GB2613211A

GB2613211A - Alkaline oral formulations

Info

Publication number: GB2613211A
Application number: GB2204804.5A
Authority: GB
Inventors: Engqvist Håkan; Lööf Jesper
Original assignee: Amplicon AB
Current assignee: Amplicon AB
Priority date: 2022-04-01
Filing date: 2022-04-01
Publication date: 2023-05-31
Anticipated expiration: 2042-04-01
Also published as: GB2613211B; GB202204804D0

Abstract

An oral formulation comprising a solid, porous chemically bonded ceramic system, nicotine or a nicotine salt and a pH regulating agent wherein the ceramic is formed in the absence of the pH regulating agent. A method of forming the formulation, a permeable, sealed bag comprising the same formulation, a tablet comprising the formulation and a bioadhesion or mucoadhesion agent, and a method of treating nicotine dependence, aiding smoking cessation or ameliorating dementia, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and depression symptoms by administering the formulations is included. The ceramic may contain calcium and be based on a calcium phosphate, sulphate, carbonate, silicate or aluminate, particularly alpha-tricalcium phosphate, tetracalcium phosphate or calcium sulphate. The composition may use a nicotine salt, particularly nicotine bitartrate dihydrate, a carbonate, hydrogen carbonate or phosphate pH agent, and be at least pH 8 in saliva. The nicotine may be in the ceramic pores and the pH agent outside of the pores. The formulation may release substantially all the nicotine when in an aqueous liquid. The bag may comprise a cavity surrounded by a permeable material associated with the pH agent. The method of production may include formation of the ceramic when in contact with the nicotine.

Description

Intellectual Property Office Application No G132204804.5 RUM Date:23 August 2022 The following terms are registered trade marks and should be read as such wherever they occur in this document: ZYN, Avicel, Swedish Match, VOLT, Nordic Spirit, Lyft Intellectual Property Office is an operating name of the Patent Office www.gov.uk/ipo

ALKALINE ORAL FORMULATIONS

Field of the Invention

The invention relates to new formulations for oral delivery of nicotine. The invention also relates to a method of manufacturing nicotine formulations suitable for oral delivery. The formulations may be employed in aiding smoking cessation, treating nicotine dependence or alleviating the symptoms of nicotine dependence. The formulations may also be used in recreational use products.

Background

Various nicotine replacement therapy products are commercially available, including patches, gums, lozenges, nicotine pouches, sublingual tablets, inhalers and nasal sprays (U. Wadgave et al., Int 3 Health Sci (Qassim), 2016 Jul; 10(3): 425-435).

Nicotine replacement therapies such as these are useful in helping tobacco users to overcome difficulties arising from nicotine withdrawal as they attempt to reduce their exposure to tobacco products, particularly cigarettes.

Some nicotine delivery systems are also used by individuals to provide pleasurable sensations resulting from nicotine uptake. Oral products that are used in this way include nicotine pouches and snus, the latter being particularly popular in Norway and Sweden. Snus is a tobacco-containing product that is typically provided as either loose snus or portion snus. Snus products are also a convenient and safer alternative to cigarettes as they offer a source of nicotine which does not expose the user to some of risks associated with cigarette smoking, such as harmful substances found in cigarette smoke (e.g. carbon monoxide, benzene and formaldehyde) and in the cigarette itself (e.g. vinyl chloride that is used in cigarette filters).

Loose snus is a moist powder which can be portioned and packed into a cylindrical or spherical shape with the fingertips or a purpose-made cylindrical device. The shaped mass of powder is then placed under their upper lip. Over time, the demand for loose snus has been replaced by portioned varieties, which benefits users due to their more discreet nature.

Portion snus is packaged as a moist powder in small teabag-like sachets, which are also intended for positioning under the upper lip. Portion snus is typically held in the mouth for a period lasting between five minutes and one hour and nicotine is released throughout this time.

Portion snus is available in three different sizes: mini, normal/large (most common) and maxi. Mini portions typically weigh close to 0.5 g, normal (large) portions weigh around 0.8 to 1 gram, and maxi portions weigh up to 1.7 g. Some manufacturers also offer the choice of "regular" and "long" versions of the normal size sachet, which are similar in content weight. These long portions differ from traditional sachets in that they are slimmer but longer, in order to fit against the gums more comfortably.

Tobacco-containing snus products often require refrigerated storage conditions, primarily to slow the drying of the tobacco. Refrigeration is also commonly used for tobacco-free nicotine pouches products in order to improve the stability of the product.

Nicotine pouches are white pre-portioned pouches containing either tobacco-derived nicotine or synthetic nicotine, potentially in salt form, but no tobacco leaf, dust, or stem. They are described as either similar to snus, or a tobacco-free version of snus. Non-tobacco-based nicotine pouches are commercially available, and one of the first examples of this was ZYN, a product marked by Swedish Match (N. Plurphanswat et al., The American Journal on Addictions, 29: 279-286, 2020; LuneII E., et al., Nicotine &Tobacco Research, 2020, 1757-1763).

Nicotine pouches have been approved by e.g. the Norwegian Medicines Agency for smoking cessation and are sold as a nicotine replacement therapy. Nicotine pouches are also increasingly used recreationally as an alternative to tobacco products such as cigarettes and snus. Nicotine pouches may be dry or moist. Pouches that are moist are generally feel more comfortable in the mouth, and often provide for quicker release of nicotine. Moist pouches typically contain glycerol.

To use a nicotine pouch, the user puts a pouch in contact with the inside surface of the mouth, typically between the upper lip and gum, behind the lower lip or against the cheek, and leaves it there while the nicotine and taste is being released, much like portion snus. The pouch is typically kept in the mouth for a period of from five minutes to one hour and are then disposed of when finished.

Fast-releasing oral nicotine products are disclosed in the international patent application with the publication no. WO 2019/110073. Pouches containing nicotine in free salt form are disclosed in US patent no. 9,161,908.

The delivery of nicotine through the oral mucosa (particularly sublingual and buccal mucosa) can be greatly enhanced by increasing the pH of the oral environment above the normal level, typically to around pH 8-9 (See Ciolino LA, McCauley HA, Fraser DB, Wolnik KA. J. Anal. Toxicol. 2001;25:15-25, and Tomar S. L. et al. Tobacco Control 1997;6:219-225). A pH regulating agent or suitable buffering agent may be incorporated into an oral product in order to achieve this pH increase.

Controlling the total amount and rate of release of nicotine from an oral product to provide long lasting therapeutic and/or non-therapeutic effects presents further challenges. There is an unmet need for oral products offering controlled release of nicotine and which also provide and maintain a suitably alkaline environment to ensure adequate uptake of nicotine into the bloodstream.

We have now discovered a novel formulation of nicotine (or a salt thereof) suitable for oral delivery, and a method for its manufacture, that have advantageous properties and which solve one or more of the problems associated with nicotine formulations suitable for oral delivery.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Disclosure of the Invention

According to a first aspect of the invention, there is provided an oral formulation comprising a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH regulating agent, wherein the chemically bonded ceramic system is formed in the absence of said pH regulating agent.

These oral formulations are hereinafter referred to as "formulations of the invention".

We have advantageously found that for formulations of the invention that are prepared in this way, i.e. where a pH regulating agent is mixed with, or provided alongside, a combination of a solid, porous chemically bonded ceramic system and nicotine (or a salt thereof) but the chemically bonded ceramic system was formed in the absence of said pH regulating agent, it is possible to achieve a high degree of loading of nicotine (or a salt thereof) into the pores of the chemically bonded ceramic system whilst still enabling the product to deliver the nicotine through the oral mucosa at a satisfactory rate and to a satisfactory extent once in the mouth.

By the use of the term "chemically bonded ceramic system" (or similar) we refer to materials that are capable of being formed at room temperature or at slightly elevated temperature (e.g. less than about 200 °C). These systems act as carriers in the formulations of the invention as they contain pores within which the nicotine (or salt thereof) may be located.

The term "chemically bonded ceramic" typically refers to a system formed from a self-setting precursor material. Chemically bonded ceramic systems include non-hydrated, partly hydrated or fully hydrated ceramics. Therefore, in an embodiment of the invention, the porous solid is based on a ceramic material that is formed from a self-setting precursor ceramic. Non-limiting examples of chemically bonded ceramic systems include those formed from calcium phosphates, calcium sulphates, calcium carbonates, calcium silicates, calcium aluminates, magnesium carbonates and combinations thereof. Preferred chemical compositions include those based on chemically bonded ceramic systems, which following hydration of one or more appropriate precursor substances consume a controlled amount of water to form a network. Precursor substances that may be mentioned in this respect include Ca0A1203, (Ca0)3(5i02), (Ca0)2(Si02), and, particularly, alpha-tricalcium phosphate, tetracalcium phosphate (Ca4(PO4)20), and calcium sulphate (e.g. calcium sulphate hemihydrate). These substances are all capable of reacting with water at room temperature to form a chemically bonded ceramic system.

Other particular systems available are those based on aluminates and silicates, both of which consume a great amount of water. Phases such CA2, CA, CA3 and C12A7, and C25 and C3S in crystalline or amorphous state (C= CaO, A =A1203, Si02 = S. according to common cement terminology) may be used, which are readily available.

The calcium aluminate and/or calcium silicate phases may be used as separate phases or as mixtures of phases. The above-mentioned phases, all in non-hydrated form, act as the binder phase (the cement) in the carrier when hydrated. The liquid(water)-tocement weight ratio is typically in the region of 0.2 to 0.5, preferably in the region of 0.3 to 0.4.

The water-to-cement ratio during manufacturing, particularly for chemically bonded ceramic systems formed from calcium aluminates and calcium silicates, is important for the pore size and pore volume. As an example, for a phase pure 1:1 CA precursor the theoretic water-to-cement ("W/C") ratio that gives complete hydration and complete use of all water is about 0.4. If the W/C ratio is increased, any excess water present will result in an increased pore volume and, to some extent, increased pore size. For calcium aluminates and calcium silicates, the permissible range of water content is quite wide, i.e. it is possible to increase the W/C ratio far above the theoretic value needed for complete hydration and still have a hardened body with sufficient structural integrity.

Further materials that may be mentioned in this respect include clay minerals such as aluminium silicate and/or aluminium silicate hydrate (crystalline or amorphous). Non-limiting examples include kaolin, dickite, halloysite, nacrite, ceolite, illite or combinations thereof, preferably halloysite.

Particular ceramic materials that may be employed include those based upon a sulphate, such as a calcium sulphate or a phosphate such as a calcium phosphate.

Particular examples of such substances include alfa or beta phase calcium sulphate hemihydrate (end product calcium sulphate dihydrate), alkaline or neutral calcium phosphate (apatite) and acidic calcium phosphate (brushite).

The use of chemically bonded ceramic systems that contain calcium may be particularly beneficial for a user's oral health. Chemically bonded ceramic systems that are capable of releasing calcium (e.g. in the form of solubilised calcium ions) into saliva are capable of remineralisation and so can, for example, contribute to mineral growth on the surfaces of teeth. Materials that allow excess ions (e.g. calcium ions, hydroxide ions and possibly also phosphate ions) to diffuse into surrounding saliva under physiological conditions (e.g. at the pH and temperature typically found in the mouth) may be particularly suited for this, and such materials include chemically bonded ceramic systems formed from alpha-tricalcium phosphate and tetracalcium phosphate. Chemically bonded ceramic system that are formed from materials other than calcium phosphates but which are still capable of releasing calcium into saliva are also useful in this context as saliva can act as a source of phosphate ions, thus contributing to the growth of minerals, such as apatite, on teeth. Such materials include chemically bonded ceramic systems formed from calcium silicates, calcium aluminates and, particularly, calcium sulfate.

The oral formulations of the invention may contain any amount of carrier that is sufficient to store and deliver the intended amount of nicotine in use. In one embodiment of the invention, the chemically bonded ceramic system is present at from about 40% to about 98% by weight of the oral formulation. The oral products described herein (e.g. nicotine pouches and sublingual tablets) typically have a mass not exceeding 2 grams. In an embodiment of the invention, the chemically bonded ceramic system is present at from about 40% to about 98% by weight of the oral product (e.g. nicotine pouches and sublingual tablets).

The chemically bonded ceramic systems used in the formulation of the invention may be loaded with nicotine or a salt thereof by soaking the ceramic material in a liquid containing the nicotine or its salt, or through any other method which facilitates the drawing up of that substance into the pores of the ceramic material via capillary forces (including spraying, brushing, rolling, dip coating, powder coating or misting). In one example, the pH regulating agent is not present during the process of loading the chemically bonded ceramic system with nicotine (or salt thereof). The pH regulating agent may then be added to the loaded chemically bonded ceramic system to provide the formulation of the invention. Alternatively, the pH regulating agent is added to the chemically bonded ceramic system prior to the nicotine.

Oral products containing the formulations of the invention, particularly nicotine pouches, may also suitable for storage under ambient temperature without significant degradation of the components, e.g. the pH regulating agents, contained within.

Avoiding the need for refrigerated storage is of clear benefit for manufacturers, retailers and users of these products.

However, preferably the nicotine (or salt thereof) is present when the chemically bonded ceramic system is formed. This allows for greater control over the extent to which the pores in the chemically bonded ceramic system are filled with the nicotine, and so allows greater control over the release characteristics of the final formulation. In particular, this loading method enables the total amount of nicotine that is stored in, and released from, the chemically bonded ceramic system to be more reliably controlled.

As is hereinbefore described, the chemically bonded ceramic system is formed from a suitable precursor material, such as a calcium sulphate or a calcium phosphate, which is typically provided in a powdered form for hydration. The mean grain size of any precursor powder particles may be below about 500 pm, e.g. below about 100 pm, preferably between about 1 pm and about 30 pm. This is to enhance hydration. Such precursor material may be transformed into a nano-size microstructure during hydration. This reaction involves dissolution of the precursor material and repeated subsequent precipitation of nano-size hydrates in the water (solution) and upon remaining non-hydrated precursor material. This reaction favourably continues until precursor materials have been transformed and/or until a pre-selected porosity determined by partial hydration using the time and temperature, as well as the H20 in liquid and/or humidity, is measured.

Pore sizes in chemically bonded ceramic systems may be controlled by various techniques during the process of fabricating the carrier material network structure. A particular method that is suitable for use with the chemically bonded ceramic systems used in the present invention is the porogen leaching method which involves the use of a sacrificial phase during the formation of the carrier. A porogenic material may be included as part of the reaction mixture during the formation of the carrier in order to assist in the formation of pores within the final carrier material network. Porogenic materials include, for example, oils, liquids (e.g. water), sugars, mannitol etc. The porogenic material may then be removed from the carrier, e.g. by burning it away through heating during the curing process, or by dissolving it away using an appropriate solvent. Dissolving is usually achieved with water in order to avoid leaving residual amounts of a substance which may have deleterious effects on the formulation or adverse effects on the user. A porogenic material with a secondary function may also be used. For example, the porogenic material may act as a source of flavour, e.g. as a sweetener. In such cases, it is not essential for the porogenic material to be removed from the carrier prior to use. Instead, some or all of the porogenic material may remain within pores in the carrier, alongside the nicotine (or salt thereof), so that both substances can be released in the user's mouth. Porogenic materials that rapidly dissolve in water are particularly suited for use in this way. Porogenic materials that may be used as sweeteners include sweetening agents known in the art, particularly mono-, oligo-and poly-saccharides; sugar alcohols such as mannitol, sorbitol, maltitol and xylitol; natural and synthetic sweeteners such as sucrose, glucose, dextrose, maltose, fructose, saccharin, aspartame, acesulfame K, sucralose, saccharin and cyclamates; and mixtures thereof.

Foaming methods may also be used to increase the pore sizes in chemically bonded ceramic systems. Such methods would be known to the skilled person and are particularly useful for forming carriers with larger pore sizes. One example of such a method involves preparing the carrier using carbonated water or water containing air bubbles. This may also be achieved without the use of foaming agents (e.g. Tween 80) The total porosity of the chemically bonded ceramic system may be from about 100k to about 70%, such as from about 20% to about 40%. Porosities and average pore sizes may be measured by methods known to the skilled person, for example the mercury intrusion method, the BET (Brunauer, Emmet, and Teller) method, and N2-adsorption techniques.

In a preferred embodiment of the invention, the nicotine (or salt thereof) is co-formedly interspersed in pores within the carrier material network. This means that, whatever process is employed to form the carrier, it must also necessarily form pores within which the nicotine is interspersed. Where the process by which the carrier is formed involves the use of porogens, the nicotine will also be interspersed within the pores arising directly from the use of said porogens. Chemically bonded ceramic systems are particularly suited for use in such embodiments as the process by which the carrier and its pore network is formed does not require very high temperatures, in contrast to sintered ceramics.

The nicotine (or salt thereof) may be mixed with precursor(s) to the chemically bonded ceramic system using a variety of techniques, such as dry powder mixing. Alternatively, the nicotine (or salt thereof) and precursor(s) may be mixed by way of a sol-gel process, as a solution, or as a slurry, a paste or a putty of, for example, particles, granules or pellets of said precursor(s), in the presence of an appropriate liquid (e.g. an aqueous or organic solvent). This mixing step is followed by some sort of "curing" process to form the chemically bonded ceramic system, which comprises pores within which the nicotine resides. Chemically bonded ceramic systems that are formed in this way may be said to be pre-loaded with the nicotine.

Such pores are themselves a three-dimensional network of channels or voids within the solid network, containing (e.g. particles of) nicotine or a salt thereof.

Such pores may thus be essentially "secondary pores" formed by chemical interactions (e.g. "bonding") between the surfaces of primary particles of carrier (which may be porous in their own right (i.e. comprise "primary" pores). Such pores may, for example, result from exposure of such materials to one or more chemical reagents that cause a physical and/or chemical transformation (such as a partial dissolution) at, and subsequent physical and/or chemical bonding together of, those surfaces (which may in itself result as a consequence of some other physico-chemical process such as drying, curing, etc.), giving rise to said pores/voids.

In such instances, the chemical reagents may be mixed together with the nicotine prior to or during preparation of the chemically bonded ceramic system. However, such secondary pores are not necessarily formed in this way, and bonding together of primary particles of chemically bonded ceramic material may also be physical and/or mechanical, or may be formed during the production of a three-dimensional, chemically bonded ceramic network as described hereinbefore, in the presence of the nicotine.

Preferably, the precursors for the chemically bonded ceramic system are mixed with the nicotine (or salt thereof) prior to the hardening process taking place. The nicotine is then present at the moment when pore formation occurs with the result that the nicotine becomes located within the pores of the chemically bonded ceramic system. Excellent control over the total amount of nicotine loaded into the formulation can be achieved by processing in this way. Therefore in one embodiment, at least a portion of the nicotine (or salt thereof) is located within the pores of the (hardened) chemically bonded ceramic system. By this, we mean that at least 20% (e.g. at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%) by weight of the nicotine (or salt thereof) is located within the pores of the chemically bonded ceramic system. In one embodiment, essentially all of the nicotine (or salt thereof) is located within the pores of the chemically bonded ceramic system. By this, we mean that at least 90% (e.g. at least 95%, preferably at least 98%) by weight of the nicotine (or salt thereof) is located within the pores of the chemically bonded ceramic system.

The amount of nicotine (or salt thereof) present in the formulations of the invention may vary considerably according to the intended form of the oral product and the intended release profile. For example, the formulation may comprise said nicotine or salt thereof in an amount of from 0.1% to 50% by weight of the formulation.

The formulations of the invention are intended for use in the oral delivery of nicotine, both for therapeutic and recreational purposes. The formulations offer an alternative to tobacco products (such as cigarettes and tobacco-containing snus) and can so be used to reduce a user's exposure to many of the potentially toxic components found in tobacco products. Nicotine is typically obtained from tobacco products, e.g. tobacco oil and other extracts. For example, the nicotine can be provided as a free base (e.g., as a mixture of nicotine free base and a porous particulate carrier such as microcrystalline cellulose), a nicotine salt (e.g., as nicotine tartrate or nicotine bitartrate or another organic acid salt of nicotine), as a resin complex of nicotine (e.g., nicotine polacrilex), or as a solvate or other suitable form.

Preferably, some or all of the nicotine is present in the formulations of the invention as a water-soluble form of nicotine. In this context, the term "water-soluble form" is understood as referring to a form of nicotine having a solubility in water of at least 10 g of salt per 100 mL water under ambient conditions, including temperature of 25°C, atmospheric pressure, and pH of 7. The nicotine present in the formulations of the invention will typically exist as an (at least largely) amorphous material. The process by which the chemically bonded ceramic systems used in the present invention are formed involves hydration of suitable precursor materials in the presence of nicotine (or a salt thereof) followed by a hardening step. At the start of the manufacturing process, the nicotine or salt thereof is preferably provided in the form of a crystalline solid because crystalline solids of high purity can be readily sourced. During the process, the nicotine (or salt) dissolves in the hydration liquid, the subsequent drying step results in the precipitation of an amorphous nicotine product within pores in the chemically bonded ceramic system. This amorphous nicotine product may be a salt of nicotine. Powder X-ray crystallography can be used to detect the presence of crystalline components (such as nicotine), and other methods for detection and quantification of crystallinity and/or a morphicity are known in the art.

In one embodiment, the formulation of the invention is prepared using a salt of nicotine, such as a nicotine bitartrate salt (e.g. nicotine bitartrate dihydrate). Other salt forms that may be mentioned include nicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotine monotartrate, nicotine chloride (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine citrate, nicotine fumarate, nicotine gentisate, 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). For the avoidance of doubt, where a formulation of the invention is prepared using a salt of nicotine, the nicotine may be present in the final formulation as nicotine free base, a salt of nicotine (e.g. nicotine bitartrate) or a mixture thereof. Furthermore, the nicotine in the formulation may be largely (e.g. at least 70%) amorphous.

Snus pouches containing the formulations of the invention may also contain ground tobacco. However, in particular embodiments, the formulations of the invention do not contain ground tobacco. The nicotine (or salt thereof) in the formulations of the invention is believed to have an enhanced stability profile compared to commercially available formulations, i.e. compared to formulations in which nicotine is not stored within pores of a chemically bonded ceramic carrier of the sort disclosed here. Without wishing to be bound by theory, it is believed that the formulations of the invention prevent or slow the oxidation of nicotine, thus extending the shelf-life of the product.

The rate at which nicotine is absorbed into the body via the oral mucosa varies depending on the pH of the saliva. Tomar S. L. etal. (Tobacco Control 1g97;6:219- 225) reported that increased alkalinity promotes the absorption of nicotine and increases its physiological effects. A pH regulating agent is therefore provided in the formulations of the invention to enhance the rate and extent of transmucosal uptake of nicotine.

The formation of an oral formulation that contains an adequate amount of nicotine (or salt thereof) together with a pH regulating agent is difficult. We have found that, during the process of forming the hardened porous chemically bonded ceramic system, a significant proportion of the nicotine can be lost. Without wishing to be bound by theory, it is believed that the primary mechanism for loss is evaporation.

We have surprisingly found that this evaporative loss can be essentially completely eliminated by allowing the chemically bonded ceramic system to harden and set without any pH regulating agent being present. Thus, in a second aspect of the invention, there is provided a method of forming an oral formulation comprising a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH regulating agent, wherein the method comprises forming the chemically bonded ceramic system in the absence of said pH regulating agent. These methods are hereinafter referred to as "methods of the invention". All embodiments and preferences disclosed herein in connection with the formulations of the invention are also disclosed in connection with the methods of the invention.

The nicotine (or salt thereof) may still be present during the hardening phase, i.e. the nicotine can be intermixed with the precursor materials for the chemically bonded ceramic system, with the result that good control of the nicotine loading can be achieved. Thus, in one embodiment of the method of the invention, the chemically bonded ceramic system is formed in the presence of nicotine or a salt thereof. The pH regulating agent may then be introduced after the chemically bonded ceramic system has hardened without evaporative loss of nicotine occurring.

As is hereinbefore described, the chemically bonded ceramic systems of the invention may alternatively be loaded with the nicotine or salt thereof after the chemically bonded ceramic mass has been formed, e.g. by soaking the ceramic material in a liquid containing the nicotine or its salt, or through any other method which facilitates the drawing up of that substance into the pores of the ceramic material via capillary forces (including spraying, brushing, rolling, dip coating, powder coating or misting).

For the avoidance of doubt, it is not essential for all of the nicotine in the formulation to be located within the pores of the chemically bonded ceramic system. Some of the nicotine in the oral formulation may be located outside of the pores. For example, where the oral formulation is provided in the form a nicotine pouch containing the powdered formulation, a portion of the nicotine (preferably a powdered salt of nicotine) may be mixed with powdered chemically bonded ceramic system (which may itself comprise pores containing an amount of nicotine or salt thereof) prior to being placed in the pouch. Said mixing may be achieved by spraying a nicotine solution onto particles of the nicotine-loaded chemically bonded ceramic system, and then allowing that mixture to dry prior to being placed in the pouch. In such embodiments, the amount of nicotine (or salt thereof) that is added to the hardened, powdered chemically bonded ceramic system is from 1 to 50%, from 5 to 40% or from 10 to 30% by weight of the total amount of nicotine (or salt thereof) in the oral product.

In a further example, where the oral formulation is provided in the form of a nicotine pouch containing either the powdered formulation or a combination of a solid, porous chemically bonded ceramic system and nicotine (or a salt thereof), a portion of the nicotine may be associated with the material that forms the pouch, i.e. a portion of the nicotine is not located within cavity of the bag (as is described elsewhere herein) but is instead bound to or incorporated within the walls of the bag itself. This may be achieved by soaking the pouch material in a solution containing nicotine (as base or dissolved nicotine salt) and then allowing the solvent (e.g. water or another appropriate solvent) to evaporate leaving nicotine or a salt thereof incorporated into the pouch material. In embodiments in which the oral formulation is provided in the form an oral product that is a nicotine pouch and a portion of the nicotine in said oral product is associated with the material that forms the pouch, the amount of nicotine (or salt thereof) associated with the material may be from 0.1 to 30%, from 0.5 to 20% or from 1 to 10% by weight of the total amount of nicotine (or salt thereof) in the oral product.

References herein to methods of the invention in which the chemically bonded ceramic system is formed in the presence of nicotine or a salt thereof include methods in which the chemically bonded ceramic system is formed in the presence of only a portion (but not the totality) of the nicotine in the final oral product. In this way, the pores of the hardened chemically bonded ceramic system contain up to 99% (such as up to 95%, up to 90%, up to 80%, or up to 70%) by weight of the total amount of nicotine or salt thereof in the final oral product.

Typically, once a hardened mass of chemically bonded ceramic (e.g. a hardened mass of chemically bonded ceramic system which has been loaded with nicotine or a salt thereof) is formed, it is then ground to form a powder which is subsequently mixed with the pH regulating agent. The grinding process may also be performed in the presence of the pH regulating agent to ensure efficient mixing.

As the pH regulating agent is not present during the formation of the chemically bonded ceramic system, the pH regulating agent does not become incorporated into the pores of the chemically bonded ceramic system. Ingress of a small amount of the pH regulating agent into the pores of the chemically bonded ceramic system may occur when the two components are brought together or during subsequent processing, but only minimal ingress will occur in this way. Therefore, in one embodiment, the pH regulating agent is predominantly located outside of the pores of the chemically bonded ceramic system. By this, we mean that at least 90% (e.g. at least 95%, preferably at least 98%) by weight of the pH regulating agent is located outside of the pores of the chemically bonded ceramic system.

The term "pH regulating agent" refers to any substance capable of altering the pH of normal saliva. The pH of normal saliva is around 6.8. The pKa of nicotine is about 8.02 (Tomar S. L. et al., Tobacco Control 1997;6:219-225). Absorption of nicotine from the oral cavity, i.e. transmucosal uptake, to the systemic circulation is dependent on the local pH of the saliva inside and close to the product in use. Nicotine will predominantly be absorbed through the mucosa in the non-protonated form. Therefore, it is preferable to provide a local pH which results in a high fraction of the nicotine being non-protonated. For this reason, alkaline conditions enhance transport of nicotine across the oral mucosa and into the bloodstream, and so it is preferred that the pH regulating agent is an alkaline agent, i.e. a substance capable of increasing the pH of saliva above normal. Alkaline buffering agents are also contemplated in this context. The term "alkaline buffering agent" may be used interchangeably with "alkaline buffer" and refers to agents for obtaining a buffer solution with an alkaline pH. Preferred alkaline agents are buffering agents selected from the group consisting of acetates, glycinates, phosphates, glycerophosphates, citrates such as citrates of alkaline metals, carbonates (including hydrogen carbonates), and borates, or mixtures thereof. In addition, strong bases may be used such as sodium hydroxide, potassium hydroxide, and mixtures thereof. In particular embodiments, a carbonate (including a hydrogen carbonate) or a phosphate (including a triphosphate) compound may be used as the pH regulating agent. Such compounds may be formed as salts with any suitable cation, such as sodium, potassium, calcium or magnesium. Particular pH regulating agents that may be mentioned include sodium carbonate, sodium bicarbonate, trisodium phosphate, and combinations thereof.

The amount of pH regulating agent present in the formulation is typically chosen to be sufficient to raise the pH of the saliva to at least 8. In an embodiment of the invention, the formulation comprises said pH regulating agent in an amount of at least 0.1%, particularly at least 0.5%, by weight of the formulation. For example, the formulation may comprise said pH regulating agent in an amount of from 0.1% to 500/o by weight of the formulation. Such weights are particularly suited to formulations in which the pH regulating agent is a sodium carbonate, i.e. when the pH regulating agent is sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3) or a mixture thereof.

In some embodiments, the pH regulating agent is a buffering agent that comprises sodium carbonate and sodium bicarbonate, e.g. in a weight-ratio between 5:1 and 2.5:1, preferably in a weight-ratio between 4.1:1 and 3.5:1. A particular buffering agent that may be mentioned is the sodium carbonate -sodium bicarbonate buffer system.

Oral Formulations The formulations of the invention are oral formulations that are intended to release nicotine (or a salt thereof) upon exposure to moisture in the mouth. The formulations are capable of both immediate and sustained release, but are particularly suited for products intended for slow and/or sustained release.

Oral formulations that are capable of providing a sustained release of nicotine allow the user to obtain a long-lasting sensory experience using a minimal number of formulations per day. Where the formulation is intended to be used as part of a therapeutic method of treating nicotine dependence, this characteristic improves patient compliance and minimises interference with the individual's lifestyle.

The term "sustained-release" is employed herein synonymously with the term "controlled-release", and will be understood by the skilled person to include formulations that provide, and/or are adapted to provide, for a "sustained", a "prolonged" and/or an "extended" release of nicotine (in which nicotine is released at a sufficiently retarded rate to produce a therapeutic response or give a pleasurable experience over an extended period of time compared to pouch formulations currently on the market).

The formulations of the invention are capable of achieving a nearly constant rate of release over an interval of from about 10 minutes to about 1 hour, potentially longer. In one embodiment, the formulations of the invention are capable of achieving a nearly constant rate of release over an interval of from about 10 to 30 minutes. What is meant by this is that nicotine release from the formulation continually occurs (at a non-zero rate) over the specified time interval. Constant release may further be defined as a composition being capable of maintaining a steady state concentration in a body fluid not deviating more than about 20% (e.g. about 10%) from the mean value during the dose interval.

The total amount of nicotine that is delivered by each formulation is preferably from about 0.5 mg to about 15 mg, e.g., from about 1 mg to about 10 mg. For example, the formulation may deliver from about 1 mg to about 8 mg, from about 1.5 mg to about 7.5 mg, from about 2 mg to about 5 mg, from about 2.5 mg to about 5 mg, from about 3 to about 10 mg, from about 3 to about 7.5 mg or from about 3 mg to about 5 mg. In a further example, the formulation may contain about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 5 mg or about 6 mg, as calculated as free nicotine base. In particular the amount of nicotine is 2 mg, 3 mg, 4 mg or 6 mg. The above values refer to the amount of nicotine in the free base form that can be delivered from each formulation, irrespective of whether the nicotine in the formulation is provided as free base, a salt or in any other form.

The amount of nicotine contained within the oral formulation prior to use may exceed the amount of nicotine that is intended to be delivered to the user. This is because a proportion of the nicotine may be trapped within the chemically bonded ceramic system in such a way that complete release of the nicotine is not possible within the likely time period of use. However, preferably the formulation is capable of releasing substantially all of the nicotine or salt thereof upon contact with an aqueous liquid (e.g. saliva). By this, we mean that, upon contact with an aqueous liquid, the formulation is capable of releasing at least 80% (e.g. at least 90%) by weight of the nicotine or salt thereof.

The oral formulations may be supplied to users in the form of oral products that include nicotine pouches (similar to snus) and tablets. The term "nicotine pouch" as used herein refers to a pouch or bag that is fully or partially loaded with a combination of a solid, porous chemically bonded ceramic system and nicotine (or a salt thereof). In one embodiment, the pouch also contains a pH regulating agent; in such cases the pouch or bag may be said to be fully or partially loaded with a formulation of the invention. In another embodiment, pH regulating agent is incorporated into (e.g. bound to) the material that forms the pouch or bag. Nicotine pouches which comprise a pH regulating agent both within the cavity of the pouch or bag and incorporated into the material that forms said pouch or bag are also contemplated.

The formulations of the invention are particularly suited for transmucosal administration whereby the oral product (e.g. in the form of a tablet, lozenge or similar product) containing the formulation is placed in contact with the lip, gum or cheek for an extended period (several minutes) while the nicotine is released. The oral products (e.g. pouches and tablets containing the formulation of the invention) may be supplied to the end user in bulk. That is, the present invention also relates to a package containing a plurality of oral products (e.g. at least two pouches or tablets).

A nicotine pouch containing the formulation of the invention may be described as a tobacco-free version of snus. In such systems, the pouch or bag contains a specific amount of the formulation, and thereby a specific amount of nicotine, but typically does not include any tobacco dust, leaf or stem.

An embodiment of the present invention concerns a nicotine pouch comprising a permeable, sealed bag containing a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH regulating agent, wherein the chemically bonded ceramic system is formed in the absence of said pH regulating agent. The bag is typically made of a permeable material that encloses a cavity. The powdered oral formulation is stored within the cavity, but soluble components of the formulation are able to pass through the bag material when the bag is exposed to water (e.g. saliva).

Suitable materials for nicotine pouches are known to the skilled person, and include paper of the sort used in tea bags, filter paper, and the like. Other materials include heat-sealable non-woven cellulose, such as long fiber paper, cotton and silk.

The formulation of the invention also provides stable storage of the nicotine (or salt thereof) prior to use. The formulation of the invention is preferably stored in an airtight container, such as a tin or bag, prior to use, and it may be stored in this way for several weeks or months without significant loss of the nicotine. Suitable storage containers are known to the skilled person and include any conventional closable container. These storage containers may provide a convenient and portable system capable of holding multiple pouches or tablets. A further aspect of the invention therefore relates to a closable container comprising one or more, and preferably a plurality of, oral products of the invention (e.g. nicotine pouches or sublingual tablets as described herein).

As is hereinbefore mentioned, the pH regulating agent is not present during the formation of the chemically bonded ceramic system, so the pH regulating agent does not become incorporated into the pores of the chemically bonded ceramic system. The pH regulating agent may therefore be incorporated into the final product through other methods, e.g. by mixing the pH regulating agent with the hardened chemically bonded ceramic system as is hereinbefore described. Alternatively, or additionally, the pH regulating agent may be associated with the bag material itself. For example, particles of the pH regulating agent (e.g. sodium carbonate and/or sodium bicarbonate) may be embedded within the permeable material of the bag so that the pH regulating agent is readily able to dissolve upon contact with saliva. Thus, in one embodiment, the bag comprises a cavity surrounded by a permeable material, and the pH regulating agent is associated with the permeable material. Other suitable methods of incorporating the pH regulating agent into the bag material would be known to the skilled person.

In an embodiment of the invention, the oral formulation is contained within a pouch, and the total weight of the loaded pouch is from 0.2 to 3 g, such as from 0.4 to 2 g. In another embodiment, the nicotine pouch has a weight and/or volume similar to commercially available portion snus products and nicotine pouches.

Nicotine pouches may be manufactured using methods known to those skilled in the art, particularly those methods used for the manufacture of snus and commercially available nicotine pouches (such as ZYN). For example, the powdered contents for the pouch may be made using the methods described herein or using conventional methods known in the art, and the powder may then be then loaded into sealable bags, e.g. heat-sealable bags. Such bags should be water insoluble and permeable to saliva.

Suitable materials for nicotine pouches are described hereinbefore, and are also known to the skilled person, for example from US patent no. 9,161,908. Heat-sealable nonwoven cellulose, such as long fiber paper, offers a particularly suitable material for use in nicotine pouches. Once a prescribed amount of the powder is filled into the pouch, it is maintained in the pouch by sealing. Uptake of nicotine in the mouth may be facilitated by incorporating a bioadhesion and/or mucoadhesion promoting agent into the nicotine pouch. The bioadhesion and/or mucoadhesion promoting agent may be provided in cavity of the bag. Alternatively, or additionally, that agent may be incorporated into or combined with the bag material.

Tablet-based oral products that may be mentioned include oral tablets, sublingual tablets and buccal tablets. In this form, the oral product containing the formulation of the invention is intended to be placed under tongue, under the lip, against the gum, or against the cheek, and the nicotine is absorbed through the surrounding mucous membranes. References to "sublingual tablets" elsewhere herein include references to oral tablets and buccal tablets except where indicated otherwise. Adhesion to the interior surface of the mouth may be facilitated by incorporating a bioadhesion and/or mucoadhesion promoting agent into the tablet.

The bioadhesion and/or mucoadhesion promoting agent is effective in making the tablet or pouch adhere to the oral mucosa and may, in addition, possess properties to swell and expand in contact with water and thus make a tablet disintegrate when wetted with saliva.

The expression "mucoadhesion" is meant to denote an adhesion to mucous membranes which are covered by mucus, such as those in the oral cavity, while the expression "bioadhesion" is meant to denote an adhesion to biological surfaces more in general, including mucous membranes which are not covered by mucus. These expressions generally overlap as definitions, and may usually be used interchangeably, although the expression "bioadhesive" has a somewhat wider scope. In the present specification and claims, the two expressions serve the same purpose as regards the objects of the invention, and this has been expressed by the use of the common term "bio/mucoadhesion". Suitably the tablet contains from 0.1 up to 25 weight percent of bio/mucoadhesion promoting compound, based on the total weight of the tablet.

It is preferred that the bio/mucoadhesion promoting agent is a polymeric substance, preferably a substance with an average molecular weight above 5,000 Daltons (weight average). A variety of polymers known in the art can be used as bio/mucoadhesion promoting agents. Examples of such bio/mucoadhesion promoting agents include cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, modified cellulose gum and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as moderately cross-linked starch, modified starch and sodium starch glycolate; acrylic polymers such as carbomer and its derivatives (Polycarbophyl, Carbopol0), etc.); polyvinylpyrrolidone; polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; poly co(methylvinyl ether/maleic anhydride); microcrystalline cellulose (Avicel); and croscarmellose (e.g. crosscarmellose sodium). Such polymers may be crosslinked.

Combinations of two or more bio/mucoadhesive polymers can also be used.

Substances like HPMC that can produce a smooth surface for the finished tablet whilst still enabling the tablet to stick to oral mucosa are particularly advantageous.

In an embodiment of the invention, the oral formulation is provided in the form of a tablet having a total weight of from 25 to 200 mg, such as from 50 to 150 mg.

Tablets (e.g. sublingual tablets) may be manufactured using methods known to those skilled in the art, such as dry powder blending, granulation and tablet pressing. Tablets may also be made by mixing the dry ingredients, including the precursor(s) for the chemically bonded ceramic system, adding water, wet mixing and then casting.

The final tablet may, for example, by a buccal tablet that does not fully dissolve in the mouth but which needs to be physically removed once used. The tablet may alternatively be a dissolving tablet in which all components are dissolved and either absorbed or swallowed.

Nicotine pouches and tablets may also contain one or more other ingredients selected from the group consisting of a filler (typically a food grade filler), water, salt, and flavouring. It is not essential that any of these other ingredients is incorporated into the pores of the chemically bonded ceramic system, however any such ingredients that are incorporated in this way and are water soluble will be expected to have a similar release profile to the nicotine contained within those pores.

Fillers that may be used in nicotine pouches include rubber arabicum, microcrystalline cellulose, maltitol. Other fillers that may be mentioned include inert inorganic fillers such as alumina, zirconia, and glass.

Fillers that may be used in sublingual tablets include conventional fillers known to the skilled person in the context of pharmaceutical formulations, particularly oral tablets and capsules. Appropriate materials are well known to the person skilled in the art; see, for instance. Dosage Forms: Tablets. Volume 1, 2nd Edition, Lieberman H A et al. New York and Basel 1989, p. 354-356, and literature cited therein.

Fillers are typically present in the oral product in an amount ranging from about 100/a to about 903'o by weight of the oral product.

Controlled release agents may also be incorporated into the formulation. Such agents slow the rate of release of nicotine from the product and thereby extend the duration of the sensory experience for the user. It is preferred that the controlled-release agent is a material that is capable of providing a sustained-release, a delayed-release or both.

In this respect, it is preferred that the controlled-release agent is a polymer. Examples of polymers that may be employed as controlled-release agents include, without limitation: alkylcellulose polymers (e.g. ethylcellulose polymers), and acrylic polymers (e.g. acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamid copolymer, poly(methyl methacryate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacryamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers). The polymer may also be a mixture of polymers. Typically, the molecular weight (weight average and/or number average) of the polymer is 1,000 to 10,000,000, 10,000 to 1,000,000, preferably 50,000 to 500,000 g/mol, as measured by gel permeation chromatography.

Preferred polymers include the alkyl cellulose polymers and acrylic polymers described herein.

In order to improve the sensory properties of the formulation of the invention, one or more sweeteners or texture improvers may be added. These substances include sugar alcohols such as mannitol, xylitol, sorbitol, maltitol and/or isomalt, or artificial sweeteners such as aspartame, acesulfame and/or saccharin. Sweeteners are particular useful for masking the taste of the nicotine in the formulation.

Other flavourings that may be used, particularly in nicotine pouches, include menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, black cherry, coffee, cinnamon, clove, tobacco, citrus, fruit flavour and mixtures thereof. In one embodiment, the flavouring is not tobacco. The formulations of the invention may be used with any flavour or combination of flavours. Such flavour may be present in an amount of at least 0.1%, and preferably not more than 5%, by weight of the nicotine

pouch or tablet.

Substances that give a cooling mouthfeel, such as sugar alcohols (e.g. erythritol), may be used in the oral products disclosed herein.

Particular oral formulations that may be mentioned include oral formulations 10 comprising: a solid, porous chemically bonded ceramic system formed from a material selected from the group consisting of alpha-tricalcium phosphate, tetracalcium phosphate, calcium sulphate and combinations thereof; a pH regulating agent that comprises a sodium carbonate (i.e. sodium bicarbonate and/or sodium carbonate); and nicotine or a salt thereof; wherein the chemically bonded ceramic system is formed in the absence of said pH regulating agent. Said oral formulations may be advantageously provided in the form of a sublingual or buccal tablet (such as a tablet containing a bioadhesion and/or mucoadhesion promoting agent) or nicotine pouch (i.e. a permeable, sealed bag containing the solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and pH regulating agent).

Medical and Recreational Uses The formulations of the invention have medical and/or recreational use.

The formulations may be placed in the mouth whereupon they are moistened through contact with saliva. The formulation may, for example, be placed in the mouth in contact with the lip, gum or cheek, and left there for an extended period. Typically, the formulation is retained in the mouth for a period of from five minutes to one hour. Longer durations are possible if the formulation is tailored to provide slower sustained release of the nicotine, e.g. by including a controlled release agent such as hydroxypropyl methyl cellulose.

In a medical context, the formulations of the invention may be used in the treatment of nicotine dependence, (e.g. nicotine addiction) with a view to aiding an individual in reducing smoking or stopping altogether. The formulations of the invention may therefore be described as being useful in aiding smoking cessation.

In a further aspect of the invention there is provided a method of treating nicotine dependence (e.g. nicotine addiction) wherein the method involves administration of a formulation of the present invention to a person suffering from symptoms of nicotine dependence. Similarly, the formulations of the invention may be useful in a method of treating (e.g. alleviating) the symptoms of nicotine dependence (including nicotine addiction or nicotine withdrawal). Such symptoms may include cravings for nicotine, anger/irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger or weight gain, and/or difficulty concentrating. Said use may also be referred to as nicotine replacement therapy.

Nicotine may also be used to ameliorate symptoms associated with various diseases, including dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression. Thus, in a yet further aspect of the invention there is provided a method of ameliorating symptoms associated with dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression, wherein the method involves administering a formulation of the present invention to a person suffering from said symptoms.

Thus, in a further aspect of the invention there is provided a method of treating nicotine dependence, treating one or more symptoms of nicotine dependence, aiding smoking cessation or ameliorating symptoms associated with a disease or conditions selected from the group consisting of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease and depression, which method comprises administering a formulation of the present invention (including any of the oral products described herein) to a person in need thereof.

Formulations the present invention are capable of releasing a pharmacologically effective amount of nicotine during normal use. By "pharmacologically effective amount", we refer to an amount of nicotine which is capable of conferring a desired therapeutic effect on a treated patient, whether administered alone or in combination with another active ingredient. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, an effect).

More preferred formulations of the invention may be adapted (for example as described herein) to provide a sufficient dose of nicotine over the dosing interval (irrespective of the number of doses per unit time) to produce a desired therapeutic effect.

The amounts of active ingredients that may be employed in formulations of the invention may thus be determined by therapeutic standards, the physician, or the skilled person, in relation to what will be most suitable for an individual patient or the condition to be treated. This is likely to vary with the type and severity of the condition that is to be treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.

Suitable daily dosages of nicotine, both for medicinal and recreational purposes, may be from about 1 to about 100 mg/day. Conventional cigarettes typically contain between about 8 and 15 mg nicotine. In one embodiment, each nicotine pouch or tablet of the invention is capable of delivering from about 3 to about 15 mg nicotine.

It is preferred that the products disclosed herein are capable of delivering an amount of nicotine that is at least equivalent to one cigarette. When the nicotine is supplied to the patient in the form of a tablet (e.g. an oral, sublingual or buccal tablets), then each tablet may contain from about 3 to about 15 mg nicotine, e.g. from about 8 mg to about 15 mg of nicotine.

The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Ingress of moisture into the pores of the chemically bonded ceramic system results in the release of the nicotine (or salt thereof) contained within. The rate and extent of nicotine absorption into the body via the oral mucosa is increased when the alkalinity of the oral environment is increased, and the pH regulating agent in the formulation facilitates this. In an embodiment of the invention, at least 50% by weight of the nicotine released from the formulation is absorbed through the oral mucosa.

Nicotine may be released alongside a sweetener and/or other flavours which help to mask the taste of the nicotine whilst ensuring that the intended benefits arising from the absorption of the nicotine are still achieved.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the symptomatic treatment, the prophylaxis, or the diagnosis, of the condition.

When used for recreational purposes, the formulations are capable of delivering a sufficient amount of nicotine to provide a pleasurable sensory experience for the user.

The formulations of the invention may also be capable of improving the oral health of the user. As is discussed hereinbefore, this is particularly the case for formulations in which the chemically bonded ceramic system contains calcium and is capable of releasing this mineral (e.g. in the form of solubilised calcium ions) into the saliva and optionally also increasing the pH of the saliva through the release of hydroxide ions.

Solubilised calcium aids with remineralisation of teeth and bone, and so can contribute to mineral growth on the surfaces of teeth. Oral formulations of this sort have potential utility in repairing dental enamel and strengthening teeth.

The formulations of the invention may have the advantage that they provide an extended release of nicotine (e.g. nicotine is released at a sufficiently retarded rate to produce a therapeutic response or give a pleasurable experience over an extended period of time compared to pouch formulations currently on the market). The formulations of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be faster acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile than, and/or have other useful pharmacological, physical, or chemical properties over, pharmaceutical compositions known in the prior art.

The use of the chemically bonded ceramic systems described herein affords for the provision of products which provide acceptable levels of release of nicotine when placed in the mouth, while minimising the risk of exposure to the stored nicotine (or salt thereof) within, e.g. through leakage.

The chemically bonded ceramic systems are also easily manufactured without the need for high temperature sintering, and therefore additional elements such as flavours, fillers and the like can be incorporated into the carrier to aid in the achieving the desired sensory experience. The ability to incorporate the nicotine (or salt thereof) into the carrier as the network structure is formed also allows for greater control over the amount of nicotine that is ultimately delivered to the user.

Wherever the word "about" is employed herein in the context of dimensions (e.g. values, temperatures, pressures (exerted forces), relative humidities, sizes and weights, particle or grain sizes, pore sizes, timeframes etc.), amounts (e.g. relative amounts (e.g. numbers or percentages) of particles, individual constituents in a composition or a component of a composition and absolute amounts, such as doses of nicotine, numbers of particles, etc.), deviations (from constants, degrees of degradation, etc.) it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1%) from the numbers specified herein.

The invention is illustrated by the following examples in which: Figure 1 shows the release profiles for nicotine loaded powders made in the presence of sodium bicarbonate (triangles) and absence of sodium bicarbonate (circles); Figure 2 shows the impact of different drying conditions and the presence of absence of sodium bicarbonate on the amount of nicotine that can be release from moulded

tablets;

Figures 3a and 3b show the nicotine release profiles for a powdered mixture with a particle size of 100-200 pm stored within ZYN pouches alongside commercial Zyn Mini Dry (particle size 100-200pm) with two time scales.

Examoles Example 1 -Impact of sodium bicarbonate and sodium carbonate on nicotine during. loading.

Materials The nicotine salt used was a USP grade nicotine bitartrate dihydrate. The pH regulating agent used was standard food grade sodium bicarbonate (referred to herein as E500). A BP, DAB grade calcium sulphate hemihydrate was used to form the chemically bonded ceramic system.

Method (i) Without E500: 12.4954 g of BP, DAB grade calcium sulphate hemihydrate and 0.5252g of nicotine bitartrate dihydrate were dry mixed using a Turbula mixer at 46 rpm for 10 minutes.

As a next step, 10.0 g of water was added to form a paste by hand mixing using a spatula. The paste was cast into a rectangular shaped plate approximately 11 x 13 cm and 2 mm thick. The plate was left to harden at 35°C and -95% humidity for approximately 1 hour whereafter the hardened paste was left to dry in room temperature for about 18 hours before crushing and sieving. The dried plates were crushed by hand using a spoon, pestle and mortar and sieved using a Retsch AS 200 Basic sieve shaker stack to obtain particle size fractions ranging from 100 pm to 500 pm.

(ii) With E500: 0.5258g of nicotine bitartrate dihydrate and 0.5249 g of E500 was mixed with 10 mL of water. As a next step, the liquid was added to 12.5064 g of calcium sulphate hemihydrate BP, DAB grade to form a paste by hand mixing using a spatula. The paste was cast into a rectangular shaped plate approximately 11 x 13 cm and 2 mm thick. The plate was left to harden at 30°C and -95% humidity overnight whereafter the hardened paste was left to dry in room temperature for about 18 hours before crushing and sieving. The dried plates were crushed by hand using a spoon, pestle and mortar and sieved using a Retsch AS 200 Basic sieve shaker stack to obtain particle size fractions.

Analysis All crushed powders were put in "Snuff" pouches commercially available for home making of wet snuff. The pouches are made out of non-woven cellulose and can be welded using gentle heat.

Extraction experiments were performed using a dissolution test set up according to USE' 711 Apparatus 2 with mini vessels. In short, the samples were put in 100m1 of phosphate buffer pH 6.8 at 37°C with the stirring paddles at 50rpm. 1 ml samples were then withdrawn for analysis at different timepoints. The amount of dissolved nicotine was determined using an HPLC system.

Results and Conclusions

In the absence of E500 during preparation of the paste, the extractable amount of nicotine present in the powder was 700/o of the amount of nicotine that was loaded. When E500 was present during loading, the extractable amount of nicotine present in the powder was 25-30% of the amount of nicotine that was loaded. Results are shown in Figure 1.

Addition of sodium bicarbonate during manufacture of the paste drastically decreased the amount of nicotine that was extractable from the samples.

Analogous experiments were also conducted in which a crushed powder was produced according to method (i) above, and then mixed with an amount of sodium bicarbonate corresponding to the amount used in method (ii). This mixture was also placed into "Snuff" pouches. Analysis of nicotine release was assessed using the method above and the release profile was found to be in line with that observed for the powder manufactured by method (i) and not subsequently mixed with sodium bicarbonate. This confirms that the sodium bicarbonate only influenced the nicotine release profile of the final powder when the sodium bicarbonate was present during the step of hardening the calcium sulfate hemihydrate aqueous paste.

Further analogous experiments have also been conducted using sodium carbonate in place of sodium bicarbonate. The results of these experiments showed that the addition of sodium carbonate to the mixture containing water, nicotine bitartrate dihydrate and calcium sulphate hemihydrate also lowered the nicotine content in the finished powder.

Example 2

This experiment was conducted to further explore the mechanism behind the nicotine loss observed in Example 1.

Method Samples formed using BP and DAB grade calcium sulphate hemihydrate and nicotine in the form of USP grade nicotine bitartrate dihydrate were prepared according to the methods descried in Example 1. Half of the samples contained sodium bicarbonate and half did not.

In contrast to Example 1, the paste was moulded into tablets using empty tablet blisters and then hardened under different conditions described below (instead of casting a plate that is crushed and sieved).

Two sets of hardening conditions were used: "Zip": the moulded paste was stored at room temperature -24 °C in an airtight zip bag not much larger than the blister.

100% RH: the plate was stored at about 100% relative humidity and 30 °C for a period of time and then "dried" at room temperature before analysis.

Analysis The analysis was performed by extraction of the moulded tablets. Each tablet was put in a 50 mL Falcon tube with 15 mL of distilled water. The tubes were put on a shaker table for approximately 1 hour whereafter the extract was analysed with a UV-spectrophotometer at a wavelength of 216 nm. Standard curves were obtained using defined solutions with nicotine base.

Results The results are shown in figure 2. Adding sodium bicarbonate (E500) to the formulation during manufacturing of the paste significantly decrease the amount of extractable nicotine. Letting the material set and harden in a moist and warm environment significantly decreased the amount of extractable nicotine.

The results show that the addition of the pH regulating agent should be made either by mixing the dry components after the chemically bonded ceramic system is hardened, crushed and sieved or incorporated into the formulation in some other fashion.

Example 3 -Comparison with commercial products Method Samples formed using BP and DAB grade calcium sulphate hemihydrate and nicotine in the form of USP grade nicotine bitartrate dihydrate were prepared and analysed according to the methods descried in Example 1. The dried plates were crushed by hand using a spoon, pestle and mortar and sieved using a Retsch AS 200 Basic sieve shaker stack to obtain particle size fractions. In this example only the 100 -200 pm size fraction was used. The particles were put into "Zyn" pouches that had been emptied and cleaned. The pouches were then re-sealed using heat.

The commercial product tested was a dry well-known Swedish product, Zyn Mini Dry, purchased at a convenience store. For the Zyn product ten pouches were cut open and the powder inside was removed and sieved as in examples above. The 100 -200 pm fraction was selected and put back into the pouches and sealed.

Analysis of nicotine release was performed as described in Example 1.

Results Incorporation of nicotine into a chemically bonded ceramic system formed from calcium sulphate was shown to result in a release of nicotine on the same level but with prolonged release compared to the commercial Zyn Mini Dry product. Results are shown in figures 3a and 3b. For comparison reasons, the scale on the Y-axis is normalised, meaning that for each curve the amount extracted at the last time point measured is set as 100%.

Example 4 -pH comparison with commercial products Method Samples using BP and DAB grade calcium sulphate hemihydrate (CaSH), nicotine in the form of USP grade nicotine bitartrate dihydrate were prepared according to the following: 23.1186 g CaSH was weighed onto a Al-foil sheet. 2.4886 g of nicotine bitartrate dihydrate was dissolved in 10 g of distilled water in a beaker. The nicotine -water solution was added to the powder and the beaker was rinsed with 8 g of distilled water that was added to the mix. The mixture was stirred by hand for about 1 minute and then spread out evenly on the sheet. The material was left to set and dry at room temperature for 48 hours. Thereafter the material was crushed using pestle and mortar and finally sieved with a Retsch AS 200 Basic sieve shaker stack to obtain particles in the range of 50 -500pm. The powder was tested using a spectrophotometer to confirm nicotine content.

300 mg of the resulting powder was mixed with 3.62 wt% of Ph. Eur grade anhydrous sodium carbonate and sealed in a pouch made of non-woven cellulose. The pH generated by a pouch in distilled water was then measured and compared to the pH obtained for seven different commercial products (Nils Cortado, ZYN Cool Mint Slim, VOLT Spearmint Breeze, ON! Berry, Nordic Spirit Elderflower, Lyft Ice Cool, and ZYN Cool Mint Mini Dry).

Analysis Nicotine analysis: 300 mg of the powder was diluted in 100 mL of distilled water and shaken for about 1 min. The dilute was then analyzed in a UV-spectrophotometer system (VWR UV-3100 PC) pH analysis: The pH measurements were performed using a calibrated Mettler Toledo Seven compact pH/Ion 5220 system with a Mettler Toledo InLab Expert Pro electrode. Each pouch was placed in a beaker with 25mL of distilled water and stirred for 30 min using a magnet and magnetic stirrer. After 30 min the magnet and pouch were removed and the pH measured.

Results Nicotine analysis: 100% of the added nicotine was recovered in the sample pH analysis: The pH results are summarised in the table below.

Product pH Chemically bonded ceramic 8.418 Nils Cortado 8.268 ZYN Cool Mint Slim 7.425 VOLT Spearmint Breeze 8.687 ON! Berry 8.442 Nordic Spirit Elderflower 8.930 eLyft Ice Cool 8.528 ZYN Cool Mint Mini Dry 8.726 It can be concluded that the pH of the chemically bonded ceramic system is in line with the commercial products.

Claims

Claims 1. An oral formulation comprising a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH regulating agent, wherein the chemically bonded ceramic system is formed in the absence of said pH regulating agent.
2. The oral formulation according to Claim 1, wherein the chemically bonded ceramic system contains calcium.
3. The oral formulation according to Claim 2, wherein the chemically bonded ceramic system is based on a calcium phosphate, a calcium sulphate, a calcium carbonate, a calcium silicate, a calcium aluminate, or a mixture thereof.
4. The oral formulation according to Claim 3, wherein the chemically bonded ceramic system is formed from alpha-tricalcium phosphate, tetracalcium phosphate or calcium sulfate.
5. The oral formulation according to any one of the preceding claims, wherein the formulation is prepared using a salt of nicotine, such as nicotine bitartrate dihydrate.
6. The oral formulation according to any one of the preceding claims, wherein the pH regulating agent is a carbonate or a hydrogen carbonate or a phosphate compound.
7. The oral formulation according to any one of the preceding claims, wherein the formulation produces a pH of at least 8 when it is brought into contact with saliva.
8. The oral formulation according to any one of the preceding claims, wherein a portion of the nicotine or salt thereof is located within the pores of the chemically bonded ceramic system.
9. The oral formulation according to any one of the preceding claims, wherein the pH regulating agent is predominantly located outside of the pores of the chemically bonded ceramic system.
10. The oral formulation according to any one of the preceding claims, wherein the formulation is capable of releasing substantially all of the nicotine or salt thereof upon contact with an aqueous liquid.
11. A permeable, sealed bag containing a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH regulating agent, wherein the chemically bonded ceramic system is formed in the absence of said pH regulating agent.
12. The bag according to Claim 11, wherein the bag comprises a cavity surrounded by a permeable material, and the pH regulating agent is associated with the permeable material.
13. An oral, sublingual or buccal tablet containing an oral formulation according to any one of Claims 1 to 10 and a bioadhesion and/or mucoadhesion promoting agent.
14. A method of forming an oral formulation comprising a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH regulating agent, wherein the method comprises forming the chemically bonded ceramic system in the absence of said pH regulating agent.
15. The method according to Claim 14, wherein the chemically bonded ceramic system is formed in the presence of nicotine or a salt thereof.
16. A method of treating nicotine dependence, treating one or more symptoms of nicotine dependence, aiding smoking cessation or ameliorating symptoms associated with a disease or conditions selected from the group consisting of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease and depression, which method comprises administering an oral formulation as defined in any one of Claims 1 to 10, a bag according to Claim 11 or 12 or a tablet according to Claim 13 to a person in need thereof.