucosa, the local concentration of biologically active compounds is significantly increased.Without being bound by theory, it is believed that this high local concentration of biologically active compounds leads to a higher absorption of biologically active compounds such as nicotine.

[0014] Taking advantage of the increased concentration of biologically active compounds at the oral mucosa and the protection provided by the particles both before and during their attachment to the oral mucosa, the present invention can also increase the overall absorption of nicotine compared to conventional oral formulations with the same content of biologically active ingredients. In this context, the present invention can also provide fewer side effects associated with swallowing biologically active compounds.

[0015] According to the present invention, oral formulations are preferably designed so that the ion exchange composition reaches the oral mucosa within a specific time. This adjusts adhesion to the oral mucosa and exposes the ion exchange composition to a minimum amount of saliva. Therefore, the ion exchange composition is preferably formulated into an oral tablet containing a certain amount of sugar alcohol that contributes to the disintegration of the tablet, thereby releasing the ion exchange composition after a relatively short time. Such tablets include rapidly disintegrating tablets (FDT) or orally disintegrating tablets (ODT), certain chewable tablets, powders themselves, and sachets.

[0016] Typically, conventional lozenges do not provide the necessary disintegration to allow the ion-exchange composition to reach the oral mucosa in a short period of time. However, in certain embodiments, the ion-exchange composition of the present invention can be formulated into a lozenge or even into the water-insoluble portion of a chewing gum. In these embodiments, the ion-exchange composition functions similarly to an ion-exchange resin, being partially retained in the formulation matrix for an extended period of time. The biologically active compound is then released over an extended period of time. Nevertheless, in contrast to ion-exchange resins, anionic mucoadhesive polymers partially dissolve over time due to the water-soluble nature of the polymer, which is considered a distinct advantage in terms of the bioavailability of the biologically active compound.

[0017] The ion exchange composition according to the present invention comprises a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound. The ion exchange composition itself may contain additional elements or components apart from the at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound, such as a buffering agent.

[0018] In addition, at least one water-soluble anionic mucoadhesive polymer is loaded with a cationic biologically active compound, such as nicotine. The ion exchange composition serves to provide a stable composition when stored by itself and when formulated into an oral tablet with additional ingredients. Furthermore, the ion binding properties function similarly to those of conventional cation exchange resins. For example, the release of the biologically active compound can be adjusted under appropriate pH conditions, while the complex can be stable under other pH conditions. The at least one water-soluble anionic mucoadhesive polymer has a similar function, i.e., a porous structure, to that of polacrilex resin, which is used to load nicotine.

[0019] Conventional ion exchange resins are polymers containing appropriately substituted acidic groups, such as carboxylic and sulfonic acids for cation exchangers, or basic groups, such as quaternary ammonium groups for anion exchangers. Variables associated with the resin include the exchange capacity; the degree of cross-linking, which determines the permeability of the resin, its swelling potential, and the accessibility of the exchange sites to drug ions; the effective pK(a) of the exchange groups, which determines the exchange affinity; and the resin particle size, which controls the accessibility of the exchanged ions.

[0020] In contrast to conventional resins, the at least one water-soluble anionic mucoadhesive polymer of the present invention is water-soluble, but the polymers of the present invention generally relate to similar side group substitution capacity, acidity properties, swelling properties, accessibility of exchange sites to drug ions, effective pK(a) of the exchange groups, and particle size.

[0021] In one embodiment of the present invention, the weight ratio of the at least one water-soluble anionic mucoadhesive polymer to the cationic biologically active compound is from 2:1 to 20:1.

[0022] In one embodiment of the present invention, the weight ratio of the at least one water-soluble anionic mucoadhesive polymer to the cationic biologically active compound is from 2:1 to 15:1.

[0023] In one embodiment of the present invention, the weight ratio of the at least one water-soluble anionic mucoadhesive polymer to the cationic biologically active compound is from 2:1 to 10:1.

[0024] In one embodiment of the present invention, the weight ratio of the at least one water-soluble anionic mucoadhesive polymer to the cationic biologically active compound is from 3:1 to 8:1.

[0025] In one embodiment of the present invention, the cationic biologically active compound comprises an amine functional group.

[0026] In one embodiment of the present invention, the cationic biologically active compound is nicotine.

[0027] In certain other embodiments of the present invention, the cationic biologically active compound is selected from the group consisting of bisphosphonates, captopril, furosemide, metformin, gabapentin, levodopa, baclofen, ciprofloxacin, tannins, prochlorperazine, tramadol, salbutamol, furosemide, piribedil, irinotecan, zolmitriptan, clonidine, amphotericin B, cetylpyridinium, ritodrine, pregabalin, and zaleplon.

[0028] The most preferred cationic biologically active compounds of the present invention are selected from the group consisting of metformin, salbutamol, and cetylpyridinium. In one embodiment of the present invention, the cationic biologically active compound is metformin. In one embodiment of the present invention, the cationic biologically active compound is salbutamol. In one embodiment of the present invention, the cationic biologically active compound is cetylpyridinium.

[0029] In one embodiment of the present invention, the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer has an average particle diameter of between 10 and 2000 microns.

[0030] In one embodiment of the present invention, the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer has an average particle diameter of between 10 and 1000 microns.

[0031] In one embodiment of the present invention, the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer has an average particle diameter of between 20 and 500 microns.

[0032] In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 10-800 microns. In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 10-700 microns. In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 10-600 microns. In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 10-500 microns. In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 20-400 microns. In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 20-400 microns. In certain other embodiments of the present invention, the average particle diameter of the plurality of particles of at least one water-soluble anionic mucoadhesive polymer is 30-400 microns. In certain other embodiments of the invention, the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer has an average particle diameter of 40-400 microns. In certain other embodiments of the invention, the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer has an average particle diameter of 50-400 microns. In certain other embodiments of the invention, the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer has an average particle diameter of 50-300 microns.

[0033] In one embodiment of the present invention, the ion exchange composition comprises a buffering agent.

[0034] In one embodiment of the present invention, the ion exchange composition comprises a buffer selected from the group consisting of a tri(hydroxymethyl)aminomethane buffer, a phosphate buffer, a carbonate buffer, and combinations thereof.

[0035] In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer is weakly acidic.

[0036] In one embodiment of the present invention, at least one water-soluble anionic mucoadhesive polymer comprises a carboxylic acid functional group.

[0037] In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer is selected from sulfonated polysaccharides, and / or anionic polysaccharides, and / or polyacrylic acids.

[0038] In one embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethylcellulose, and combinations thereof. In one embodiment of the invention, the at least one water-soluble anionic mucoadhesive polymer is xanthan gum.

[0039] In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 80 kDa.

[0040] In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 50 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 75 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 100 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 150 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 200 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of at least 250 kDa.

[0041] In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 80 to 3500 kDa.

[0042] In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 80 to 600 kDa.

[0043] In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 50 to 700 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 100 to 600 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 150 to 700 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 200 to 600 kDa. In certain other embodiments of the invention, at least one water-soluble anionic mucoadhesive polymer comprises a molecular weight (mw) of 250 to 500 kDa.

[0044] In one embodiment of the present invention, the oral tablet disintegrates in a maximum of 2 minutes upon contact with saliva.

[0045] In one embodiment of the present invention, the oral tablet disintegrates in up to 1 minute upon contact with saliva.

[0046] In one embodiment of the present invention, the oral tablet disintegrates in up to 30 seconds upon contact with saliva.

[0047] In certain other embodiments of the present invention, the oral tablet disintegrates in contact with saliva in up to 90 seconds. In certain other embodiments of the present invention, the oral tablet disintegrates in contact with saliva in up to 75 seconds. In certain other embodiments of the present invention, the oral tablet disintegrates in contact with saliva in up to 45 seconds. In certain other embodiments of the present invention, the oral tablet disintegrates in contact with saliva in up to 20 seconds. In certain other embodiments of the present invention, the oral tablet disintegrates in contact with saliva in up to 10 seconds.

[0048] In one embodiment of the invention, the oral tablet is an orally disintegrating tablet (ODT). In one embodiment of the invention, the oral tablet is a rapidly disintegrating tablet (ODT).

[0049] In one embodiment of the present invention, the oral tablet is a chewable tablet, which should be chewed when administered orally.

[0050] In one embodiment of the present invention, the oral tablet comprises the ion exchange composition in an amount of 0.1 to 25% by weight of the tablet. In one embodiment of the present invention, the oral tablet comprises the ion exchange composition in an amount of 0.5 to 25% by weight of the tablet. In one embodiment of the present invention, the oral tablet comprises the ion exchange composition in an amount of 1 to 25% by weight of the tablet. In one embodiment of the present invention, the oral tablet comprises the ion exchange composition in an amount of 1 to 20% by weight of the tablet. In one embodiment of the present invention, the oral tablet comprises the ion exchange composition in an amount of 5 to 25% by weight of the tablet. In one embodiment of the present invention, the oral tablet comprises the ion exchange composition in an amount of 5 to 20% by weight of the tablet.

[0051] In one embodiment of the present invention, the oral tablet comprises a buffering agent in an amount of 1-5% by weight of the tablet.

[0052] In one embodiment of the present invention, the oral tablet comprises a buffer selected from the group consisting of a tri(hydroxymethyl)aminomethane buffer, a phosphate buffer, a carbonate buffer, and combinations thereof.

[0053] In one embodiment of the present invention, the oral tablet contains nicotine in an amount of 0.5 to 8.0 mg.

[0054] In one embodiment of the present invention, the oral tablet contains nicotine in an amount of 1.0 to 4.0 mg. In one embodiment of the present invention, the oral tablet contains nicotine in an amount of 1.0 to 3.0 mg. In one embodiment of the present invention, the oral tablet contains nicotine in an amount of 2.0 to 4.0 mg.

[0055] In one embodiment of the present invention, the oral tablet comprises one or more sugar alcohol particles in an amount of at least 40% by weight of the tablet.

[0056] In one embodiment of the present invention, the oral tablet comprises one or more sugar alcohol particles in an amount of at least 60% by weight of the tablet.

[0057] In one embodiment of the present invention, the one or more sugar alcohol particles comprise a sugar alcohol selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof.

[0058] In one embodiment of the present invention, the one or more sugar alcohol particles include directly compressible (DC) and non-directly compressible (non-DC) sugar alcohol particles.

[0059] In one embodiment of the present invention, the one or more sugar alcohol particles comprise non-DC sugar alcohol particles in an amount of at least 30% by weight of the tablet.

[0060] In one embodiment of the present invention, the one or more sugar alcohol particles comprise non-DC sugar alcohol particles selected from non-DC particles of erythritol, maltitol, xylitol, isomalt, and combinations thereof.

[0061] In one embodiment of the present invention, the one or more sugar alcohol particles comprise at least 20% by weight of non-DC sugar alcohol particles having a particle size greater than 500 μm.

[0062] In one embodiment of the present invention, the one or more sugar alcohol particles comprise DC sugar alcohol particles in an amount of at least 30% by weight of the tablet.

[0063] In one embodiment of the present invention, the one or more sugar alcohol particles comprise directly compressible (DC) and non-directly compressible (non-DC) sugar alcohol particles present in the tablet in a mass ratio of non-DC sugar alcohol particles to DC sugar alcohol particles of 0.2 and 1.2.

[0064] In one embodiment of the invention, one or more sugar alcohol particles are tableted into a first unit and combined with a second population of particles tableted into a second unit, the second unit having a different composition than the first unit.

[0065] In one embodiment of the invention, one or more sugar alcohol particles are tableted into a first unit and combined with a second population of particles tableted into a second unit, the first unit comprising an ion exchange composition.

[0066] In one embodiment of the invention, one or more sugar alcohol particles are tableted into a first unit and combined with a second population of particles tableted into a second unit, the second unit comprising a gum base.

[0067] In one embodiment of the present invention, the oral tablet further comprises a disintegrant.

[0068] In one embodiment of the present invention, the oral tablet further comprises a disintegrant in an amount of 1 to 10% by weight of the tablet.

[0069] In one embodiment of the present invention, the oral tablet further comprises the disintegrant cross-linked polyvinylpyrrolidone.

[0070] In one embodiment of the present invention, the ion exchange composition, when hydrated with saliva, forms a gel upon contact with the oral mucosa.

[0071] In certain other aspects of the present invention, there is provided an ion exchange composition for oral mucosal delivery of a biologically active compound, the composition comprising a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound.

[0072] In one embodiment of this aspect, the ion exchange composition is a powder.

[0073] In one embodiment of this aspect, the ion exchange composition is contained in a tablet.

[0074] In one embodiment of this aspect, the ion exchange composition is contained in a pouch.

[0075] In one embodiment of this aspect, the ion-exchange composition is made by providing a water slurry of at least one water-soluble anionic mucoadhesive polymer, adding nicotine and optionally a buffering agent, and evaporating water from the slurry to obtain a final water content of less than 10% by weight of the composition.

[0076] In one embodiment of this aspect, the ion-exchange composition is made by providing an aqueous dispersion of at least one water-soluble anionic mucoadhesive polymer, adding nicotine and optionally a buffering agent, and precipitating the composition from the dispersion using an appropriate agent to obtain a final water content of less than 10% by weight of the composition.

[0077] In one embodiment of this aspect, the ion exchange composition is prepared using deionized water. In certain embodiments, divalent cations may be present in non-deionized water, which may result in undesirable cross-linking according to the present invention. In certain other embodiments, monovalent cations may be present in non-deionized water, which may result in undesirable ion exchange competition with biologically active compounds. Thus, if the ion exchange complex is saturated with monovalent cations, such as sodium ions, this may adversely affect the properties of the ion exchange resin, such as loading characteristics, stability, and release function, even before nicotine is introduced during production. For example, such adverse effects may occur when nicotine is loaded into sodium alginate.

[0078] In one embodiment of this aspect, the ion exchange composition is configured according to the tablet embodiment.

[0079] In certain other aspects of the present invention, there is provided an ion exchange composition for oral mucosal delivery of nicotine, the composition comprising a plurality of particles of at least one polacrilex resin loaded with nicotine, the polacrilex resin being at least partially coated with at least one water-soluble anionic mucoadhesive polymer.

[0080] In one embodiment of this aspect, the at least one water-soluble anionic mucoadhesive polymer is configured according to the tablet embodiment.

[0081] In certain other aspects of the present invention, there is provided a method for oral mucosal delivery of a biologically active compound, the method comprising the steps of: i) providing an oral formulation comprising an ion exchange composition comprising a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound; ii) disintegrating the oral formulation on contact with saliva without substantially hydrating the polymer particles; iii) contacting at least a portion of the polymer particles with the oral mucosa; iv) hydrating the polymer particles with saliva to form a gel on contact with the oral mucosa; and v) delivering the biologically active compound from the polymer particles to the oral mucosa.

[0082] In one embodiment of this aspect, the ion exchange composition is configured according to the tablet embodiment. [Brief explanation of the drawings]

[0083] [Figure 1] Figure 1 shows the properties of particles of a water-soluble anionic mucoadhesive polymer according to the invention. Two series of experiments were carried out in which particles of a water-soluble anionic mucoadhesive polymer were added to a Petri dish containing 1 ml of purified water. In experiment G (IPA), powder according to Example 3 was applied. In experiment G, powder according to Example 1 was applied. Photographs were taken initially (T0), after 5 minutes (T-5 min), and after 10 minutes (T-10 min), after which additional water was added. The powder settled in the water and was seen as a distinct blue area at the bottom of the Petri dish. [Figure 2] 1 is a diagram of adhesion to the oral mucosa according to the present invention. A tablet prepared according to Example 14-4 was administered to a subject, and the ion exchange composition was exchanged with the particles of Example 1, which have a blue color. After 5 minutes, the subject was monitored for color development. DETAILED DESCRIPTION OF THE INVENTION

[0084] Accordingly, the present invention provides an oral tablet for oral mucosal delivery of a biologically active compound, the tablet comprising: a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet; and an ion exchange composition comprising a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound.

[0085] As used herein, the term "oral tablet" refers to a tablet for oral use. In particular, oral tablets are considered to be formed by tableting, i.e., by compressing a particulate composition. Typically, oral tablets can also be referred to as tablets.

[0086] The term "mass of an oral tablet" or similar phrases meaning the same is defined in the present context as the mass of an oral tablet not including the mass of any outer coating, such as a hard coating, a soft coating, etc.

[0087] As used herein, the terms "%" and "percent" refer to percent by weight unless otherwise specified.

[0088] As used herein, the term molecular weight or Mw(mw) is intended to mean weight average molecular weight.

[0089] The terms "sustained release" or "extended release," as used herein, are intended to mean a sustained release over time. The terms "fast release" or "rapid release" or "high release," as used herein, are intended to mean a relatively high content released in a given period of time. The term "controlled release" is intended to mean the release of a substance from an oral tablet by utilizing active use of the oral tablet in the oral cavity of a subject, thereby controlling the amount of substance released by this active use.

[0090] The verb "comprise" as used in this specification and claims, and variations thereof, is used in its open-ended sense, meaning that items following the word are included, but items not specifically mentioned are not excluded. Furthermore, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one element is present, unless the context clearly requires that there be only one. Thus, the indefinite article "a" or "an" usually means "at least one." Furthermore, the words "a" and "an" used in connection with the words include or contain in this document indicate "one or more." The expression "one or more" is intended to mean one, two, three or more.

[0091] In this context, the term "mucoadhesion" or simply "adhesion" is used to describe when two surfaces, one of which is mucus or a mucous membrane and the other of which is typically the surface of a drug delivery system, are held together over an extended period of time by interfacial forces.

[0092] "Ion exchange" refers to a complex (loose association) formed between a biologically active compound and a polymer according to the present invention, a complex formed between functional groups of a biologically active compound (e.g., amines and pyridines) and functional groups of a polymer according to the present invention (e.g., sulfates, alcohols, carboxylates, etc.), and a non-covalent bond (e.g., ionic interactions and hydrogen bonds) formed between a biologically active compound and a polymer according to the present invention. Complex formation between a biologically active compound and a polymer according to the present invention can be affected by the environment (e.g., pH, solvent, concentration, and temperature).

[0093] The phrase "a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound" or similar phrases refers to individual particles "of" at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound. In this context, the term "of" indicates that the particle consists essentially of at least one water-soluble anionic mucoadhesive polymer loaded with a cationic biologically active compound. Thus, this phrase is not intended to include component "gels" or similar forms that would not be considered particles, but is specifically intended to include component "particles." In particular, gels that have been lyophilized or similarly processed into a solid form are not considered to be particles according to the present invention.

[0094] The term "non-DC sugar alcohol particles" refers to particles of non-directly compressible (non-DC) sugar alcohols. Note that the terms "non-DC sugar alcohol particles" and "non-DC particles" are used interchangeably. In this context, non-DC sugar alcohol particles refer to particles that have not been pre-treated by granulation with other sugar alcohols or binders, etc., for the purpose of obtaining so-called directly compressible particles (DC). In this context, non-DC sugar alcohol particles include particles obtained by crystallization followed by grinding without other sugar alcohols or binders. Therefore, non-DC sugar alcohol particles are considered to be particles made of non-DC sugar alcohols.

[0095] In this context, the term "non-DC region" refers to a small volume or space formed during tableting from non-DC particles of a non-DC sugar alcohol. Furthermore, each non-DC region may be composed of a single non-DC sugar alcohol particle or may contain several non-DC sugar alcohol particles. When the non-DC regions are discrete, i.e., not dispersed, they may be uniformly dispersed throughout the tablet, or, if the tablet contains two or more units, may be uniformly dispersed throughout at least one of the units. Thus, in such embodiments in which the non-DC regions are uniformly distributed throughout the tablet or at least one of its units, the non-DC regions may promote uniform saliva production in the mouth during chewing.

[0096] The term "DC sugar alcohol particles" refers to particles of a directly compressible (DC) sugar alcohol. It should be noted that the terms "DC sugar alcohol particles" and "DC particles" are used interchangeably. DC sugar alcohol particles can be obtained, for example, as particles of a sugar alcohol that originally has a DC grade, such as sorbitol, or can be obtained by granulating a non-DC sugar alcohol with other sugar alcohols or binders, etc., for the purpose of obtaining so-called directly compressible particles (DC). Granulation of a non-DC sugar alcohol with water as a binder is also considered to result in "DC sugar alcohol particles" in this context.

[0097] As used herein, the term "orally disintegrating tablet" or "ODT" is intended to mean a tablet as understood by one skilled in the art of ODT tablets, i.e., a solid dosage form that disintegrates rapidly (within seconds) without water when placed on the tongue.

[0098] As used herein, the term "fast disintegrating tablet" or "FDT" is intended to mean a tablet as understood by one skilled in the art of FDT tablets, i.e., a solid dosage form that disintegrates rapidly (within seconds) without water when placed on the tongue.

[0099] As used herein, the term "disintegrate" refers to the reduction of an object into elements, fragments, or particles. Disintegration time is measured in vitro. In vitro measurements are performed in accordance with European Pharmacopoeia 9.0, section 2.9.1 Disintegration of tablets and capsules.

[0100] As used herein, the term "dissolving" refers to the process by which a solid substance enters a solvent (oral saliva) to form a solution. Unless otherwise specified, dissolution encompasses complete dissolution of the compound in question.

[0101] As used herein, the term "disintegrant" refers to a component that promotes the disintegration of an orally disintegrating tablet when it comes into contact with saliva.Disintegrants that can be used within the scope of the present invention include starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate, and starch derivatives), cellulose, microcrystalline cellulose, alginates, ion exchange resins, and superdisintegrants, such as cross-linked cellulose (such as sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural superdisintegrants, and calcium silicate.Disintegrants can often be considered a means of promoting the breakdown of a dosage form into smaller pieces upon administration, allowing the drug to begin dissolving and ultimately absorbing.

[0102] As used herein, the term "pH adjusting agent" refers to an agent that actively adjusts and regulates the pH value of a solution to which it is added or to which it is to be added. Thus, pH adjusting agents can be acids and bases, including acidic buffers and alkaline buffers. On the other hand, pH adjusting agents do not include substances and compositions that can affect pH only through dilution. Furthermore, pH adjusting agents do not include, for example, flavorings, fillers, etc.

[0103] As used herein, the term "buffering agent" is used interchangeably with "buffer" and refers to an agent for obtaining a buffer solution. Buffering agents include acidic buffering agents, i.e., those for obtaining a buffer solution at an acidic pH, and alkaline buffering agents, i.e., those for obtaining a buffer solution at an alkaline pH.

[0104] When referring to the induction of saliva production, saliva production is tested using the following method unless otherwise specified: The subject refrains from eating or drinking at least 30 minutes before the start of the test. The subject swallows immediately before introducing the tablet into the oral cavity. The subject refrains from swallowing during the test. Immediately after introducing the tablet into the oral cavity, the subject begins chewing the tablet at a frequency of one chew per second for 20 seconds. The saliva and tablet remains are then held in the mouth for 10 seconds while chewing. 30 seconds after the start of the test, the subject discards the saliva, including tablet fragments, into a plastic cup, which is weighed. Saliva is also discarded 90 seconds, 180 seconds, 300 seconds, 420 seconds, and 600 seconds after the start of chewing. At all times, subjects should move as little as possible and refrain from swallowing.

[0105] As used herein, the term "particle size" refers to the mean particle size as determined in accordance with European Pharmacopoeia 9.1 when using test method 2.9.38 Particle size distribution estimation by sieving analysis, unless otherwise specifically stated.

[0106] The term "particle" or similar phrase is intended to indicate a single, discrete composition of solid matter, such as a granule or individual element in a powder, having a particular size that can deviate considerably.

[0107] As used herein, the term "biologically active ingredient" or simply "active ingredient" refers to a substance that is biologically active and has a physiological effect on the human body for the benefit of the human body or a portion thereof. Active ingredients include not only active pharmaceutical ingredients but also other active ingredients such as nutraceuticals.

[0108] The term "release" in this context is intended to mean tested under "in vivo" conditions, unless otherwise specified. In this context, if the tablet is chewed, "in vivo" conditions are intended to mean that the sample is chewed at a chewing frequency of 60 chews per minute for a specified period of time in a test panel of eight testers, unless otherwise specified. These testers refrain from eating or drinking for at least 30 minutes before the start of the test. The testers are healthy individuals objectively selected according to specific requirements.

[0109] The terms "water-insoluble gum base" or "gum base" or "gum base matrix" or similar phrases refer primarily to the water-insoluble and hydrophobic components of the gum base. A "gum base" may include gum base polymers, as well as plasticizers, waxes, emulsifiers, fats, and / or fillers.

[0110] As used herein, the term "nicotine" refers to any form of nicotine, including free base nicotine, nicotine salts, nicotine bound to ion exchange resins, nicotine bound to zeolites; nicotine bound to cellulose, e.g., microcrystalline cellulose or starch microspheres such as those of microbial origin, nicotine bound to CaCO3, and mixtures thereof. Thus, when referring to the amount of nicotine, these amounts refer to the amount of pure nicotine. Therefore, when measuring the concentration of nicotine added as a nicotine salt, it is the mass of the corresponding amount of pure nicotine that is relevant, not the mass of the salt.

[0111] As used herein, the term "nicotine salt" refers to the ionized form of nicotine electrostatically bound to a counterion.

[0112] In one embodiment of the invention, the nicotine salt is selected from nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine bitartrate, nicotine chloride (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, nicotine gensitate, nicotine lactate, nicotine mucate, nicotine laurate, nicotine levulinate, nicotine malate, nicotine perchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate, nicotine succinate, nicotine zinc chloride, nicotine sulfate, nicotine tosylate, and hydrates thereof (e.g., nicotine zinc chloride monohydrate).

[0113] In one embodiment of the present invention, the nicotine salt comprises nicotine bitartrate. In this context, nicotine bitartrate includes its hydrate. According to one embodiment of the present invention, the nicotine salt is a water-soluble nicotine salt. In this context, the term "water-soluble salt" is understood to be a salt having a solubility in water of at least 10 g salt per 100 mL of water under standard laboratory conditions, including a temperature of 25 degrees Celsius, atmospheric pressure, and pH 7. It should also be understood that when nicotine comprises a nicotine salt, optionally in combination with other forms of nicotine, the nicotine salt may consist of only one nicotine salt or may be a combination of two or more nicotine salts. In an embodiment of the present invention, nicotine is provided as free nicotine base.

[0114] As used herein, the term "nicotine release" refers to nicotine that has been made bioavailable, i.e., made available for absorption through the mucous membranes in the oral cavity. Some forms of nicotine require dissolution to be bioavailable, while other forms can be readily absorbed by the body without dissolution.

[0115] As used herein, the term "NBT" refers to nicotine bitartrate and its hydrates.

[0116] Nicotine (NCT) is the primary alkaloid found in tobacco and is responsible for its addictive potential. NCT can be found in its free base form as a liquid, or as an ionic complex in the form of a salt with counterions such as chloride (Cl-) or sulfate (HSO4-).

[0117] Prolonged oral residence time of NCT means that nicotine is present in the oral cavity for a longer period than that observed for a formulation not comprising a mucoadhesive nicotine complex formulation according to the present invention. Furthermore, prolonged oral residence time of NCT may also mean that the entire amount of nicotine is not washed away from the oral mucosa within the first 2 minutes, or within the first 5 minutes, or within the first 10 minutes. According to the present invention, NCT may be present in the buccal cavity in an amount of 20%, for example 30%, for example 40%, for example 50%, for example 60%, for example 70%, for example 80%, for example 90% for 10 minutes or more. According to the present invention, NCT may be present in the buccal cavity in an amount of 20%, for example 30%, for example 40%, for example 50%, for example 60%, for example 70%, for example 80%, for example 85% for 20 minutes or more.

[0118] Contrary to expectations, experiments have shown that increasing the nicotine concentration results in a relatively small decrease in nicotine permeability across the buccal mucosa. For example, experiments have shown that increasing the nicotine concentration from 100 micrograms / mL to 14,000 micrograms / mL results in an approximately two-fold decrease. This is highly surprising and is exploited by aiming for much higher nicotine concentrations in the oral cavity than have previously been seen or desired. Thus, the present delivery vehicle benefits from and aims for a very high nicotine content in the oral cavity, thereby increasing nicotine absorption. Therefore, it is further recognized that the effect of nicotine concentration is at least equivalent to the effect of pH regulation in the oral cavity. This is contrary to expectations.

[0119] In one embodiment of the present invention, the oral tablet comprises nicotine and a pH adjusting agent, the formulation is designed to release its nicotine content within a 90 second period upon contact with oral saliva, the formulation is designed to release its pH adjusting agent content within a 60 second period upon contact with oral saliva, the formulation comprises nicotine in an amount of at least 0.5 mg, for example, nicotine in an amount of 0.5 mg to 8 mg, and the nicotine is provided as a nicotine salt, the nicotine salt being nicotine ascorbate, nicotine aspartate, nicotine benzoate, or the like. The nicotine monotartrate, nicotine bitartrate, nicotine chloride (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, nicotine germinate, nicotine lactate, nicotine mucate, nicotine laurate, nicotine levulinate, nicotine malate, nicotine perchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate, nicotine succinate, nicotine zinc chloride, nicotine sulfate, nicotine tosylate, and hydrates thereof (e.g., nicotine zinc chloride monohydrate).

[0120] This achievement was surprising to the inventors, as typical conventional products and conventional wisdom seek to slow the breakdown of nicotine and retard its dissolution.

[0121] The water-soluble anionic polymers used in the present invention can be either synthetic or natural. Water-soluble anionic polymers can be classified as linear, branched, cross-linked, or network polymers. Preferably, the polymers are not cross-linked. At least one mucoadhesive water-soluble anionic polymer can be a linear polymer. At least one mucoadhesive water-soluble anionic polymer can be a branched polymer. At least one mucoadhesive water-soluble anionic polymer can be a cross-linked polyacrylic acid polymer. At least one mucoadhesive water-soluble anionic polymer can be selected from sulfated polysaccharides and / or anionic polysaccharides. The polysaccharides can be polymers of monosaccharides that can be derived from plants, from seaweed extracts (e.g., carrageenan), or from microorganisms (e.g., xanthan gum). The polysaccharides can be anionic (charged) and / or sulfated.

[0122] In one embodiment, the formulation comprises a combination of at least one mucoadhesive water-soluble anionic polymer.

[0123] In one embodiment, the formulation comprises a combination of at least one xanthan gum and at least one carrageenan. In one embodiment, the formulation comprises a combination of at least one xanthan gum and at least one carbomer. In one embodiment, the formulation comprises a combination of at least one carrageenan and at least one carbomer.

[0124] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises at least two water-soluble anionic mucoadhesive polymers.

[0125] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises at least two water-soluble anionic mucoadhesive polymers selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethylcellulose, and combinations thereof.

[0126] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises at least two water-soluble anionic mucoadhesive polymers in a weight ratio of 1:1 to 1:4.

[0127] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises xanthan gum and carrageenan in a weight ratio of 1:1 to 1:4.

[0128] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises at least two water-soluble anionic mucoadhesive polymers in a weight ratio of 1:1 to 1:2.

[0129] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises xanthan gum and carrageenan in a weight ratio of 1:1 to 1:2.

[0130] In one embodiment, the at least one water-soluble anionic mucoadhesive polymer comprises at least three water-soluble anionic mucoadhesive polymers.

[0131] One of the advantages of combining more than one anionic mucoadhesive polymer according to the present invention is that the duration of mucoadhesion with the oral mucosa may be significantly increased. Without being bound by theory, it is believed that nicotine absorption at the oral mucosa may consequently be significantly increased in this embodiment.

[0132] Carrageenans are a family of linear sulfated polysaccharides. They are used for their gelling, thickening, and stabilizing properties. There are three main types of carrageenans, which differ in their degree of sulfate: kappa carrageenan has one sulfate group per disaccharide, iota carrageenan has two, and lambda carrageenan has three. Gelcarin is a carrageenan, a linear polymer.

[0133] Gelcarin® GP 379 NF is an iota-carrageenan that can be used for gelling, thickening, and stabilizing applications.

[0134] Xanthan gum is a polysaccharide used as a thickening additive. It is composed of repeating pentasaccharide units containing glucose, mannose, and glucuronic acid. Xanthan gum is a branched polymer.

[0135] XANTURAL® 180 is an 80 mesh (180 μm) xanthan gum product suitable for use as a pharmaceutical excipient. It prevents phase separation in suspensions and emulsions, ensuring that the products remain free-flowing throughout their shelf life. XANTURAL® 180 is typically used in oral suspensions and syrups.

[0136] Carbomer is a high molecular weight cross-linked polyacrylic acid polymer, which is sold, for example, under the trademark Carbopol®. Carbopol is a carbomer.

[0137] The ion exchange composition or oral formulation may further comprise at least one preservative. The at least one preservative may be selected from an alcohol, such as a monoalcohol, a diol, or a polyalcohol. In one embodiment, the at least one preservative is an alcohol selected from ethanol or propylene glycol. The at least one preservative may be chlorhexidine.

[0138] In one embodiment, a buffer can be added to the ion exchange composition or oral formulation to adjust the pH. The buffer can help promote nicotine absorption. The buffer can be selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate, potassium citrate, and dipotassium phosphate, or a mixture thereof.

[0139] In one embodiment of the invention, the formulation comprises nicotine that is not complexed with at least one mucoadhesive water-soluble anionic polymer.

[0140] In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer is carrageenan. In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer is carbomer. In one embodiment of the present invention, the at least one water-soluble anionic mucoadhesive polymer is carboxymethylcellulose.

[0141] In one embodiment of the invention, the mucoadhesive oromucosal formulation according to the invention may be administered to a human subject up to 80 times per day, such as up to 70 times per day, such as up to 60 times per day, for example up to 50 times per day, hi one embodiment, the mucoadhesive oromucosal formulation may be administered up to 6 times per hour.

[0142] In one embodiment of the invention, the formulation further comprises a disintegrant.

[0143] In one embodiment of the present invention, the disintegrant is selected from starch, pregelatinized starch, modified starch (including potato starch, corn starch, starch 1500, sodium starch glycolate, and starch derivatives), cellulose, microcrystalline cellulose, alginates, ion exchange resins, and superdisintegrants such as cross-linked cellulose (such as sodium carboxymethylcellulose), cross-linked polyvinylpyrrolidone (PVP), cross-linked starch, cross-linked alginic acid, natural superdisintegrants, and calcium silicate, and combinations thereof.

[0144] One advantage of the above embodiment may be that the disintegrant facilitates the disintegration and dissolution of the formulation, thereby achieving release of the nicotine and pH controlling agent.

[0145] In the present context, use in the relief of nicotine cravings should be understood to involve oral administration of orally disintegrating nicotine tablets.

[0146] In one embodiment of the present invention, the oral tablet comprises non-directly compressible (non-DC) sugar alcohol particles, which preferably provide the tablet with a plurality of distinct non-DC regions.

[0147] In this context, non-DC sugar alcohol particles are understood and defined by those skilled in the art in relation to their typical commercial grades. In one embodiment of the present invention, the non-DC sugar alcohol particles are not granulated prior to tableting. Thus, the non-DC sugar alcohol particles are provided as non-granulated particles.

[0148] These are typically available in non-DC forms of the relevant sugar alcohols, i.e., particles that have not been pre-treated by granulation with other sugar alcohols or binders to obtain so-called directly compressible particles (DC) based on sugar alcohol particles that are not suitable for direct compression by themselves. Such non-DC particles of sugar alcohols typically consist of sugar alcohols. Thus, non-DC sugar alcohol particles typically consist of particles of non-directly compressible sugar alcohols in their pure form. Examples of sugar alcohols that are non-directly compressible when provided as particles of the sugar alcohol in question include erythritol, xylitol, maltitol, mannitol, lactitol, isomalt, etc. Therefore, preferred non-DC grade sugar alcohols can include pure sugar alcohol particles.

[0149] In one embodiment of the present invention, the oral tablet comprises at least two units, where one or more sugar alcohol particles are tableted into a first unit and combined with a second population of particles tableted into a second unit, the second unit having a different composition from the first unit.

[0150] In one embodiment of the present invention, the oral tablet comprises at least two units, where one or more sugar alcohol particles are tableted into a first unit and combined with a second population of particles tableted into a second unit, the first unit comprising an ion exchange composition.

[0151] In this context, "tabletted into" should be understood to also allow other ingredients to be part of the tableted unit, and thus the unit may contain further ingredients apart from the one or more sugar alcohol particles.

[0152] In one embodiment of the present invention, the oral tablet comprises at least two units, one or more sugar alcohol particles including directly compressible (DC) and non-directly compressible (non-DC) sugar alcohol particles, which are tableted into a first unit and combined with a second particle population tableted into a second unit, the second unit having a different composition from the first unit.

[0153] In one embodiment of the present invention, the oral tablet comprises at least two units, one or more sugar alcohol particles comprising directly compressible (DC) and non-directly compressible (non-DC) sugar alcohol particles, which are tableted into a first unit and combined with a second particle population tableted into a second unit, the first unit comprising an ion exchange composition.

[0154] One advantage of the previous embodiment may be that the second unit may have higher mechanical strength due to a different composition, such as including a significantly higher amount of a directly compressible component, such as a DC sugar alcohol.

[0155] A further advantage of the previous embodiment may be that the second unit has a higher loading capacity for, for example, an active ingredient, due in part to the resulting higher mechanical strength achievable with a large amount of directly compressible ingredient, such as a DC sugar alcohol.

[0156] Thus, in the previous embodiment, the particle population is tableted into a first unit, and the tablet further comprises a second particle population tableted into a second unit. The first unit may be tableted before the second unit, or vice versa. In some embodiments, the tablet may comprise one or more additional units.

[0157] In one embodiment of the present invention, the oral tablet comprises at least two units. A tablet comprising two or more units will have a unit size that is equivalent to the volume of a complete tablet. In this context, equivalent means that the unit is not understood as a small particle, and the unit should be at least larger than 1 / 20 of the volume of a complete tablet, preferably larger than 1 / 10 of the volume of a complete tablet.

[0158] In this context, a building block is intended to mean a plurality of particles that are compressed together to form a cluster of particles.

[0159] In one embodiment of the present invention, the oral tablet comprises multiple oral tablet units. In this context, the application of, for example, two units is particularly advantageous, since the use of a non-DC sugar alcohol can inherently result in a more brittle tablet, or at least in a unit with a non-DC sugar alcohol. In other words, the non-DC sugar alcohol can be present primarily in one unit, thereby optimizing the desired salivation and sensory experience from the unit and the tablet itself, while another unit can function as an auxiliary to ensure the desired stability and friability of the complete tablet.

[0160] According to one embodiment of the present invention, the tablet has two units. Optionally, a coating can be applied around the two units to form the final tablet.

[0161] It should be noted that while the advantages of using two building blocks are as described above, this effect can also be achieved when applying layers of very different nature. Such applications can include, for example, the use of a gum building block and a non-gum building block, where the non-gum building block contains non-DC sugar alcohol particles. In this way, the non-gum layer can release the advantageous non-DC sugar alcohol, and the gum layer can stabilize the tablet as described above and interact with the non-DC sugar alcohol, especially during the initial release, to establish a very pleasant and impressive initial chewing phase. This includes an increase in saliva and a sense of moisture.

[0162] In one embodiment of the present invention, the oral tablet comprises at least two units, where one or more sugar alcohol particles are tableted into a first unit and combined with a second population of particles tableted into a second unit, the second unit comprising a gum base.

[0163] In one embodiment of the present invention, the oral tablet comprises at least two units, one or more sugar alcohol particles comprising directly compressible (DC) and non-directly compressible (non-DC) sugar alcohol particles, which are tableted into a first unit and combined with a second population of particles tableted into a second unit, the second unit comprising a gum base.

[0164] In one embodiment of the invention, the particle population is tableted into a first unit and combined with a second particle population tableted into a second unit, the second unit not including non-DC sugar alcohol particles.

[0165] In one embodiment, the second particle population comprises a large amount of DC sugar alcohol, e.g., a larger amount than the first particle population. For example, the second particle population may comprise at least 30% by weight of DC sugar alcohol, e.g., at least 50% by weight of DC sugar alcohol, e.g., at least 70% by weight of sugar alcohol. In an exemplary embodiment, the second particle population may comprise 50-99.9% by weight of sugar alcohol, e.g., 70-99% by weight of sugar alcohol. The amount of DC sugar alcohol may depend on the type and amount of active ingredient applied to the tablet.

[0166] In one embodiment of the invention, the population of particles is tableted into a first unit and combined with a second population of particles tableted into a second unit, the second unit being an orally disintegrating tablet (ODT).

[0167] In one embodiment of the present invention, the tablet is a chewable tablet.

[0168] In one embodiment of the present invention, at least 20% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 μm. In one embodiment of the present invention, at least 30% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 μm. In one embodiment of the present invention, at least 40% by weight of the non-DC sugar alcohol particles have a particle size greater than 500 μm.

[0169] What was surprising to the inventors was that, according to the present invention, larger non-DC sugar alcohol particles were found to be particularly beneficial. In particular, larger non-DC sugar alcohol particles were found to induce saliva production, e.g., to produce a greater total mass of saliva, compared to smaller non-DC particles. Also, the perceived watering effect may be increased compared to smaller non-DC particles. These findings were not anticipated by the inventors.

[0170] In one embodiment of the present invention, the non-DC sugar alcohol particles are non-DC erythritol particles. In one embodiment of the present invention, the non-DC sugar alcohol particles are non-DC xylitol particles. In one embodiment of the present invention, the non-DC sugar alcohol particles are non-DC isomalt particles.

[0171] In one embodiment of the present invention, the tablet comprises non-DC sugar alcohol particles in an amount of at least 10% by weight of the tablet. In one embodiment of the present invention, the tablet comprises non-DC sugar alcohol particles in an amount of at least 20% by weight of the tablet. In one embodiment of the present invention, the tablet comprises non-DC sugar alcohol particles in an amount of at least 30% by weight of the tablet. In one embodiment of the present invention, the first constituent unit comprises non-DC sugar alcohol particles in an amount of at least 30% by weight of the first constituent unit. In one embodiment of the present invention, the first constituent unit comprises non-DC sugar alcohol particles in an amount of at least 40% by weight of the first constituent unit.

[0172] In one embodiment of the present invention, the DC sugar alcohol particles comprise a sugar alcohol selected from DC particles of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof. Sorbitol is an example of a sugar alcohol that is considered DC grade when provided as particles composed of sorbitol, i.e., in pure form. On the other hand, some other sugar alcohols are considered non-DC grade when provided as particles composed of that particular sugar alcohol. Therefore, such non-DC sugar alcohols are conventionally processed into DC grade sugar alcohols by, for example, granulating them with a binder. Examples of commercial grades of DC sugar alcohols include sorbitol particles, e.g., as Neosorb® P 300 DC from Rockete; mannitol particles, e.g., as Pearlitol® 300 DC or Pearlitol 200 SD from Rockete; maltitol, e.g., as SweetPearl® P 300 DC; and xylitol, e.g., as Xylisorb® 200 DC or Xylitab 200 from DuPont.

[0173] In one embodiment of the present invention, the tablet comprises DC sugar alcohol particles in an amount of at least 10% by weight of the tablet. In one embodiment of the present invention, the tablet comprises DC sugar alcohol particles in an amount of at least 20% by weight of the tablet. In one embodiment of the present invention, the tablet comprises DC sugar alcohol particles in an amount of at least 30% by weight of the tablet. According to one embodiment of the present invention, the particle population comprises DC sugar alcohol particles in an amount of at least 10% by weight. According to one embodiment of the present invention, the first constituent units comprise DC sugar alcohol particles in an amount of at least 10% by weight of the first constituent units. According to one embodiment of the present invention, the first constituent units comprise DC sugar alcohol particles in an amount of at least 30% by weight of the first constituent units. In one embodiment of the present invention, the second constituent units comprise DC sugar alcohol particles in an amount of at least 30% by weight of the second constituent units. In one embodiment of the present invention, the second constituent units comprise DC sugar alcohol particles in an amount of at least 50% by weight of the second constituent units. In one embodiment of the present invention, the second building block comprises DC sugar alcohol particles in an amount of at least 70% by weight of the second building block. In one embodiment of the present invention, the second building block comprises DC sugar alcohol particles in an amount of at least 90% by weight of the second building block. In one embodiment of the present invention, the DC sugar alcohol particles in the second building block are selected from DC particles of sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof.

[0174] In one embodiment of the present invention, the tablet comprises one or more binders other than those forming part of the DC sugar alcohol particles in an amount of 0.1 to 6% by weight of the tablet.

[0175] Suitable binders include gum arabic, methylcellulose, liquid glucose, tragacanth, ethylcellulose, gelatin, hydroxypropylmethylcellulose (HPMC), starch, hydroxypropylcellulose (HPC), pregelatinized starch, sodium carboxymethylcellulose (NaCMC), alginic acid, polyvinylpyrrolidone (PVP), maltodextrin (MD); cellulose, polyethylene glycol (PEG), polyvinyl alcohol, polymethacrylate, copovidone, or microcrystalline cellulose (MCC), alone or in combination.

[0176] According to one embodiment of the present invention, the one or more binders include one or more cellulose binders. In one embodiment of the present invention, the one or more binders include microcrystalline cellulose (MCC), hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC), or any combination thereof. In one embodiment of the present invention, the oral tablet includes a hydroxypropyl cellulose (HPC) binder in an amount of 0.1 to 6% by weight of the tablet, for example, 0.1 to 5% by weight, for example, 0.1 to 4% by weight, for example, 0.1 to 3% by weight, for example, 0.1 to 2% by weight. HPC may be applied as a particularly attractive binder. Therefore, this binder, when used with a non-DC sugar alcohol such as erythritol, provides a favorable sensory experience compared to other well-known binders. In particular, the use of HPC in an amount of less than 4% by weight of the tablet, for example, 0.1 to 3% by weight, for example, 0.1 to 2% by weight of the tablet, is advantageous.

[0177] In one embodiment of the present invention, the non-DC sugar alcohol particles are ungranulated particles and the one or more binders are present as separate components in the tablet.

[0178] In one embodiment of the present invention, the tablet has a mass ratio of non-DC sugar alcohol particles to DC sugar alcohol particles of 0.2 to 1.2. In one embodiment of the present invention, the tablet has a mass ratio of non-DC sugar alcohol particles to DC sugar alcohol particles of 0.3 to 1.0. In one embodiment of the present invention, the tablet has a mass ratio of non-DC sugar alcohol particles to DC sugar alcohol particles of 0.3 to 0.7.

[0179] According to one embodiment of the present invention, the mass ratio of non-DC sugar alcohol particles to DC sugar alcohol particles has proven to be important in the sense that a relatively large amount of non-DC sugar alcohol particles must be present to achieve the mouthfeel and taste obtained by the present invention. However, this taste and mouthfeel is also present in DC sugar alcohol particles. An example of such a DC sugar alcohol particle is DC-grade xylitol, which, together with the non-DC sugar alcohol particles, can provide a unique and highly appealing mouthfeel to test panels.

[0180] In one embodiment of the present invention, the tablet comprises a flavoring agent. For example, the amount of flavoring agent may be 0.1 to about 10% by weight of the tablet, such as 0.1 to about 6% by weight of the tablet.

[0181] Available flavors include almond, almond amaretto, apple, Bavarian cream, black cherry, black sesame seed, blueberry, brown sugar, bubble gum, butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake (graham crust), chili, cinnamon red hot, cotton candy, circus cotton candy, clove, coconut, coffee, clear coffee, double chocolate, energy cow, ginger, glutamic acid, graham cracker, grape juice, green apple, Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, kula-da, lemon, lemon lime, tobacco, maple syrup, maraschino cherry, marshmallow, menthol, milk chocolate, mocha, and Mountain Dew™, peanut butter, pecan, peppermint, raspberry, banana, ripe banana, root beer, RY4, spearmint, strawberry, sweet cream, sweet tart, 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, piña colada, pineapple, plum, pomegranate, praline and cream, red licorice, salt water taffy, strawberry banana, strawberry kiwi, tropical punch, tutti frutti, vanilla, or any combination thereof.

[0182] In one embodiment of the invention, the tablet comprises particles comprising a gum base, the tablet being designed to be chewed into a sticky residue containing water-insoluble elements. In one embodiment of the invention, the oral tablet comprises particles comprising a gum base, the gum base comprising at least 5% by weight of an elastomer.

[0183] The specific use of a relatively high proportion of elastomer in the gum base can be effectively used to modify the release of active ingredients in terms of time and amount, and the elastomer can also provide a robust structure for the tablet, making it easier to chew the tablet into a sticky residue containing water-insoluble components. Some active ingredients risk causing residue disintegration, but the elastomer can increase the stickiness and compensate for aggressive active ingredients. In one embodiment of the present invention, the gum base comprises at least 10% by weight of elastomer. In one embodiment of the present invention, the gum base comprises at least 15% by weight of elastomer. In one embodiment of the present invention, the gum base comprises 15% to 25% by weight of elastomer. In one embodiment of the present invention, the gum base comprises 17% to 23% by weight of elastomer. In one embodiment of the present invention, the tablet does not comprise a gum base.

[0184] Hereinafter, raw material refers to the mixed particles to be compressed into a tablet according to an embodiment of the present invention, unless otherwise stated.

[0185] The following description outlines a description of how the tablets of the present invention may be made, as well as further details about what may be added to the compositions of the present invention.

[0186] Typically, the tablet manufacturing method of the present invention can be carried out in a single tablet press, such as a rotary tablet press. However, in some situations, it may be beneficial to use separate tablet presses. Preferably, the upper punch is convex, which imparts a concave shape to the upper surface of the pressed tablet. Of course, it should be noted that the shape of the punch may depend on the desired tablet shape. In some embodiments of the present invention, tablet pressing is carried out at a force of 20 to 50 kN.

[0187] In further embodiments, sucrose fatty acid esters may also be utilized to increase the release of sweeteners, including so-called high-potency sweeteners such as saccharin, cyclamate, aspartame, thaumatin, dihydrochalcones, stevioside, glycyrrhizin, or salts or compounds thereof.

[0188] When the formulation contains a gum base, the sugar alcohol typically constitutes about 5 to about 95% by weight of the tablet, more typically about 20 to about 80% by weight, for example, 30 to 70% by weight or 30 to 60% by weight of the tablet.

[0189] In such an embodiment of the invention, the tablet comprises not only the sugar alcohol already described, but also an ingredient selected from the group consisting of bulk sweeteners, flavorings, dry binders, tableting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, intense sweeteners, softeners, colorants, or any combination thereof.

[0190] High-intensity artificial sweeteners can be used alone or in combination with the aforementioned sweeteners. Preferred high-intensity sweeteners include, but are not limited to, sucralose, aspartame, acesulfame salts, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside (natural intensity sweetener), and the like, alone or in combination. To provide a longer-lasting sweetness and flavor perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweetener. Techniques such as wet granulation, wax granulation, spray drying, spray chilling, fluidized bed coating, preservation, encapsulation in yeast cells, and fiber extrusion can be used to achieve the desired release characteristics. Encapsulation of the sweetener can also be achieved using a separate tablet component, such as a resin compound.

[0191] The use level of artificial sweeteners varies widely and will depend on factors such as sweetener potency, release rate, desired sweetness of the product, the level and type of flavoring used, and cost considerations. Thus, the active level of artificial sweeteners can vary from about 0.001 to about 8% by weight (preferably about 0.02 to about 8% by weight). When a carrier used for encapsulation is included, the use level of the encapsulated sweetener will be proportionately higher. Combinations of sugar and / or non-sugar sweeteners may be used in tablet formulations.

[0192] Tablets according to the present invention may optionally contain one or more fillers / texturizers including, by way of example, magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium oxide, mono-, di- and tricalcium phosphate, cellulose polymers, and combinations thereof. [Example]

[0193] The following non-limiting examples illustrate different variations of the present invention.

[0194] Example 1 Preparation of ion exchange composition particles containing brilliant blue Purified water (10 ml) was placed in a plastic beaker with a screw cap. The water-soluble anionic mucoadhesive polymer was slowly added to the water, the plastic beaker was closed with a cap, and the dispersion was then stirred at approximately 100°C for 6 hours. 1.5 ml of a 1% brilliant blue stock solution was added, and the gel mixture was vigorously stirred at 60-80°C for 1 hour. Precipitation was carried out by pipetting 2 ml of the polymer gel into 30 ml of isopropyl alcohol (IPA) using a positive displacement pipette under stirring conditions. The supernatant was discarded. The precipitate was washed with fresh IPA until no solvent coloration was observed. The remaining water and IPA were evaporated from the precipitate until the product structure was substantially solid. The product was ground to a given average particle size.

[0195] Example 2 Preparation of ion exchange composition particles containing brilliant blue Purified water (10 ml) was placed in a plastic beaker with a screw cap. The water-soluble anionic mucoadhesive polymer was slowly added to the water, the plastic beaker was closed with a cap, and the dispersion was then stirred at approximately 100°C for 6 hours. 1.5 ml of a 1% brilliant blue stock solution was added, and the gel mixture was vigorously stirred at 60-80°C for 1 hour. Precipitation was carried out by pipetting 2 ml of the polymer gel into 30 ml of acetone using a positive displacement pipette under stirring conditions. The supernatant was discarded. The precipitate was washed with fresh acetone until no solvent coloration was observed. Residual water and acetone were evaporated from the precipitate until the product structure was substantially solid. The product was ground to a given average particle size.

[0196] Example 3 Preparation of ion exchange composition particles containing brilliant blue Isopropyl alcohol (30 ml) was placed in a plastic beaker with a screw cap. 3 ml of an aqueous solution of brilliant blue (1%) was added. The water-soluble anionic mucoadhesive polymer was slowly added to the mixture, the plastic beaker was closed with a cap, and the dispersion was then stirred for 1 hour. After a 1-hour rest period for the powder to settle, the supernatant was poured off and discarded. The IPA was evaporated from the residue, yielding a fine, colored polymer powder.

[0197] Example 4A Preparation of nicotine-bearing ion exchange composition particles Purified water (10 ml) was placed in a plastic beaker with a screw cap. The water-soluble anionic mucoadhesive polymer was slowly added to the water, the plastic beaker was closed with a cap, and the dispersion was then stirred at approximately 100°C for 6 hours. L-nicotine 99% was added, and the gel mixture was vortexed. It was then vigorously stirred at 60-80°C for 1 hour. Precipitation was carried out by pipetting 2 ml of the polymer gel into 30 ml of isopropyl alcohol (IPA) using a positive displacement pipette under stirring conditions. The supernatant was poured off and discarded. The remaining water and IPA were allowed to evaporate from the precipitate until the product structure was substantially solid. The product was ground to a given average particle size.

[0198] Example 4B Preparation of nicotine-bearing ion exchange composition particles Isopropyl alcohol (30 ml) was placed in a plastic beaker with a screw cap, followed by the addition of nicotine. The water-soluble anionic mucoadhesive polymer was slowly added to the mixture, the plastic beaker was closed with a cap, and the dispersion was then stirred for 1 hour. After a 1-hour rest period for the powder to settle, the supernatant was poured off and discarded. The IPA was evaporated from the residue, yielding a fine nicotine-containing polymer powder.

[0199] Example 4C Preparation of nicotine-bearing ion exchange composition particles Purified water (10 ml) was placed in a plastic beaker with a screw cap. The water-soluble anionic mucoadhesive polymer was slowly added to the water, the plastic beaker was closed with a cap, and the wet powder was then stirred at approximately 40°C for 30 minutes. L-nicotine 99% was added, and the suspension was vigorously stirred at 30-40°C for 1 hour. Water was evaporated from the suspension until the product structure was substantially solid. The product was milled to a given average particle size.

[0200] Example 5A Preparation of Brilliant Blue Polacrilex Resin Coated with Water-Soluble Anionic Mucoadhesive Polymer Purified water (10 mL) was placed in a plastic beaker with a screw cap. The water-soluble anionic mucoadhesive polymer was slowly added to the water, the plastic beaker was closed with a cap, and the dispersion was then stirred at approximately 100°C for 6 hours. Purified water (10 mL) was placed in a separate plastic beaker, and brilliant blue stock solution (1%) was added. Polacrilex resin (99% <300 microns) was added to the coloring solution (Amberlite IRP64, Rohm and Haas, Paris, Cedex, France), and the mixture was similarly stirred at 100°C for 6 hours. Both solutions were mixed and immediately precipitated. Precipitation was carried out by pipetting 2 mL of the polymer gel mixture into 30 mL of isopropyl alcohol (IPA) using a positive displacement pipette under stirring conditions. The supernatant was discarded. The precipitate was washed with fresh IPA until no solvent coloration was observed. Residual water and IPA were allowed to evaporate from the precipitate until the product structure was substantially solid. The product was ground to a given average particle size.

[0201] Example 5B Preparation of coated nicotine polacrilex resin with water-soluble anionic mucoadhesive polymer Purified water (10 mL) was placed in a plastic beaker with a screw cap. The water-soluble anionic mucoadhesive polymer was slowly added to the water, the plastic beaker was closed with a cap, and the dispersion was then stirred at approximately 100°C for 6 hours and cooled. Nicotine polacrilex resin (99% <300 microns, nicotine loading 15% by weight) was added to the solution (Amberlite IRP64, Rohm and Haas, Paris, Cedex, France), followed by precipitation. Precipitation was carried out by pipetting 2 mL of the polymer gel mixture into 30 mL of isopropyl alcohol (IPA) using a positive displacement pipette under stirring conditions. The supernatant was discarded. The precipitate was washed with fresh IPA. Residual water and IPA were evaporated from the precipitate until the product structure was substantially solid. The product was milled to a given average particle size. The resulting product had a nicotine content equivalent to that of the starting nicotine polacrilex resin.

[0202] Example 6 Preparation of ion-exchange composition particles with different types of water-soluble anionic mucoadhesive polymers Different types of water-soluble anionic mucoadhesive polymers were applied to the methods of Examples 1 to 5 to obtain different ion-exchange composition particles.

[0203] [Table 1]

[0204] Example 7 Preparation of ion exchange composition particles having associated polymers To investigate the effect of combining different anionic mucoadhesive polymers, ion exchange composition particles combining carrageenan of Example 6a and xanthan gum of Example 6b were prepared according to the methods of Examples 1-5.

[0205] [Table 2]

[0206] Example 8 Preparation of ion exchange composition particles with different pH To evaluate the effect of polymer solution pH on precipitation, the ion exchange composition with polyacrylic acid (450 kDa) of Example 6i was adjusted to various pH values ​​by adding solutions of hydrochloric acid (1 M) or sodium hydroxide (1 M). Particles were prepared according to the methods of Examples 1-2.

[0207] [Table 3]

[0208] Example 9 Preparation of ion exchange composition particles with different particle sizes To evaluate the effect of different particle size, ion exchange compositions with carrageenan of Example 6a were prepared according to the methods of Examples 1-5 with different average particle size diameters.

[0209] [Table 4]

[0210] Example 10 Preparation of ion exchange composition particles with different nicotine loadings To evaluate the effect of cationic biologically active compound loading on the water-soluble anionic mucoadhesive polymer, nicotine was loaded into the carrageenan of Example 6a at different loading ratios according to the methods of Examples 1-5.

[0211] [Table 5]

[0212] Example 11 Preparation of ion exchange composition particles with different molecular weights To evaluate the effect of molecular weight of the water-soluble anionic mucoadhesive polymer, polyacrylic acids of different numbers of repeating units of Example 6h were applied according to the method of Examples 1-2.

[0213] [Table 6]

[0214] Example 12 Preparation of oral tablets with different compositions Fast disintegrating tablet (FDT) formulations with ion-exchange composition particles (IE) were prepared according to Examples 1 to 11. Oral formulations were prepared with variations according to Examples 6 to 11.

[0215] A specific fast disintegrating tablet (FDT) formulation is exemplified below. The formulation was prepared using ion-exchange composition particles (IE) prepared according to Example 4A. The water-soluble anionic mucoadhesive polymer was iota-carrageenan (Example 6a) with an average particle size of 100 microns (Example 9d). The nicotine loading was 1:4 (Example 10d). Punch used: 7.00 mm, round, shallow concave, D tooling. Tablet weight: 100.0 mg.

[0216] [Table 7]

[0217] Rapidly disintegrating tablets were produced in a laboratory-scale machine, such as a RIVA Piccola bilayer tablet press. The tablet press was operated by adjusting the fill depth and compression force so that the tablet mass and hardness met the acceptable standards. A pre-compression force may be included to prevent capping.

[0218] [Table 8]

[0219] In this embodiment, the bulk sweetener and / or filler should have relatively good compressibility and still have fast disintegration, although friability acceptance criteria should be met so that the resulting rapidly disintegrating tablets can be packaged.

[0220] The rapidly disintegrating tablets according to the present invention may contain colorants. According to one embodiment of the present invention, the rapidly disintegrating tablets may contain colorants and brighteners, such as FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide, and combinations thereof.

[0221] Example 13 Preparation of oral tablets with ready-to-use system Fast disintegrating tablet (FDT) formulations with ion-exchange composition particles (IE) were prepared according to Examples 1 to 11. Oral formulations were prepared with variations according to Examples 6 to 11.

[0222] A specific fast disintegrating tablet (FDT) formulation is exemplified below. The formulation was prepared using ion-exchange composition particles (IE) prepared according to Example 4A. The water-soluble anionic mucoadhesive polymer was iota-carrageenan (Example 6a) with an average particle size of 100 microns (Example 9d). The nicotine loading was 1:4 (Example 10d). Punch used: 7.00 mm, round, shallow concave, D tooling. Tablet weight: 100.0 mg.

[0223] Suitable for the purpose may be, but are not limited to: Pearlitol Flash (Roquette), Pharmaburst 500 (SPI Pharma), Ludiflash (BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (Fuji Chemical), SmartEx50, or SmartEx100 (Shin Etsu / Harke Pharma). These ready-to-use systems are co-processed systems in which fillers, disintegrants, lubricants, etc. are implemented in one powder mix. This saves handling of multiple excipients and ensures uniformity between the excipients.

[0224] [Table 9]

[0225] Example 14 Preparation of oral chewable tablets Chewable tablet formulations with ion-exchange composition particles (IE) were prepared according to Examples 1 to 11. Oral formulations were prepared with variations according to Examples 6 to 11.

[0226] A specific chewable tablet formulation is exemplified below. The formulation was prepared using ion-exchange composition particles (IE) prepared according to Example 4A. The water-soluble anionic mucoadhesive polymer was iota-carrageenan (Example 6a) with an average particle size of 100 microns (Example 9d). The nicotine loading was 1:4 (Example 10d). Punch used: 7.00 mm, round, shallow concave, D tooling. Tablet weight: 100.0 mg.

[0227] [Table 10]

[0228] [Table 11]

[0229] [Table 12]

[0230] [Table 13]

[0231] [Table 14]

[0232] Process Flow The compositions shown in Tables 10, 11, and 12 above were processed into bilayer tablets having the compositions outlined in Examples 14-1 to 14-12, 14-13 to 14-24, and 14-25 to 14-36, respectively. In other words, Examples 14-1 to 14-12 are bilayer tablets having a first layer according to Tables 10 and 11, and the second layer is primarily based on DC maltitol. In Examples 14-13 to 14-24, the second layer is primarily based on DC xylitol. In Examples 14-25 to 14-36, the second layer is primarily based on DC isomalt, as shown in Table 12.

[0233] The compositions of Tables 13 and 13A are also processed into corresponding bilayer tablets of each composition as shown in Examples 14-37 and 14-38, and Examples 14-38A and 14-38B.

[0234] For each of Examples 14-1 to 14-38, and Examples 14-38A and 14-38B, the raw materials are sieved through a 1600 micron sieve and then weighed into appropriate amounts according to the exemplary compositions in Tables 10 to 13 and 13A.

[0235] The weighed amount is then added to a Turbula mixer in a stainless steel container and blended for 5 minutes at 50 rpm. After 4 minutes of blending, the MgSt was added.

[0236] The mixture is then tableted using a Piccola RIVA DC-SC-041-2 or a Fette 3090i.

[0237] The applied molds have a circular cross section with a diameter of 16 mm and are hollow to produce concave and / or curved tablets. Obviously, other mold sizes and shapes may be applied within the scope of the present invention.

[0238] Then, the tablets obtained according to Examples 14-1 to 14-38, and Examples 14-38A and 14-38B are obtained by tableting with appropriate pressure force.

[0239] For each tablet of Examples 14-1 to 14-38, and Examples 14-38A and 14-38B, the second layer, designated as the second layer in Tables 13 and 13A, as outlined in Table 12, is first pressed at a first relatively low pressure. The blended composition of the so-called first layer, i.e., the composition of Tables 10 and 11, and the first layer in Tables 13 and 13A, is then fed into a die, and the final bilayer tablet is then compressed at a pressure higher than that applied to the first layer, thereby producing the final bilayer tablet according to Examples 14-1 to 14-38, and Examples 14-38A and 14-38B. Note that the final bilayer tablets for Examples 14-1 through 14-38, as well as Examples 14-38A and 14-38B, are 1.8 gram tablets, with the first layer of the tablet weighing 0.9 grams and the second layer of the tablet weighing 0.9 grams.

[0240] Details of the relevant compounds applied in the examples described above are given below. HPC: Hydroxypropyl cellulose. Ashland's Klucel Nutra D Non-DC xylitol: DuPont's Xivia C Cargill PharmSorbidex non-granulated sorbitol Non-DC Isomalt: Isomalt GS from Beneo Paltinit Non-DC mannitol: Pearlitol from Rockete Non-DC maltitol: Maltisorb P200 from Rockete Non-DC erythritol: Cargill Zerose 16952 DC Erythritol - Cargill Zerose 16966 DC Xylitol - Dupont's Xylitab 200 DC Isomalt - Beneo Paltinit Isomalt DC 101 DC Mannitol - Pearlitol SD200 by Rockete DC Maltitol - Rockete's Sweetpearl 300 DC

[0241] Examples 14-39 to 14-41

[0242] [Table 15]

[0243] All ingredients were obtained in powder form. DC Isomalt - Beneo Paltinit Isomalt DC 101 Non-DC erythritol: Cargill Zerose 16952 HPC: Hydroxypropyl cellulose. Ashland's Klucel Nutra D DC CaCO3: Scoralite 97 PVP from Scora

[0244] Process Flow For each of Examples 14-39 to 14-41, the raw materials are sieved through a 1600 micron sieve and then weighed into appropriate amounts according to the exemplary compositions in Table 14.

[0245] For each example, a weighed amount is then added to a Turbula mixer in a stainless steel container and blended for 4 minutes at 50 rpm, then the magnesium stearate is added and blended for an additional 1 minute.

[0246] Then, the tablets obtained according to Examples 14-39 to 14-41 are obtained by tableting the mixture using Piccola RIVA DC-SC-041-2. Fette 3090i is also applicable.

[0247] evaluation

[0248] [Table 16]

[0249] The above two-layer Examples 14-13 through 14-18 were evaluated by a test panel according to three parameters.

[0250] Two of the parameters were suitability as a chewable tablet and one was the perceived watering effect. Due to the more complex nature of the bilayer tablets, two additional parameters were evaluated: resistance to chewing and friability.

[0251] Firstly, it was noted that Examples 14-13, 14-15, 14-16 and 14-18, i.e., the examples based on non-DC xylitol, non-DC isomalt, non-DC erythritol and non-DC maltitol, were considered to have a relatively high watering effect, which is considered to represent or be equivalent to the salivation effect described elsewhere.

[0252] The test panel clearly indicated that the overall chewing process and mouthfeel were no less impressive compared to the non-DC erythritol-based Examples 14-16. It was also noted that the test panel identified the non-DC xylitol of Examples 14-13 and the non-DC maltitol of Examples 14-18 as having an impressive watering effect, for example, when compared to the sorbitol-based examples.

[0253] As a complement to the sensory evaluation, chewing resistance and friability were measured and are shown in Examples 14-13 to 14-24, i.e., with reference to bilayer tablets having a first layer as shown in Table 10 and Table 11 and a second layer based primarily on DC xylitol as shown in Table 12.

[0254] Chewing resistance is determined according to European Pharmacopoeia 9.1 test method 2.9.8 by using a tester model of chewing resistance of pharmaceuticals, type PTB 311, from Pharma Test.

[0255] Friability is measured using a Pharma Test Pharmaceutical Friability Tester PTF 10E according to European Pharmacopoeia 9.1 test method 2.9.7.

[0256] Note that while saliva production from all non-DC sugar alcohols is initially impressive, it is also noted that saliva production over time is no less impressive compared to Examples 14-16. Thus, it is noted that the salivation effect increases for a significant period of time after the majority of the non-DC erythritol-based tablets have been swallowed or collected during the measurement. It is also observed that the relatively low initial perceived salivation effect of Example 14-14, i.e., the sorbitol-based example, confirms the sensory evaluation as noted above.

[0257] Examples 14-42 to 14-43. Preparation of bilayer tablets with ODT tablets

[0258] [Table 17]

[0259] [Table 18]

[0260] Examples 14-44 to 14-46 Preparations with Varying Levels of Non-DC Sugar Alcohols

[0261] [Table 19]

[0262] Examples 14-47 to 14-50 Preparations with Varying Levels of Non-DC Sugar Alcohols

[0263] [Table 20]

[0264] Process Flow The compositions shown in Tables 16, 17, 18, and 19 above (Tables 17, 18, 19, and 20) were processed into bilayer tablets having the compositions outlined in Examples 14-42 to 14-50 and 14-43B, respectively.

[0265] For each of Examples 14-42 to 14-50 and 14-43B, the raw materials are sieved through a 1600 micron sieve and then weighed into appropriate amounts according to the exemplary composition.

[0266] The weighed amount is then added to a Turbula mixer in a stainless steel container and blended for 5 minutes at 50 rpm. If applicable, magnesium stearate was added after 4 minutes of blending.

[0267] The mixture is then tableted using a Piccola RIVA DC-SC-041-2 or a Fette 3090i.

[0268] The applied molds have a circular cross section with a diameter of 16 mm and are hollow to produce concave and / or curved tablets. Obviously, other mold sizes and shapes may be applied within the scope of the present invention.

[0269] Then, the tablets produced according to Examples 14-42 to 14-50 and 43B are obtained by tableting with appropriate pressure force.

[0270] For each tablet of Examples 14-44 to 14-50, the second layer is pressed first at a first relatively low pressure. The blended composition of the so-called first layer is then fed into a die, and the final bilayer tablet is then compressed at a pressure higher than that applied to the first layer, thereby producing the final bilayer tablet according to Examples 14-44 to 14-50. For Examples 14-42 to 14-43 and 14-43B, the first layer is pressed first at a first relatively low pressure. The blended composition of the so-called second layer is then fed into a die, and the final bilayer tablet is then compressed at a pressure higher than that applied to the first layer, thereby producing the final bilayer tablet according to Examples 14-42 to 14-43 and 14-43B.

[0271] Note that the final bilayer tablets of Examples 14-42 and 14-43 are 1.5 gram tablets with a Layer 1 to Layer 2 ratio of 55:45. The tablet mass is 1.5 g. Therefore, the mass of Layer 1 is 0.825 g and the mass of Layer 2 is 0.675 g.

[0272] Note that the final bilayer tablet of Example 14-43B is a 1.2 gram tablet with a layer 1 to layer 2 ratio of 75:25. The tablet mass is 1.2 g. Therefore, the mass of layer 1 is 0.90 g and the mass of layer 2 is 0.30 g.

[0273] Note that the final bilayer tablets for Examples 14-44 through 14-50 are 1.5 gram tablets with a Layer 1 to Layer 2 ratio of 55:45. The tablet mass is 1.5 g. Therefore, the mass of Layer 1 is 0.825 g and the mass of Layer 2 is 0.675 g.

[0274] Details of the relevant compounds applied in the examples described above are given below. HPC: Hydroxypropyl cellulose. Ashland's Klucel Nutra D Non-DC xylitol: DuPont's Xivia C Cargill PharmSorbidex non-granulated sorbitol Non-DC Isomalt: Isomalt GS from Beneo Paltinit Non-DC mannitol: Pearlitol from Rockete Non-DC maltitol: Maltisorb P200 from Rockete Non-DC erythritol: Cargill Zerose 16952 DC Erythritol - Cargill Zerose 16966 DC Xylitol - Dupont's Xylitab 200 DC Isomalt - Beneo Paltinit Isomalt DC 101 DC Mannitol - Pearlitol SD200 by Rockete DC Maltitol - Rockete's Sweetpearl 300 DC DC CaCO3: Scoralite 97 PVP from Scora Pearlitol Flash is a trademark of Rockete, Inc. Microcrystalline cellulose (MCC): Avicel PH-105 from FMC CrosPovidone: Kollidon CL-SF from BASF

[0275] Example 15 Nicotine tablet disintegration In vitro disintegration of the rapidly disintegrating tablets FDT(a)-(f) and FDT(g)-(k) was performed according to section 2.9.1 Disintegration of tablets and capsules of the European Pharmacopoeia 9.0. As explained in the Examples, each batch was manufactured with various tablet sublots that varied in compression force, and therefore output parameters such as hardness and friability would vary. These output parameters also affect the in vitro disintegration. The results of FDT(a)-(f) are summarized in Table 20. The minimum and maximum measured disintegration values ​​are shown, which are more or less a function of hardness.

[0276] [Table 21]

[0277] For example, when looking at FDT(a), the minimum average disintegration time of 21 seconds corresponds to a tablet pressed to a minimum average hardness of 14 N, and similarly, the maximum average disintegration time of 24 seconds corresponds to another tablet pressed to a maximum average hardness of 63 N. Thus, a tablet with an FDT(a) having an average friability of 0.3% corresponds to a tablet with an average hardness of 63 N. In other words, in Table 4, FDT(a) refers to two different tablets pressed at two different pressures, the relationship of which is shown above.

[0278] The results of FDT(g)-(k) are summarized in Table 21.

[0279] [Table 22]

[0280] It is understood that in vitro disintegration can vary significantly among the disclosed fast-disintegrating tablets. This allows for disintegration profiles to be used in conjunction with high in vivo pH, where necessary, thereby allowing for more efficient use of nicotine. Most preferably, an in vitro disintegration profile of less than 60 seconds is desired, as this ensures a high concentration of nicotine combined with a relatively high in vivo pH.

[0281] In vitro disintegration is a rapid method for determining the time and mechanism of tablet performance. More preferably, or in combination, in vivo disintegration is measured. In vivo disintegration time is the value for the actual disintegration of the sublingual tablet under the tongue. Tables 22 and 23 highlight the in vivo disintegration results.

[0282] [Table 23]

[0283] [Table 24]

[0284] As recognized for the previous in vitro disintegration results, the rate of in vivo disintegration may vary among the disclosed batches. Disintegration time should be complete within 60 seconds from the onset of disintegration or preferably faster.

[0285] Example 16 Evaluation of oral tablets with respect to burning sensation, bioavailability, adhesion to oral mucosa, and stability Overall, these experiments demonstrated that oral tablets containing ion exchange compositions provide less burning sensation of cationic biologically active compounds, including nicotine, compared to conventional tablets. These experiments also demonstrated that these tablets provide increased bioavailability of cationic biologically active compounds, including nicotine.

[0286] Furthermore, these experiments have revealed that ion-exchange particles are particularly beneficial in reducing the burning sensation and off-notes associated with nicotine, and also in increasing the bioavailability of nicotine.According to the present invention, the incorporation of ion-exchange compositions into particles is particularly beneficial.Importantly, it has been found that adhesion of particles to the oral mucosa during use of oral tablets occurs to a significant extent.Therefore, the particles according to the present invention that come into contact with the oral mucosa are useful for delivering nicotine for mucosal absorption, and significantly contribute to the increased bioavailability and taste masking of cationic biologically active compounds such as nicotine.

[0287] Table 24 below shows an example of the adhesion of one of the anionic polymers according to the present invention when formed into particles. It can be seen that the mucoadhesion is very beneficial in Example 14-38A, much higher than the inventors expected. The results of this powdered ion-exchange composition according to the present invention were also much better than would be expected if the anionic polymer were present in a gel. Furthermore, it can be seen that the mucoadhesion was even more beneficial in Example 14-38B, where a combination of two anionic polymers according to the present invention was applied.

[0288] [Table 25]

[0289] These effects were particularly beneficial for the mean particle size of water-soluble anionic mucoadhesive polymer particles loaded with a specific range of cationic biologically active compounds, such as nicotine. The molecular weight of the water-soluble anionic polymer also affected both bioavailability and off-note properties. Combinations of water-soluble anionic mucoadhesive polymers were particularly advantageous in some embodiments with respect to adhesion to the oral mucosa.

[0290] Figure 1 shows the characteristics of particles of a water-soluble anionic mucoadhesive polymer according to the invention. Two series of experiments were carried out in which particles of a water-soluble anionic mucoadhesive polymer were added to a Petri dish containing 1 ml of purified water. In experiment G (IPA), the powder according to Example 3 was applied. In experiment G, the powder according to Example 1 was applied. Photographs were taken initially (T0), after 5 minutes (T-5 min), and after 10 minutes (T-10 min), after which additional water was added. The powder settled in the water and appeared as a distinct blue area at the bottom of the Petri dish. As a function of time, the blue color became more intense. In particular, in experiment G, the distinct blue areas were found to be more pronounced after 5 and 10 minutes. This demonstrates the principle of adhesion by hydration. Swelling occurred, and the particles of the water-soluble anionic mucoadhesive polymer according to the invention increased in size.

[0291] Figure 2 shows adhesion to the oral mucosa according to the present invention. A subject was administered a tablet prepared according to Example 14-4, and the ion exchange composition was replaced with the particles of Example 1, which have a blue color. After 5 minutes, the subject was monitored for coloration. It can be seen that the blue color remains on the oral mucosa even after 5 minutes. This demonstrates the principle of adhesion by hydration. Swelling occurs, and the particles of the water-soluble anionic mucoadhesive polymer according to the present invention increase in size.

[0292] Finally, the stability of the oral tablets and ion-exchange particles was found to be comparable to conventional ion-exchange systems. A specific loading of cationic biologically active compounds, including nicotine, was found to further improve stability. The polymer:nicotine ratio was found to affect the stability of the ion-exchange compositions. This ratio also further affected other properties, such as bioavailability and taste masking.

Claims

1. 1. An oral tablet for buccal delivery of nicotine, comprising: i) a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet; ii) an ion exchange composition in powder form comprising a plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with nicotine; wherein the weight ratio of said at least one water-soluble anionic mucoadhesive polymer to nicotine is from 2:1 to 20:1; the one or more sugar alcohol particles comprise a sugar alcohol selected from sorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, and combinations thereof; 10. An oral tablet, wherein the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethylcellulose, and combinations thereof.

2. 2. The oral tablet of claim 1, wherein the weight ratio of the at least one water-soluble anionic mucoadhesive polymer to nicotine is from 2:1 to 15:1, from 2:1 to 10:1, or from 3:1 to 8:

1.

3. 3. The oral tablet according to claim 1 or 2, wherein the average particle diameter of the plurality of particles of the at least one water-soluble anionic mucoadhesive polymer is from 10 to 1000 microns, or from 20 to 500 microns.

4. 4. The oral tablet according to claim 1, which is an orally disintegrating tablet.

5. 5. The oral tablet of any one of claims 1 to 4, comprising the ion exchange composition in an amount of 0.1 to 25% by weight of the tablet, or 1 to 5% by weight of the tablet.

6. 6. The oral tablet of claim 1, further comprising a disintegrant.

7. 7. The oral tablet according to any one of claims 1 to 6, wherein the at least one water-soluble anionic mucoadhesive polymer comprises at least two water-soluble anionic mucoadhesive polymers selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethylcellulose, and combinations thereof.

8. 8. The oral tablet according to any one of claims 1 to 7, wherein the at least one water-soluble anionic mucoadhesive polymer comprises at least two water-soluble anionic mucoadhesive polymers in a weight ratio of 1:1 to 1:4, or in a weight ratio of 1:1 to 1:

2.

9. 9. The oral tablet according to any one of claims 1 to 8, wherein the at least one water-soluble anionic mucoadhesive polymer comprises at least three water-soluble anionic mucoadhesive polymers.

10. 1. An ion-exchange composition in powder form for oral mucosal delivery of nicotine, said ion-exchange composition comprising: A plurality of particles of at least one water-soluble anionic mucoadhesive polymer loaded with nicotine wherein the weight ratio of said at least one water-soluble anionic mucoadhesive polymer to nicotine is from 2:1 to 20:1; An ion exchange composition, wherein the at least one water-soluble anionic mucoadhesive polymer is selected from the group consisting of xanthan gum, carrageenan, carbomer, carboxymethylcellulose, and combinations thereof.

11. 11. The ion exchange composition of claim 10 contained in a tablet or sachet.

12. 12. The ion exchange composition of claim 10 or 11, constructed in accordance with any one of claims 1 to 9.

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