Intraoral preparations, permeable sealed bags, tablets, methods and uses thereof

Abstract

An intraoral formulation is provided that includes a solid, porous, chemically bonded ceramic system, nicotine or a salt thereof, and a pH modifier, where the chemically bonded ceramic system is formed in the absence of the pH modifier. The formulation includes nicotine and has particular utility in aiding smoking cessation, treating nicotine dependence, alleviating the symptoms of nicotine dependence, and in other medical uses for which nicotine is known.

Description

[Technical field]

[0001] The present invention relates to new formulations for buccal delivery of nicotine. The present invention also relates to a method for producing a nicotine formulation suitable for buccal delivery. The formulations may be used to aid smoking cessation, treat nicotine dependence, or alleviate the symptoms of nicotine dependence. The formulations may also be used in recreational products. [Background technology]

[0002] A variety of nicotine replacement therapy products are available on the market, including patches, gums, lozenges, nicotine pouches, sublingual tablets, inhalers, and nasal sprays (U. Wadgave et al., Int J Health Sci (Qassim), 2016 Jul; 10 (3): 425-435). Nicotine replacement therapies such as these are useful in helping tobacco users overcome the difficulties that arise from nicotine withdrawal when trying to reduce their exposure to tobacco products, especially cigarettes.

[0003] Some nicotine delivery systems are also used by individuals to provide a pleasurable sensation resulting from nicotine intake. Oral products used in this manner include nicotine pouches and snus, the latter of which is particularly popular in Norway and Sweden. Snus is a tobacco-containing product that is typically provided as either loose snus or portioned snus. Snus products are also a convenient and safe alternative to cigarettes because they provide a nicotine source that does not expose the user to some of the 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 used in cigarette filters).

[0004] Loose snus is a moist powder that can be divided and filled into cylinders or spheres with a fingertip or a purpose-made device. The formed mass of snus is then placed under the upper lip. Over time, the demand for loose snus is replaced by portioned varieties, which benefit users due to their easy handling and more discreet nature.

[0005] Portioned snus is packaged as a moist powder in small teabag-like pouches that are also intended to be placed under the upper lip. Like snus, portioned snus is typically held in the mouth for a period lasting from 5 minutes to an hour, with nicotine being released throughout this time.

[0006] Portioned snus is available in three different sizes: mini, normal / large (most common), and maxi. Mini portions typically weigh close to 0.5g, normal (large) portions weigh about 0.8 to 1 gram, and maxi portions weigh up to 1.7g. Some manufacturers also offer a choice of "regular" and "long" versions of the normal-sized pouches, which are similar in content weight. These long portions differ from traditional pouches in that they are thinner but longer to fit 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 pouch products to improve product stability.

[0007] Nicotine pouches are white pre-portioned pouches that contain either tobacco-derived nicotine, potentially in salt form, or synthetic nicotine, but do not contain tobacco leaves, ground tobacco (i.e., dust), or tobacco stems. They are described as being similar to snus or as 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 branded by Swedish Match® (N. Plurphanswat et al., The American Journal on Addictions, 29:279-286, 2020; Lunell E., et al., Nicotine & Tobacco Research, 2020, 1757-1763). A number of cellulose-containing commercial products that deliver nicotine are available. However, when placed in the mouth, cellulose can interact with water to form a slimy mass in the consumer's mouth, which likely negatively impacts the user's flavor experience and therefore nicotine release.

[0008] Nicotine pouches, for example, are approved by the Norwegian Medicines Agency for smoking cessation and are marketed as nicotine replacement therapy. Nicotine pouches are also increasingly used recreationally as an alternative to tobacco products such as cigarettes and snus. Nicotine pouches can be dry or moist. Moist pouches generally feel more comfortable in the mouth and often provide a more rapid release of nicotine. Moist pouches typically contain glycerol.

[0009] To use a nicotine pouch, the user places the pouch in contact with the inside of the mouth, typically between the upper lip and gums, behind the lower lip, or against the cheek, and leaves it there while the nicotine and flavor are released, much like portioned snus. The pouch is typically held in the mouth for a period of five minutes to an hour, and then disposed of when finished.

[0010] Immediate release oral nicotine products are disclosed in international patent application published under number WO 2019 / 110073. Pouches containing nicotine in free base form are disclosed in U.S. Pat. No. 9,161,908.

[0011] Nicotine delivery through the oral mucosa (especially the sublingual and buccal mucosa) can be greatly enhanced by raising the pH of the oral environment above normal levels, typically to about pH 8-9 (see Ciolino LA, McCauley HA, Fraser DB, Wolnik KA. J. Anal. Toxicol. 2001;25:15-25, and Tomar Slet al. Tobacco Control 1997;6:219-225). To achieve this pH increase, pH adjusters or suitable buffering agents can be incorporated into the oral product.

[0012] Commercially available nicotine pouches typically have a release profile in which a significant proportion of the nicotine is released in a short period of time, which may lead to the nicotine being swallowed and / or cause saturation of the mucosa. It is speculated that if the mucosa and the immediately surrounding saliva are saturated, a significant amount of the available nicotine will be washed away by the saliva and swallowed. Controlling the total amount and rate of nicotine release from an intraoral product to provide long-lasting therapeutic and / or non-therapeutic effects presents an additional challenge. There is an unmet need for an oral transmucosal (intraoral) product that provides a controlled release of nicotine and provides and maintains a suitably alkaline environment to ensure proper uptake of nicotine into the bloodstream.

[0013] We have now devised novel formulations of nicotine (or salts thereof) suitable for buccal delivery, and methods for making same, which have advantageous properties and which solve one or more of the problems associated with nicotine formulations suitable for buccal delivery.

[0014] 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. Summary of the Invention

[0015] According to a first aspect of the present invention, there is provided an intraoral formulation comprising a solid, porous, chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjuster, wherein the chemically bonded ceramic system is formed in the absence of the pH adjuster.

[0016] These intraoral preparations are hereinafter referred to as "preparations of the invention".

[0017] It has been advantageously found that for formulations of the invention prepared in this manner, i.e., where a pH adjusting agent is mixed with or provided together with the combination of a solid, porous chemically bonded ceramic system and nicotine (or a salt thereof), but where the chemically bonded ceramic system is formed in the absence of said pH adjusting agent, it is possible to achieve a high degree of loading of the pores of the chemically bonded ceramic system with nicotine (or a salt thereof), whilst still enabling the product, once in the mouth, to deliver nicotine across the oral mucosa at a satisfactory rate and to a satisfactory extent.

[0018] By using the term "chemically bonded ceramic systems" (or the like), we refer to materials that can be formed at room temperature or slightly elevated temperatures (e.g., less than about 200° C.). These systems function as carriers in the formulations of the present invention because they contain pores in which nicotine (or a salt thereof) can be located.

[0019] The term "chemically bonded ceramic" typically refers to a system formed from a self-solidifying precursor material. Chemically bonded ceramic systems include unhydrated, partially hydrated, or fully hydrated ceramics. Thus, in one embodiment of the present invention, the porous solid is based on a ceramic material formed from a self-solidifying precursor ceramic. Non-limiting examples of chemically bonded ceramic systems include those formed from calcium phosphate, calcium sulfate, calcium silicate, calcium aluminate, magnesium carbonate, and combinations thereof. Preferred chemical compositions include those based on chemically bonded ceramic systems, which consume a controlled amount of water to form a network after hydration of one or more suitable precursor materials. Precursor materials that may be mentioned in this regard include CaOAl2O3, (CaO) 12 These include (Al2O3)7, (CaO)3(Al2O3), (CaO)(Al2O3)2, (CaO)3(SiO2), (CaO)2(SiO2), and especially alpha-tricalcium phosphate, tetracalcium phosphate (Ca4(PO4)2O), and calcium sulfate (e.g., calcium sulfate hemihydrate). All of these materials can react with water at room temperature to form chemically bonded ceramic systems. The water may be provided in liquid form, or the precursor materials may be exposed to a humid atmosphere for a sufficient time for the material to vulcanize and harden.

[0020] Other available specific systems are based on aluminates and silicates, both of which consume large amounts of water. Phases such as CA2, CA, C3A and C12A7, as well as C2S and C3S (following common cement terminology, C=CaO, A=Al2O3, SiO2=S), in crystalline or amorphous state may be used and are readily available. Calcium aluminate and / or calcium silicate phases may be used as separate phases or mixtures of phases. The above phases, all in unhydrated form, act as binding phases (cements) in the carrier when hydrated. The liquid (water) to cement weight ratio is typically in the range of 0.2-0.5, preferably 0.3-0.4.

[0021] The water-to-cement ratio during manufacture, especially for chemically bonded ceramic systems formed from calcium aluminates and calcium silicates, is important for pore size and pore volume. As an example, for a phase-pure 1:1 CA precursor, the theoretical water-to-cement ("W / C") ratio that results in 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 increased pore volume and, to some extent, increased pore size. For calcium aluminates and calcium silicates, the tolerance range of water content is very wide, i.e., it is possible to increase the W / C ratio well beyond the theoretical value required for complete hydration and still have a set body with sufficient structural integrity.

[0022] Other ceramic materials that may be used include those based on sulfates such as calcium sulfate or phosphates such as calcium phosphate. Specific examples of such materials include alpha or beta phase calcium sulfate hemihydrate (final product calcium sulfate dihydrate), alkaline or neutral calcium phosphates (apatite), and acidic calcium phosphates (brushite).

[0023] The use of calcium-containing chemically bonded ceramic systems may be particularly beneficial for the oral health of the user. Chemically bonded ceramic systems capable of releasing calcium (e.g., in the form of solubilized calcium ions) into saliva may be capable of remineralization and thus contribute, for example, to mineral growth on the tooth surface. Materials that allow excess ions (e.g., calcium ions, hydroxide ions, and possibly phosphate ions) to diffuse into the surrounding saliva under physiological conditions (e.g., at pH and temperature typically found in the mouth) may be particularly suitable for this, such materials including chemically bonded ceramic systems formed from alpha-tricalcium phosphate and tetracalcium phosphate. Chemically bonded ceramic systems formed from materials other than calcium phosphate, but still capable of releasing calcium into saliva, are also useful in this context, since saliva may act as a source of phosphate ions and thus contribute to mineral growth such as dental apatite. Such materials include chemically bonded ceramic systems formed from calcium silicates, calcium aluminates, and especially calcium sulfate.

[0024] The buccal formulation of the present invention may contain any amount of carrier sufficient to hold and deliver the intended amount of nicotine during use. In one embodiment of the present invention, the chemically bonded ceramic system is present in about 40% to about 98% by weight of the buccal formulation. The buccal products described herein (e.g., nicotine pouches, and sublingual and buccal tablets) typically have a mass of not more than 2 grams. In an embodiment of the present invention, the chemically bonded ceramic system is present in about 40% to about 98% by weight of the buccal product (e.g., nicotine pouches, and sublingual and buccal tablets).

[0025] The chemically bonded ceramic system used in the formulation of the present invention can be loaded with nicotine or its salt by immersing the chemically bonded ceramic material in a liquid containing nicotine or its salt, or through any other method that facilitates drawing the substance into the pores of the chemically bonded ceramic material via capillary forces (including spraying, brushing, rolling, dip coating, powder coating, misting, or vacuum-enhanced loading). In one example, the pH adjuster is not present during the process of loading the chemically bonded ceramic system with nicotine (or its salt). The pH adjuster can then be added to the loaded chemically bonded ceramic system to provide the formulation of the present invention. Alternatively, the pH adjuster is added to the chemically bonded ceramic system before nicotine.

[0026] Oral products, particularly nicotine pouches, containing the formulations of the present invention may also be suitable for storage at ambient temperature without significant degradation of the components contained therein, such as pH adjusting agents. Avoiding the need for refrigerated storage is clearly beneficial to manufacturers, retailers, and users of these products.

[0027] However, preferably, nicotine (or a 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 nicotine, and therefore greater control over the release characteristics of the final formulation. In particular, this loading method allows for greater control over the total amount of nicotine stored in and released from the chemically bonded ceramic system.

[0028] As mentioned above, chemically bonded ceramic systems are formed from suitable precursor materials, such as calcium sulfate or calcium phosphate, typically provided in powder form for hydration. The average granule size of any precursor powder particles can be less than about 500 μm, such as less than about 100 μm, preferably about 1 μm to about 30 μm. This is to enhance hydration. Such precursor materials can be transformed into nano-sized microstructures during hydration (e.g., upon contact with liquid water or a humid atmosphere). This reaction involves repeated dissolution of the precursor material and subsequent precipitation of nano-sized hydrates in water (solution) and where unhydrated precursor material remains. This reaction is advantageously continued until the precursor material is transformed and / or a preselected porosity, as determined by partial hydration using time and temperature, and H2O in liquid and / or humidity, is measured.

[0029] The pore size of the chemically bonded ceramic system can be controlled in various ways during the fabrication process of the carrier material network structure. A particular method that is suitable for use with the chemically bonded ceramic system used in the present invention is the porogen leaching method, which involves the use of a sacrificial phase during the formation of the chemically bonded ceramic system. A porogenic material may be included as part of the reaction mixture during the formation of the chemically bonded ceramic system to aid in the formation of pores in the final carrier material network. Porogenic materials include, for example, oils, liquids (e.g., water), sugars, mannitol, and the like. The porogenic material can then be removed from the carrier by burning the carrier, for example, through heating during the vulcanization process, or by dissolving it using a suitable solvent. Dissolution is usually accomplished with water to avoid leaving residual amounts of materials that may adversely affect the formulation or adversely affect the user. In such cases, nicotine or a salt thereof can then be loaded into the pores in the chemically bonded ceramic system by any of the methods disclosed elsewhere herein. Porogenic materials with secondary functions can also be used. For example, the porogenic material may act as a source of flavor, e.g., as a sweetener. In such cases, it is not necessary that the porogenic material is removed from the carrier before use. Instead, some or all of the porogenic material may remain in the carrier, together with the nicotine (or a salt thereof), so that both substances can be released in the mouth of the user. Porogenic materials that dissolve quickly in water are particularly suitable for use in this method. Furthermore, porogenic materials that dissolve slowly in water may be useful for controlling the release of alkaline active pharmaceutical agents, for example, when a sustained release is desired.Porogenic materials that may be used as sweeteners include sweeteners known in the art, particularly monosaccharides, oligosaccharides, and polysaccharides; 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 cyclamate; and mixtures thereof.

[0030] Foaming methods can also be used to increase the pore size in chemically bonded ceramic systems. Such methods are known to those skilled in the art and are particularly useful for forming support materials with larger pore sizes. One example of such a method involves preparing the support using carbonated water or water containing air bubbles. This can be accomplished without the use of foaming agents (e.g., Tween 80).

[0031] The total porosity of the chemically bonded ceramic system can be from about 10% to about 70%, for example, from about 20% to about 40%. Porosity and average pore size can be measured by methods known to those skilled in the art, such as mercury intrusion, BET (Brunauer, Emmett, and Teller) and N2 adsorption techniques.

[0032] In a preferred embodiment of the present invention, nicotine (or a salt thereof) is co-formed and interspersed in the pores in the carrier material network. This means that whatever process is used to form the carrier, it must necessarily form pores interspersed with nicotine. If the process by which the carrier is formed involves the use of a porogen, nicotine is also interspersed in the pores that result directly from the use of said porogen. Chemically bonded ceramic systems are particularly suitable for use in such embodiments, since the process by which the carrier and its pore network are formed does not require very high temperatures, in contrast to sintered ceramics.

[0033] Nicotine (or its salt) can be mixed with the precursor(s) to the chemically bonded ceramic system using various techniques such as dry powder mixing. Alternatively, nicotine (or its salt) and precursor(s) can be mixed in the presence of a suitable liquid (e.g., aqueous or organic solvent) by a sol-gel process, as a solution, or as a slurry, paste, or putty of the precursor(s), e.g., particles, granules, or pellets. This mixing step is followed by some kind of "vulcanization" process to form a chemically bonded ceramic system containing pores in which the nicotine resides. A chemically bonded ceramic system formed in this way can be said to be pre-loaded with nicotine.

[0034] The pores themselves are a three-dimensional network of channels or voids within the solid network containing the nicotine or salt thereof (eg, of particles thereof).

[0035] Such pores may therefore essentially be "secondary pores" formed by chemical interactions (e.g., "bonding") between the surfaces of the primary particles of the support (which may themselves be porous (i.e., contain "primary" pores)). Such pores may result, for example, from exposure of such materials to one or more chemical reagents that cause a physical and / or chemical transformation (such as partial dissolution) at their surfaces and a subsequent physical and / or chemical bonding of those surfaces together (which may itself result from some other physicochemical process, such as, for example, drying, hardening, etc.), giving rise to the pores / voids in question.

[0036] In such cases, the chemical reagent may be mixed together with nicotine prior to or during preparation of the chemically bonded ceramic system. However, such secondary pores are not necessarily formed in this manner, and the bonding of the primary particles of the chemically bonded ceramic material may also be physical and / or mechanical, or may form during the generation of the three-dimensional chemically bonded ceramic network as described above, in the presence of nicotine.

[0037] Preferably, the precursor of the chemically bonded ceramic system is mixed with nicotine (or its salt) before the curing process is carried out. Nicotine is then present at the moment when pore formation occurs, so that nicotine is located in the pores of the chemically bonded ceramic system. By processing in this manner, excellent control over the total amount of nicotine loaded into the formulation can be achieved. Thus, in one embodiment, at least a portion of the nicotine (or its salt) is located in the pores of the (cured) chemically bonded ceramic system. By this, it is meant that at least 20% by weight (e.g., at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, or at least 80% by weight) of the nicotine (or its salt) is located in the pores of the chemically bonded ceramic system. In one embodiment, essentially all of the nicotine (or its salt) is located in the pores of the chemically bonded ceramic system. By this, it is meant that at least 90% by weight (e.g., at least 95% by weight, preferably at least 98% by weight) of the nicotine (or its salt) is located in the pores of the chemically bonded ceramic system.

[0038] The amount of nicotine (or salts thereof) present in the formulations of the invention can vary considerably according to the intended form and intended release profile of the intraoral product, for example, the formulations may contain said nicotine or salts thereof in an amount of 0.1% to 50% by weight of the formulation.

[0039] The formulations of the present invention are intended for use in the oral delivery of nicotine for both therapeutic and recreational purposes.The formulations can be used to provide an alternative to tobacco products (such as cigarettes and tobacco-containing snus), thus reducing the user's exposure to many of the potentially toxic components found in tobacco products.Nicotine is typically obtained from tobacco products, such as tobacco oils and other extracts.For example, 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), as a nicotine salt (e.g., as nicotine tartrate or 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.

[0040] Preferably, some or all of the nicotine is present in the formulation of the present invention as a water-soluble form of nicotine. In this context, the term "water-soluble form" is understood to refer to a form of nicotine that has a solubility in water of at least 10 g of salt per 100 mL of water under ambient conditions, including a temperature of 25°C, atmospheric pressure, and a pH of 7. It is believed that the nicotine present in the formulation of the present invention is present (at least in large part) as an amorphous material. The process by which the chemically bonded ceramic system used in the present invention is formed involves the hydration of a suitable precursor material in the presence of nicotine (or a salt thereof), followed by a curing step. At the start of the manufacturing process, nicotine or a salt thereof is preferably provided in the form of a crystalline solid, since a crystalline solid of high purity can be easily provided. During the process, the nicotine (or salt) is dissolved and / or diluted in a hydration liquid, and a subsequent drying step results in the precipitation of an amorphous nicotine product in the 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 salts), and other methods for detecting and quantitating crystallinity and / or amorphousness are known in the art.

[0041] In one embodiment, the formulation of the present invention is prepared using a salt of nicotine, such as nicotine bitartrate (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, when the formulations of the present invention are 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. Further, the nicotine in the formulation may be predominantly (e.g., at least 70%) amorphous.

[0042] The snus pouch containing the formulation of the present invention may also contain ground tobacco. However, in certain embodiments, the formulation of the present invention does not contain ground tobacco. It is believed that the nicotine (or its salt) in the formulation of the present invention has an enhanced stability profile compared to commercial formulations, i.e., compared to formulations in which nicotine is not stored in the pores of the chemically bonded ceramic carrier of the type disclosed herein. Without wishing to be bound by theory, it is believed that the formulation of the present invention prevents or slows down the oxidation of nicotine, thus extending the shelf life of the product.

[0043] The rate at which nicotine is absorbed into the body through the oral mucosa varies depending on the pH of saliva. Tomar Slet al. (Tobacco Control 1997;6:219-225) reported that increasing alkalinity enhances the absorption of nicotine and enhances its physiological effects. Therefore, a pH adjuster is provided in the formulation of the present invention to increase the rate and extent of transmucosal uptake of nicotine.

[0044] Formulation of an intraoral formulation containing an appropriate amount of nicotine (or its salt) together with a pH adjuster is difficult. It has been found that a significant proportion of nicotine can be lost during the process of forming the hardened porous chemically bonded ceramic system. Without wishing to be bound by theory, it is believed that the primary mechanism of loss is evaporation.

[0045] Surprisingly, it has been found that this evaporation loss can be significantly reduced or essentially completely eliminated by allowing the chemically bonded ceramic system to harden and solidify without the presence of a pH adjusting agent.Therefore, in a second aspect of the present invention, there is provided a method of forming an intra-oral formulation comprising a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjusting agent, the method forming the chemically bonded ceramic system in the absence of the pH adjusting agent.These methods are hereinafter referred to as "methods of the present invention".All embodiments and preferences disclosed herein in relation to the formulations of the present invention are also disclosed in relation to the methods of the present invention.

[0046] Nicotine (or its salt) may still be present during the curing phase, i.e., nicotine may be mixed with the precursor material for the chemically bonded ceramic system, and as a result, good control of the nicotine loading may be achieved. Thus, in one embodiment of the method of the present invention, the chemically bonded ceramic system is formed in the presence of nicotine or its salt. The pH adjuster may then be introduced after the chemically bonded ceramic system has cured without evaporative loss of nicotine occurring.

[0047] As mentioned above, the chemically bonded ceramic systems of the present invention may alternatively be loaded with nicotine or a salt thereof after the chemically bonded ceramic mass is formed, for example, by immersing the ceramic material in a liquid containing nicotine or a salt thereof, or through any other method that promotes drawing the substance into the pores of the ceramic material via capillary forces (including spraying, brushing, rolling, dip coating, powder coating, misting, or vacuum-enhanced loading).

[0048] For the avoidance of doubt, it is not essential that all of the nicotine in the formulation is located within the pores of the chemically bonded ceramic system. A portion of the nicotine in the intraoral formulation may be located outside the pores. For example, if the intraoral formulation is provided in the form of a nicotine pouch containing a powder formulation, a portion of the nicotine (preferably a powdered salt of nicotine) may be mixed with the powdered chemically bonded ceramic system (which itself may contain pores containing an amount of nicotine or a salt thereof) before being placed in the pouch. Such mixing may be achieved by spraying the particles of the nicotine-loaded chemically bonded ceramic system with a nicotine solution and then allowing the mixture to dry before being placed in the pouch. In such embodiments, the amount of nicotine (or a salt thereof) added to the hardened powdered chemically bonded ceramic system is 1-50%, 5-40%, or 10-30% by weight of the total amount of nicotine (or a salt thereof) in the intraoral product.

[0049] In a further example, when the intraoral formulation is provided in the form of a nicotine pouch containing either a powder 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 forming the pouch, i.e., a portion of the nicotine is not located within the cavity of the bag (as described elsewhere herein), but instead is bound or incorporated within the walls of the bag itself. This may be achieved, for example, by immersing the pouch material in a solution containing nicotine (as a base or a dissolved nicotine salt) and then evaporating the solvent (e.g., water or another suitable solvent), leaving the nicotine or salt thereof incorporated in the pouch material. In embodiments where the intraoral formulation is provided in the form of an intraoral product that is a nicotine pouch, and a portion of the nicotine in the intraoral product is associated with the material forming the pouch, the amount of nicotine (or salt thereof) associated with the material may be 0.1-30%, 0.5-20%, or 1-10% by weight of the total amount of nicotine (or salt thereof) in the intraoral product.

[0050] 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 all) of the nicotine in the final oral product, in which the pores of the hardened chemically bonded ceramic system contain up to 99% by weight (such as up to 95%, up to 90%, up to 80%, or up to 70% by weight) of the total amount of nicotine or a salt thereof in the final oral product.

[0051] Typically, once the hardened mass of chemically bonded ceramic (e.g., the hardened mass of a chemically bonded ceramic system loaded with nicotine or a salt thereof) is formed, it is then milled to form a powder, which is then mixed with a pH adjuster. The milling process may be carried out in the presence of a pH adjuster to ensure efficient mixing.

[0052] Since the pH adjusting agent is not present during the formation of the chemically bonded ceramic system, the pH adjusting agent is not incorporated into the pores of the chemically bonded ceramic system. Although a small amount of ingress of the pH adjusting agent into the pores of the chemically bonded ceramic system may occur when the two components are brought together or during subsequent processing, in this method, only minimal ingress occurs. Thus, in one embodiment, the pH adjusting agent is primarily located outside the pores of the chemically bonded ceramic system. By this, it is meant that at least 90% by weight (e.g., at least 95% by weight, preferably at least 98% by weight) of the pH adjusting agent is located outside the pores of the chemically bonded ceramic system.

[0053] The term "pH adjusting agent" refers to any substance capable of changing the pH of normal saliva. The pH of normal saliva is about 6.8. The pKa value of nicotine is about 3.2 and 8.02 (Tomar Slet al., Tobacco Control 1997;6:219-225). The absorption of nicotine from the oral cavity, i.e. transmucosal uptake, into the systemic circulation depends on the local pH of the saliva inside and near the product in use. Nicotine is absorbed mainly through the mucosa in an unprotonated form. It is therefore preferable to provide a local pH that results in a high proportion of nicotine being unprotonated. For this reason, alkaline conditions enhance the transport of nicotine through the oral mucosa and into the bloodstream, and therefore it is preferable that the pH adjusting 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 an agent for obtaining a buffer solution with an alkaline pH. Preferred alkaline agents are buffers selected from the group consisting of acetates, glycinates, phosphates, glycerophosphates, citrates such as citrates of alkali metals, carbonates (including bicarbonates), and borates, or mixtures thereof. In addition, strong bases such as sodium hydroxide, potassium hydroxide, and mixtures thereof may be used. In certain embodiments, carbonates (including bicarbonates) or phosphates (including triphosphates) compounds may be used as pH adjusters. Such compounds may be formed as salts with any suitable cation, such as sodium, potassium, calcium, or magnesium. Specific pH adjusters that may be mentioned include sodium carbonate, sodium bicarbonate, trisodium phosphate, and combinations thereof.

[0054] Further examples of pH adjusters that can be used include calcium aluminate, calcium silicate, calcium phosphate, and calcium carbonate, as well as chemically bonded ceramic systems made from any of these calcium salts (as described elsewhere herein), and mixtures thereof. For the avoidance of doubt, it is not essential that any pores in the chemically bonded ceramic system contain nicotine or its salts. When a chemically bonded ceramic system made from any of the calcium salts mentioned herein is used as a pH adjuster, the system is formed (e.g., by hardening a hydrated mass of the calcium salt) before being added to the other components of the formulation of the present invention. The pH adjuster in such an example can be referred to as a "second" chemically bonded ceramic system. The formulation of the present invention already contains a chemically bonded ceramic system (formed in the absence of a pH adjuster), which can therefore be referred to as a "first" chemically bonded ceramic system.

[0055] In a particular example of such a formulation of the present invention, the second chemically bonded ceramic system (i.e., the pH adjusting agent) may be formed from calcium aluminate and the first chemically bonded ceramic system may be formed from calcium sulfate in the absence of the pH adjusting agent. Once the first chemically bonded ceramic system is formed, it may be loaded with nicotine or a salt thereof through a method such as soaking the first chemically bonded ceramic system. However, the first chemically bonded ceramic system is preferably formed in the presence of nicotine in its salt form.

[0056] The amount of pH adjusting agent present in the formulation is typically selected to be sufficient to raise the pH of saliva inside and adjacent to the product during use to at least 8. In one embodiment of the invention, the formulation comprises said pH adjusting agent in an amount of at least 0.1% by weight of the formulation, in particular at least 0.5% by weight. For example, the formulation may comprise said pH adjusting agent in an amount of 0.1% to 50% by weight of the formulation. Such weights are particularly suitable for formulations in which the pH adjusting agent is sodium carbonate, i.e., when the pH adjusting agent is sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), or a mixture thereof.

[0057] In some embodiments, the pH adjusting agent is a buffer comprising sodium carbonate and sodium bicarbonate, for example in a weight ratio of 5:1 to 2.5:1, preferably 4.1:1 to 3.5:1. A particular buffer that may be mentioned is the sodium carbonate-sodium bicarbonate buffer system.

[0058] Sustained Flavor Release The solid, porous, chemically bonded ceramic system disclosed herein in relation to the first aspect of the present invention has also been found to be surprisingly effective in providing sustained release of flavors in the mouth.As shown in the examples, dry powders containing such ceramic systems, in which one or more flavors are loaded into the pores in the ceramic, can surprisingly release flavors at a sufficient rate and for a sufficient period of time to provide a meaningful sensory experience to the user, substantially longer than achieved by commercial formulations.In some cases, flavors lasted nearly 20 times longer using the formulations of the present invention compared to commercial products.

[0059] Thus, according to a third aspect of the present invention, there is provided a combination of a solid, porous, chemically bonded ceramic system as disclosed herein and a flavourant, the flavourant being incorporated into the pores in the chemically bonded ceramic system using any of the methods described above for nicotine.

[0060] In one embodiment, the chemically bonded ceramic system used in the formulation of the present invention is loaded with a flavorant (or flavorants) by immersing the ceramic material in a liquid containing the flavorant, or through any other method that promotes drawing the flavorant into the pores of the ceramic material via capillary forces (including spraying, brushing, rolling, dip coating, powder coating, atomization, or vacuum-enhanced loading). Some flavorants may be provided, for example, as a liquid product, for example as a solution, suspension, or emulsion. Such a liquid product may be contacted with the chemically bonded ceramic system by simply mixing the two components so that the flavorant is incorporated into the pores in the ceramic. As shown in the examples, the ceramic pores may also contain nicotine before the introduction of the flavorant, and the product can still provide a sustained release of both nicotine and flavorant.

[0061] In another embodiment, the flavoring is co-formed and interspersed within the pores of the chemically bonded ceramic system. For example, the precursor of the chemically bonded ceramic system may be mixed with the flavoring (or flavors) before the curing process takes place. The flavoring is then present (optionally together with nicotine or a salt thereof) at the moment when the pore formation occurs, so that the flavoring is located within the pores of the chemically bonded ceramic system.

[0062] Examples of flavourings include the sweeteners and flavours (or "flavourings") described elsewhere herein. For the avoidance of doubt, this includes sugars such as sucrose, glucose, dextrose, maltose, and / or fructose, sugar alcohols such as mannitol, xylitol, sorbitol, maltitol, and / or isomalt, or artificial sweeteners such as sucralose, cyclamate, aspartame, acesulfame, and / or saccharin.

[0063] Other flavorings that may be used in particular in nicotine pouches include menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, black cherry, coffee, cinnamon, clove, tobacco, citrus, fruit flavors, and mixtures thereof. In one embodiment, the flavoring is not tobacco or nicotine. Such flavorings may be present in combination in an amount of at least 0.1% by weight, and preferably no more than 50% by weight, of the combination of the solid, porous, chemically bonded ceramic system and flavoring(s).

[0064] The flavoring agent may be used in combination with any of the chemically bonded ceramic systems described elsewhere herein. For the avoidance of doubt, this includes any chemically bonded ceramic system formed from calcium phosphate, calcium sulfate, calcium silicate, calcium aluminate, magnesium carbonate, or combinations thereof. Preferred chemical compositions include those based on chemically bonded ceramic systems, which consume a controlled amount of water to form a network after hydration of one or more suitable precursor materials. Precursor materials that may be mentioned in connection with the third aspect of the invention include CaOAl2O3, (CaO) 12 Included are (Al2O3)7, (CaO)3(Al2O3), (CaO)(Al2O3)2, (CaO)3(SiO2), (CaO)2(SiO2), and in particular alpha-tricalcium phosphate, tetracalcium phosphate (Ca4(PO4)2O), and calcium sulfate (e.g., calcium sulfate hemihydrate).

[0065] The combinations according to the third aspect of the invention may be used, for example, in the manufacture of oral products of the kind described herein, as well as food products (chewing gums, sweets, breath mints, etc.) and health products intended to be held in the mouth for extended periods of time (e.g., more than 5 minutes). In one embodiment, they may be used in the manufacture of nicotine pouches, for example, by adding the combination to nicotine (or a salt thereof) before filling the pouch according to any of the methods disclosed herein. The combinations according to the third aspect of the invention may advantageously be provided for this or any other use as powders, since the combinations may be provided as powders, which are easy to handle. Such combinations may be stored in any suitable container, for example an airtight container. They may also be provided in any quantity for the purposes of manufacture, for example, from 1 g to 100 kg.

[0066] In a further embodiment, there is provided a pouch (eg a nonwoven pouch) containing a combination according to the third aspect of the invention.

[0067] Oral preparations The formulations of the present invention are buccal formulations 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 to products intended for delayed and / or sustained release.

[0068] Buccal formulations capable of providing sustained release of nicotine allow users to obtain a long-lasting sensory experience using a minimal number of formulations per day. When the formulations are intended to be used as part of a therapy to treat nicotine dependence, this property improves patient compliance and minimizes interference with an individual's lifestyle.

[0069] The term "sustained release" is used interchangeably herein with the term "controlled release" and will be understood by those skilled in the art to include formulations that provide and / or are adapted to provide "sustained," "prolonged," and / or "extended" release of nicotine (wherein nicotine is released at a rate sufficiently delayed to provide a therapeutic response or provide a pleasurable experience over an extended period of time, as compared to pouch formulations currently on the market).

[0070] The formulations of the present invention can achieve a nearly constant release rate over an interval of about 10 minutes to about 1 hour, potentially longer. In one embodiment, the formulations of the present invention can achieve a nearly constant release rate over an interval of about 10 to 30 minutes. By this, it is meant that nicotine release from the formulation occurs continuously (at a non-zero rate) over a specified time interval. Constant release may be further defined as a composition capable of maintaining a steady state concentration in a bodily fluid that does not deviate from the mean value by more than about 20% (e.g., about 10%) during the dosing interval.

[0071] The formulations of the present invention, when held in the mouth, can advantageously release a high percentage of the material held in the pores. By this, it is meant that when the formulation is held in the mouth for an extended period of time (e.g., at least 10 minutes, or preferably at least 20 minutes), at least 75% (e.g., at least 80%, at least 85%, or at least 90%) of the nicotine stored in the pores of the chemically bonded ceramic system is released from the pores and becomes available to the user. This characteristic of near complete release allows the user to know more accurately how much nicotine is being taken up in the body, which can be advantageous when administering to a patient for therapeutic purposes. When the formulations of the present invention are used in a nicotine pouch, such as those described herein, in which nicotine is held in the pores in the chemically bonded ceramic system, once the nicotine (or its salt) is released from those pores, it can quickly leak out of the pouch and be absorbed by the user.

[0072] In addition, the formulations of the present invention can achieve essentially complete release in a time frame suitable for therapeutic use. As shown in the examples, the formulations of the present invention can release almost all of the releasable nicotine in about 20 minutes when held in the mouth. A user of a nicotine pouch typically holds an individual pouch in the mouth for a period of 5 minutes to 1 hour during which nicotine is released, with 20 minutes to 30 minutes being the most common time frame. This property helps minimize the loss of unused nicotine when the product is consumed, making the formulations of the present invention, and the pouches containing the formulations, particularly suitable for use in therapeutic treatments such as nicotine replacement therapy or smoking cessation aids.

[0073] The dry formulation of the present invention has also been found to provide rapid release of water-soluble components.A study involving human volunteers found that the onset of sensation associated with flavoring was more rapid for the dry formulation of the present invention compared to the dry commercial formulation.The time required for the onset of nicotine sensation for the dry formulation of the present invention is less than or equal to that for the dry commercial formulation.Therefore, the formulation of the present invention can provide a rapid sensory experience for users.

[0074] The total amount of nicotine delivered by each formulation is preferably about 0.5 mg to about 15 mg, for example about 1 mg to about 10 mg. For example, the formulation may deliver about 1 mg to about 8 mg, about 1.5 mg to about 7.5 mg, about 2 mg to about 5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 10 mg, about 3 mg to about 7.5 mg, or 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, calculated as free nicotine base. Specifically, the amount of nicotine is 2 mg, 3 mg, 4 mg, or 6 mg. The above values ​​refer to the amount of nicotine in free base form that can be delivered from each formulation, regardless of whether the nicotine in the formulation is provided as a free base, a salt, or in any other form.

[0075] The formulations of the present invention are suitable for use in conventional size nicotine pouches, which are intended to be used by holding the pouch in the mouth under the lips. Typically, such pouches are rectangular and have a length of about 25 to about 35 mm and a width of about 10 to about 15 mm.

[0076] The formulations of the present invention may also provide nicotine in a relatively concentrated form, thus allowing the production of small pouches that still contain conventional amounts of nicotine and have the advantageous release characteristics described herein. The formulations of the present invention may contain at least 50 mg (such as at least 60 mg, at least 70 mg, or at least 80 mg) of nicotine (calculated as free base, regardless of the form in which it is present) per gram of powder. As an example, 12 mg of nicotine (calculated as free base) can be incorporated into a chemically bonded ceramic system to obtain a powder with a total mass of 0.15 g or less. In this context, the small pouch may not have dimensions greater than 20 mm, preferably greater than 15 mm. Typically, the small pouch is rectangular and has a length of about 10 to about 15 mm and a width of about 8 to about 10 mm.

[0077] The amount of nicotine contained in the intraoral preparation before use may exceed the amount of nicotine intended to be delivered to the user. This is because a certain percentage of nicotine may be trapped in the chemically bonded ceramic system in such a way that complete release of nicotine is not possible within the possible period of use. However, preferably, the preparation is capable of releasing substantially all of the nicotine or its salt upon contact with an aqueous liquid (e.g., saliva). By this, it is meant that the preparation is capable of releasing at least 80% by weight (e.g., at least 90% by weight) of nicotine or its salt upon contact with an aqueous liquid.

[0078] The oral formulation may be provided to the user in the form of oral products, including nicotine pouches (similar to snus) and tablets. As used herein, the term "nicotine pouch" refers to a pouch or bag that is fully or partially filled 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 adjuster, and in such a case, the pouch or bag can be said to be fully or partially filled with the formulation of the present invention. In another embodiment, the pH adjuster is incorporated (e.g., bonded) into the material that forms the pouch or bag. Nicotine pouches that contain a pH adjuster both in the cavity of the pouch or bag and that are incorporated into the material that forms the pouch or bag are also contemplated.

[0079] The formulations of the present invention are particularly suitable for transmucosal administration, whereby an oral product containing the formulation (e.g., in the form of a tablet, wafer, lozenge, or similar product) is placed in contact with the lips, gums, or cheek for an extended period of time (minutes) during which nicotine is released. The oral products (e.g., pouches and tablets containing the formulations of the present invention) may be supplied in bulk to end users. Thus, the present invention also relates to a package containing multiple oral products (e.g., at least two pouches or tablets).

[0080] Nicotine pouches containing the formulations of the present invention may be described as tobacco-free versions of snus. In such systems, the pouch or bag contains a particular amount of the formulation, and therefore a particular amount of nicotine, but typically does not contain any tobacco dust, leaves, or stems.

[0081] One embodiment of the present invention relates to a nicotine pouch comprising a permeable sealed bag containing a solid, porous, chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjusting agent, the chemically bonded ceramic system being formed in the absence of the pH adjusting agent. The bag is typically made of a permeable material surrounding a cavity. The powdered buccal formulation is retained within the cavity, while soluble components of the formulation can pass through the bag material when the bag is exposed to water (e.g., saliva). Materials suitable for nicotine pouches are known to those skilled in the art and include the types of papers used for tea bags, filter paper, and the like. Other materials include heat-sealable non-woven celluloses such as long fiber paper, cotton, silk, and the like.

[0082] The formulations of the present invention also provide stable storage of nicotine (or salts thereof) before use. The formulations of the present invention are preferably stored in airtight containers such as cans or bags before use and can be stored in this manner for weeks or months (e.g., up to at least one year) without significant loss of nicotine. Suitable storage containers are known to those skilled in the art and include any conventional closable container. These storage containers can provide a convenient and portable system capable of holding multiple pouches or tablets. Thus, a further aspect of the present invention relates to a closable container that contains one or more, and preferably multiple, intraoral products of the present invention (e.g., nicotine pouches or sublingual and buccal tablets as described herein).

[0083] As mentioned above, the pH adjusting agent is not present during the formation of the chemically bonded ceramic system, so the pH adjusting agent is not incorporated into the pores of the chemically bonded ceramic system. Thus, the pH adjusting agent may be incorporated into the final product by other methods, for example, by mixing the pH adjusting agent with the cured chemically bonded ceramic system as mentioned above. Alternatively, or additionally, the pH adjusting agent may be associated with the bag material itself. For example, particles of the pH adjusting agent (e.g., sodium carbonate and / or sodium bicarbonate) may be embedded within the permeable material of the bag so that the pH adjusting agent can be readily dissolved upon contact with saliva. Thus, in one embodiment, the bag includes a cavity surrounded by a permeable material, and the pH adjusting agent is associated with the permeable material. Other suitable methods of incorporating the pH adjusting agent into the bag material will be known to those skilled in the art.

[0084] In one embodiment of the invention, the buccal formulation is contained within a pouch, the total weight of the filled pouch being 0.2-3 g, e.g., 0.4-2 g. In another embodiment, the nicotine pouch has a weight and / or volume similar to commercially available portioned snus products and nicotine pouches. In a further embodiment of the invention, the buccal formulation is contained within a small pouch having a total weight of 0.1-0.5 g, e.g., 0.1-0.4 g. Small pouches are discussed elsewhere herein, and the utility of such low weight products is possible due to the fact that the chemically bonded ceramic systems referred to herein can provide a very compact and stable storage of nicotine while maintaining a suitable release profile.

[0085] The nicotine pouch may be manufactured using methods known to those skilled in the art, in particular those used to manufacture snus and commercial nicotine pouches (such as ZYN®). For example, the powder content of the pouch may be made using the methods described herein or using conventional methods known in the art, and the powder may then be filled into a sealable bag, e.g., a heat-sealable bag. Such bags should be water-insoluble and permeable to saliva. Suitable materials for nicotine pouches have been described above and are also known to those skilled in the art, e.g., from U.S. Pat. No. 9,161,908. Heat-sealable non-woven cellulose, such as long fiber paper, provides a particularly suitable material for use in nicotine pouches. Once a predetermined amount of powder has been filled into the pouch, it is maintained within the pouch by sealing. The uptake of nicotine in the mouth may be promoted by incorporating a bioadhesive and / or mucoadhesive promoter into the nicotine pouch. A bioadhesive and / or mucoadhesive promoter may be provided within the cavity of the bag. Alternatively, or additionally, the agent may be incorporated into or combined with the bag material.

[0086] Tablet-based buccal products that may be mentioned include sublingual tablets, buccal tablets, wafers, and lozenges. In this form, the buccal product containing the formulation of the present invention is intended to be placed under the tongue, under the lips, against the gums, or against the cheek, and the nicotine is absorbed through the surrounding mucous membrane. References elsewhere in this specification to "sublingual tablets" include references to buccal tablets, unless otherwise indicated. Adhesion to the inner surface of the mouth may be promoted by incorporating bioadhesive and / or mucoadhesion promoting agents into the sublingual tablets, wafers, or lozenges.

[0087] Bioadhesive and / or mucoadhesive promoters are effective in adhering the tablet or pouch to the oral mucosa and, in addition, have the property of swelling and expanding on contact with water, thus allowing the tablet to disintegrate when wetted with saliva.

[0088] The term "mucoadhesive" is intended to indicate adhesion to mucous membranes covered by mucus, such as those in the oral cavity, while the term "bioadhesive" is intended to indicate adhesion to more general biological surfaces, including mucous membranes not covered by mucus. These terms generally overlap in definition and can usually be used interchangeably, although the term "bioadhesive" has a somewhat broader scope. In the present specification and claims, the two terms serve the same purpose with respect to the goal of the present invention, which is represented by the use of the general term "bio / mucoadhesive". Preferably, the tablet contains 0.1 to up to 25 weight percent of the bio / mucoadhesion-promoting compound, based on the total weight of the tablet.

[0089] The bio / mucoadhesion promoter is preferably a polymeric material, preferably having an average molecular weight of more than 5,000 Daltons (weight average). A variety of polymers known in the art can be used as bio / mucoadhesion promoters. Examples of such bio / mucoadhesive promoters include cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, modified cellulose gums and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starch, modified starch, and sodium starch glycolate; acrylic polymers of carbomer and its derivatives (Polycarbophyl®, Carbopol®, etc.); polyvinylpyrrolidone; polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); microcrystalline cellulose (Avicel®); and croscarmellose (e.g., croscarmellose sodium). Such polymers may be crosslinked. Combinations of two or more bio / mucoadhesive polymers may also be used. Materials such as HPMC, which can provide a smooth surface to the finished tablet while still allowing the tablet to adhere to the oral mucosa, are particularly advantageous.

[0090] In one embodiment of the present invention, the buccal formulation is provided in the form of a tablet having a total weight of 25-200 mg, for example, 50-150 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 compression. Tablets may also be made by mixing dry ingredients, including the precursor(s) of the chemically bonded ceramic system, adding water, wet mixing, and then molding.

[0091] The final tablet may, for example, be a buccal tablet that does not completely dissolve in the mouth but must be physically removed (e.g., swallowed) once used. The tablet may alternatively be a dissolving tablet in which all components are dissolved and absorbed or swallowed.

[0092] The nicotine pouches and tablets may also contain one or more other ingredients selected from the group consisting of fillers (typically food grade fillers), water, salt, and flavorings. It is not necessary that any of these other ingredients be incorporated into the pores of the chemically bonded ceramic system, but any such ingredient incorporated in this manner and that is water soluble is expected to have a release profile similar to the nicotine contained within those pores.

[0093] Fillers that increase saliva production may also be advantageously used in the products described herein. Such substances, sometimes known as sialagogues, are known in the art and include salts (NaCl), sweeteners (e.g., xylitol), and acidic substances (such as malic acid and ascorbic acid). The nicotine in the product of the present invention can dissolve in saliva and then be absorbed through the oral mucosa. The flavoring agents in the product are also transported by saliva to the taste buds in the oral cavity. The incorporation of substances that increase saliva production improves the user's experience by ensuring that the sensations resulting from the nicotine and flavoring agents in the product can occur more quickly.

[0094] Other fillers that may be used in nicotine pouches include gum arabicum, microcrystalline cellulose, maltitol. Further fillers that may be mentioned include inert inorganic fillers such as alumina, zirconia, and glass.

[0095] Fillers that can be used in sublingual tablets (and wafers, lozenges, etc.) include conventional fillers known to those skilled in the art in the context of pharmaceutical formulations, particularly oral tablets and capsules. Suitable materials are well known to those skilled in the art, see, for example, Dosage Forms: Tablets. Volume 1, 2nd Edition, Lieberman HA et al. New York and Basel 1989, p. 354-356, and references cited therein.

[0096] Fillers are typically present in the oral product in an amount ranging from about 10% to about 90% by weight of the oral product.

[0097] Controlled release agents may also be incorporated into the formulation. Such agents slow down the rate of release of nicotine from the product, thereby extending the duration of the sensory experience for the user. Controlled release agents are preferably materials that can provide sustained release, delayed release, or both.

[0098] In this regard, the controlled release agent is preferably a polymer. Examples of polymers that can be used as controlled release agents include alkyl cellulose polymers (e.g., ethyl cellulose polymers) and acrylic polymers (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylate copolymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamide copolymers, poly(methyl methacrylate(m Examples of suitable polymers include, but are not limited to, 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 copolymer. The polymer may 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.

[0099] Preferred polymers include the alkylcellulose polymers and acrylic polymers described herein.

[0100] To improve the sensory properties of the formulation of the present invention, one or more sweeteners or texture improvers can be added.These substances include sugars such as sucrose, glucose, dextrose, maltose, and / or fructose, sugar alcohols such as mannitol, xylitol, sorbitol, maltitol, and / or isomalt, or artificial sweeteners such as sucralose, cyclamate, aspartame, acesulfame, and / or saccharin.Sweeteners are particularly useful for masking the taste of nicotine in the formulation.

[0101] Other flavorings that may be used in particular in nicotine pouches include menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, black cherry, coffee, cinnamon, clove, tobacco, citrus, fruit flavors, and mixtures thereof. In one embodiment, the flavoring is not tobacco. The formulations of the present invention may be used with any flavor or combination of flavors. Such flavorings may be present in an amount of at least 0.1% by weight of the nicotine pouch or tablet, and preferably no more than 5% by weight.

[0102] Substances that impart a cooling mouthfeel, such as sugar alcohols (eg, erythritol), may be used in the intraoral products disclosed herein.

[0103] The nicotine pouches described herein may also contain a moist buccal formulation. A moist buccal formulation is an intra-oral formulation of the present invention that further contains a component that is liquid under ambient conditions or a low-melting solid. Suitable components are known in the art and include glycerol, propylene glycol ("PG", E1520), polyethylene glycol ("PEG"), and sodium alginate (E401). The addition of relatively small amounts of such components advantageously binds the smallest particles together to minimize the formation of fine dust. Fine dust can pass through or block pores in the types of nonwoven fabrics typically used in the manufacture of nicotine pouches. Typically, the liquid or low-melting solid is added after the powder is formed (e.g., by grinding a larger solid mass) and, optionally, after the coarse particles of the chemically bonded ceramic system have been removed. A person skilled in the art will be able to determine the amount of liquid or low-melting solid that needs to be added to the formulation of the present invention. Suitable amounts may range from 0.1% to 10% (such as 2-5%) by weight of the formulation, preferably low enough to provide a powdered material that is easily manufactured, handled, transported, divided, and / or processed.

[0104] Wet pouches, i.e. pouches containing wet oral preparations, generally feel more comfortable in the mouth and typically provide a more rapid initial release of nicotine compared to dry pouches.However, we have found that the wet oral preparations of the present invention also have surprising sustained release properties similar to those of dry preparations.That is, the wet preparations can release nicotine (or its salts), as well as other flavorings, over a sustained period of time.The use of PG, or any other humectant of the type mentioned above, can also advantageously help prevent undesired release of material from the pouch, for example by agglomerating finer portions of powder that may otherwise be able to cross pores in the pouch membrane.

[0105] Wet buccal formulations typically have the form of a dough or paste. Such formulations may be made by simply mixing liquid or low melting components with the dry formulation of the present invention.

[0106] The oral formulation of the present invention may also contain one or more preservatives.Materials that can be used as preservatives include sodium benzoate and potassium sorbate, and other materials known in the art to have similar functionality.Preservatives may be particularly suitable for use in moist oral preparations, such as those that contain glycerol and / or propylene glycol.

[0107] Specific buccal preparations that may be mentioned include: a solid, porous, chemically bonded ceramic system formed from a material selected from the group consisting of alpha-tricalcium phosphate, tetracalcium phosphate, calcium sulfate, and combinations thereof; a pH adjuster comprising sodium carbonate (i.e., sodium bicarbonate and / or sodium carbonate); and nicotine or a salt thereof, The chemically bonded ceramic system is formed in the absence of the pH adjusting agent. The buccal formulation may advantageously be provided in the form of a sublingual or buccal tablet (such as a tablet containing a bioadhesive and / or mucoadhesive promoting agent), or a nicotine pouch (i.e., a permeable sealed bag containing a solid, porous chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjusting agent).

[0108] Medical and recreational uses The formulations of the present invention have medical and / or recreational uses.

[0109] The formulation may be placed in the mouth where it becomes moistened through contact with saliva. The formulation may be placed in the mouth, for example in contact with the lips, gums, or cheeks, and left there for an extended period of time. Typically, the formulation is held in the mouth for a period of 5 minutes to 1 hour. Longer durations are possible if the formulation is adapted to provide a slower sustained release of nicotine, for example by including a controlled release agent such as hydroxypropyl methylcellulose.

[0110] In a medical context, the formulations of the present invention can be used in the treatment of nicotine dependence (e.g., nicotine addiction) with the aim of helping individuals reduce or completely stop smoking. Thus, the formulations of the present invention can be described as useful for aiding smoking cessation. The formulations of the present invention have several advantages that make them particularly suitable for aiding smoking cessation. First, they can release almost all of the nicotine held in the formulation, allowing the user or clinician to know exactly how much nicotine is being administered to the patient. Second, the formulations provide essentially complete release in a time frame suitable for therapeutic use, such as within 20 minutes or 30 minutes. This time frame coincides with the time that commercially available nicotine pouches are typically held in the mouth when used. Nicotine wastage is also minimized, since there is little unused nicotine once the product is used.

[0111] In a further aspect of the invention, a method of treating nicotine dependence (e.g., nicotine addiction) is provided, the method involving administering a formulation of the invention to a person suffering from symptoms of nicotine dependence. Similarly, the formulation of the invention may be useful in a method of treating (e.g., alleviating) symptoms of nicotine dependence (including nicotine addiction or nicotine withdrawal symptoms) or aiding in smoking cessation. Such symptoms include nicotine craving, anger / irritability, anxiety, depression, impatience, sleep disorders, restlessness, hunger or weight gain, and / or difficulty concentrating. Such uses may also be referred to as nicotine replacement therapy.

[0112] Nicotine may also be used to ameliorate symptoms associated with a variety of diseases, including dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression. Thus, in a 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, the method involving administering a formulation of the invention to a person suffering from the condition.

[0113] The formulations of the present invention can release a pharmacologically effective amount of nicotine during normal use. "Pharmacologically effective amount" refers to an amount of nicotine that can provide a desired therapeutic effect to a treated patient, whether administered alone or in combination with another active ingredient. Such an effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows an indication of or feels an effect).

[0114] More preferred formulations of the present invention may be adapted (e.g., as described herein) to provide a sufficient dose of nicotine over a dosing interval (regardless of the number of doses per unit time) to produce a desired therapeutic effect.

[0115] Thus, the amount of active ingredient that may be used in the formulations of the present invention may be determined by a medical practitioner, or by a person skilled in the art, as to what will be most suitable for an individual patient or condition being treated, which may vary depending on the type and severity of the condition being treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient being treated.

[0116] A suitable daily dosage of nicotine for both medicinal and recreational purposes may be about 1 to about 100 mg / day. Conventional cigarettes typically contain about 8 to 15 mg of nicotine. In one embodiment, each nicotine pouch or tablet of the present invention can deliver about 3 to about 15 mg of nicotine. It is preferred that the products disclosed herein can deliver an amount of nicotine that is at least equivalent to one cigarette. When nicotine is provided to a patient in the form of a tablet (e.g., a sublingual or buccal tablet), each tablet can contain about 3 to about 15 mg of nicotine, for example, about 8 mg to about 15 mg of nicotine.

[0117] The above dosages are exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.

[0118] Ingress of moisture into the pores of the chemically bonded ceramic system releases the nicotine (or salts thereof) contained therein. The rate and extent of nicotine absorption into the body through the oral mucosa increases with increasing alkalinity of the oral environment at the absorption site in the mouth, and pH modifiers in the formulation facilitate this. In one embodiment of the present invention, at least 50% by weight of the nicotine released from the formulation is absorbed through the oral mucosa.

[0119] Nicotine may be released with sweeteners and / or other flavors that help mask the taste of nicotine while ensuring that the intended benefits resulting from nicotine absorption are still achieved.

[0120] For the avoidance of doubt, "treatment" includes not only the symptomatic treatment of symptoms, prevention, or diagnosis of a condition, but also therapeutic treatment.

[0121] When used recreationally, the formulations can deliver a sufficient amount of nicotine to provide a pleasant sensory experience to the user.

[0122] The formulations of the present invention may also improve the oral health of the user.As mentioned above, this is especially true for formulations in which the chemically bonded ceramic system contains calcium, releases this mineral (e.g., in the form of solubilized calcium ions) into saliva, and optionally increases the pH of the saliva inside and near the product during use through the release of hydroxide ions.Solubilized calcium can contribute to mineral growth on the tooth surface, helping to remineralize teeth and bones.This type of intraoral formulation has potential utility in repairing tooth enamel and strengthening teeth.

[0123] The formulations of the present invention may have the advantage that they provide a sustained release of nicotine (e.g., nicotine is released at a delayed rate sufficient to provide a therapeutic response or provide a pleasant experience over an extended period of time, as compared to pouch formulations currently on the market). The formulations of the present invention may also have the advantage that they are more effective, less toxic, faster acting, more potent, produce fewer side effects, are more readily absorbed, and / or have a better pharmacokinetic profile, have improved bioavailability, and / or have other useful pharmacological, physical, or chemical properties than compositions known in the prior art.

[0124] The use of the chemically bonded ceramic systems described herein allows for the provision of products that provide acceptable levels of nicotine release when placed in the mouth, while minimizing the risk of exposure to the nicotine (or salts thereof) stored therein, e.g., due to leakage.

[0125] Chemically bonded ceramic systems are also easily manufactured without the need for high temperature sintering, and therefore additional elements such as flavorants, fillers, etc. can be incorporated into the carrier to help achieve the desired sensory experience. The ability to incorporate nicotine (or a salt thereof) into the carrier when the network structure is formed also allows for greater control over the amount of nicotine ultimately delivered to the user.

[0126] Whenever the word "about" is used herein in the context of a dimension (e.g., value, temperature, pressure (applied force), relative humidity, size and weight, particle or granule size, pore size, time frame, etc.), amount (e.g., relative amount (e.g., number or percentage) of particles, individual components in a composition or component of a composition, and absolute amounts such as dose of nicotine, number of particles, etc.), deviation (from a constant, degree of degradation, etc.), it will be understood that such variable is an approximation and thus may vary by ±10%, for example ±5%, and preferably ±2% (e.g. ±1%) from the number specified herein.

[0127] The present invention is illustrated by the following examples: [Brief description of the drawings]

[0128] [Figure 1] 3 shows the release profiles for nicotine-loaded powders made in the presence (triangles) and absence (circles) of sodium bicarbonate. [Diagram 2] FIG. 1 shows the effect of different drying conditions and the presence or absence of sodium bicarbonate on the amount of nicotine that can be released from molded tablets. [Figure 3a] Figure 2 shows the nicotine release profile for a powder mix with particle size of 100-200 μm stored in a ZYN® pouch, along with commercially available Zyn® Mini Dry (particle size 100-200 μm) over a time scale. [Figure 3b] Figure 2 shows the nicotine release profile for a powder mix with particle size of 100-200 μm stored in a ZYN® pouch, along with commercially available Zyn® Mini Dry (particle size 100-200 μm) over a time scale. [Figure 4a] FIG. 1 shows nicotine release for three powder blends according to the invention. [Figure 4b] 1 shows pH measurements for three powder mixtures according to the present invention. [Figure 5a]FIG. 1 shows nicotine release for a wet pouch of the invention (containing propylene glycol) and a dry pouch of the invention. [Figure 5b] 4 shows pH measurements for a wet pouch of the invention (containing propylene glycol) and a dry pouch of the invention. [Figure 6a] FIG. 1 shows nicotine release after storage at 60% RH for up to 34 days for a dry formulation of the present invention, a dry commercial product, and a wet commercial product. [Figure 6b] 1 shows pH results for a dry formulation of the present invention, a dry commercial product, and a wet commercial product after storage at 60% RH for up to 34 days. [Figure 6c] FIG. 1 shows nicotine release after storage for up to 34 days at 33% RH for a dry formulation of the present invention, a dry commercial product, and a wet commercial product. [Figure 6d] 1 shows pH results for a dry formulation of the present invention, a dry commercial product, and a wet commercial product after storage at 33% RH for up to 34 days. [Figure 7] FIG. 1 shows the nicotine release profile for a mixture of an alkaline bioceramic pH adjuster and calcium sulfate loaded with nicotine. [Figure 8] 1 shows the pH profile for a mixture of an alkaline bioceramic pH adjuster and calcium sulfate loaded with nicotine. [Figure 9] The percentage of nicotine released from various products over a 20 minute period is shown. EXAMPLES

[0129] Example 1 - Effect of Sodium Bicarbonate and Sodium Carbonate on Nicotine in Packaging material The nicotine salt used was USP grade nicotine bitartrate dihydrate. The pH adjuster used was standard food grade sodium bicarbonate (referred to herein as E500). BP, DAB grade calcium sulfate hemihydrate was used to form a chemically bonded ceramic system.

[0130] method (i) Without E500: 12.4954g of BP, DAB grade calcium sulfate hemihydrate, and 0.5252g of nicotine bitartrate dihydrate were dry mixed for 10 minutes at 46 rpm using a Turbula mixer. As a next step, 10.0g of water was added and a paste was formed by hand mixing using a spatula. The paste was cast into a rectangular shaped plate of approximately 11×13 cm and 2 mm thick. The plate was cured at 35° C. and about 95% humidity for approximately 1 hour, after which the cured paste was dried at room temperature for approximately 18 hours before being crushed and sieved. The dried plate was crushed by hand using a spoon, pestle, and mortar and sieved using a Retsch AS 200 Basic sieve shaker stack to obtain a particle size fraction ranging from 100 μm to 500 μm.

[0131] (ii) With E500: 0.5258g of nicotine bitartrate dihydrate and 0.5249g of E500 were mixed with 10mL of water. As a next step, the liquid was added to 12.5064g of calcium sulfate hemihydrate BP, DAB grade and mixed by hand using a spatula to form a paste. The paste was cast into a rectangular shaped plate of approximately 11x13cm and 2mm thick. The plate was cured overnight at 30°C and about 95% humidity, after which the cured paste was dried at room temperature for about 18 hours before being crushed and sieved. The dried plate was 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.

[0132] analysis All ground powders were placed into commercially available "snuff" pouches for the preparation of wet snuff at home. The pouches are made of non-woven cellulose and can be welded using mild heat.

[0133] Extraction experiments were performed using a small vessel and a dissolution test set according to USP 711 Apparatus 2. Briefly, samples were placed in 100 ml of phosphate buffer at pH 6.8 at 37° C. with a stirring paddle at 50 rpm. 1 ml samples were then withdrawn for analysis at different time points. The amount of dissolved nicotine was determined using an HPLC system.

[0134] Results and Conclusions When E500 was not present during the preparation of the paste, the extractable amount of nicotine present in the powder was 70% of the amount of nicotine loaded. When E500 was present during loading, the extractable amount of nicotine present in the powder was 25-30% of the amount of nicotine loaded. The results are shown in Figure 1.

[0135] The addition of sodium bicarbonate during the preparation of the paste significantly reduced the amount of nicotine that was extractable from the samples.

[0136] A similar experiment was also carried out in which a milled powder was produced according to method (i) above and then mixed with an amount of sodium bicarbonate corresponding to that used in method (ii). This mixture was also placed in a "snuff" pouch. Nicotine release analysis was evaluated using the method described above and the release profile was found to be consistent with that observed for a powder produced by method (i) and not subsequently mixed with sodium bicarbonate. This confirms that sodium bicarbonate only affected the nicotine release profile of the final powder when sodium bicarbonate was present during the step of setting the calcium sulfate hemihydrate aqueous paste.

[0137] Additionally, similar experiments were performed using sodium carbonate instead of sodium bicarbonate. The results of these experiments showed that the addition of sodium carbonate to a mixture containing water, nicotine bitartrate dihydrate, and calcium sulfate hemihydrate also reduced the nicotine content in the finished powder.

[0138] Example 2 To further explore the mechanisms behind the nicotine loss observed in Example 1, this experiment was performed.

[0139] method Samples formed using nicotine in the form of BP and DAB grade calcium sulfate hemihydrate and USP grade nicotine bitartrate dihydrate were prepared according to the method described in Example 1. Half of the samples contained sodium bicarbonate and half did not.

[0140] In contrast to Example 1, the paste was formed into tablets using empty tablet blisters and then cured under different conditions described below (instead of molding crushed and sieved plates).

[0141] Two sets of curing conditions were used: "Zip": The molded paste was stored in an airtight zip bag not much larger than the blister at room temperature, approximately 24°C. 100% RH: Plates were stored at approximately 100% relative humidity and 30° C. for a period of time and then allowed to "dry" at room temperature before analysis.

[0142] analysis Analysis was performed by extraction of the molded tablets. Each tablet was placed in a 50 mL Falcon tube containing 15 mL of distilled water. The tubes were placed on a shaker table for approximately 1 hour, after which the extract was analyzed with a UV spectrophotometer system (VWR UV-3100PC) at a wavelength of 260 nm. A standard curve was obtained using a defined solution with nicotine base.

[0143] result The results are shown in Figure 2. Adding sodium bicarbonate (E500) to the formulation during paste manufacture significantly reduced the amount of extractable nicotine. Allowing the material to set and harden in a moist, warm environment significantly reduced the amount of extractable nicotine.

[0144] The results indicate that the addition of the pH adjuster should be done by mixing the dry components after the chemically bonded ceramic system has been cured, crushed and sieved, or incorporated into the formulation in some other way.

[0145] Example 3 - Comparison with commercial products method Samples formed using nicotine in the form of BP and DAB grade calcium sulfate hemihydrate, and USP grade nicotine bitartrate dihydrate were prepared and analyzed according to the method described in Example 1. 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. Only the 100-200 μm size fraction was used in this example. The particles were placed into emptied and washed "Zyn®" pouches. The pouches were then resealed using heat.

[0146] The commercial product tested was Zyn® Mini Dry, a dry, well-known Swedish product purchased at a convenience store. For the Zyn® product, 10 pouches were cut open, the powder inside was removed, and sieved as in the above example. The 100-200 μm fraction was selected, placed back into the pouch, and sealed.

[0147] Analysis of nicotine release was performed as described in Example 1.

[0148] result The incorporation of nicotine into a chemically bonded ceramic system formed from calcium sulfate was shown to result in the release of nicotine at the same level, but with a longer release, compared to the commercially available Zyn® Mini Dry product. The results are shown in Figures 3a and 3b. For comparison reasons, the scale on the Y-axis is normalized, meaning that for each curve, the amount extracted at the last measured time point is set to 100%.

[0149] Example 4 - pH comparison with commercial products method Samples using nicotine in the form of BP and DAB grade calcium sulfate hemihydrate (CaSH), USP grade nicotine bitartrate dihydrate were prepared as follows: 23.1186 g of CaSH was weighed onto an aluminum 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 which was added to the mixture. The mixture was stirred by hand for about 1 minute and then spread evenly on the sheet. The material was allowed to solidify and dried at room temperature for 48 hours. The material was then crushed using a pestle and mortar and finally sieved using a Retsch® AS 200 Basic sieve shaker stack to obtain particles in the range of 50-500 μm. The powder was tested using a spectrophotometer to confirm the nicotine content.

[0150] 300 mg of the resulting powder was mixed with 3.62% by weight of Ph.Eur grade anhydrous sodium carbonate and sealed in a pouch made of non-woven cellulose. The pH produced by the 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).

[0151] analysis Nicotine Analysis: 300 mg of powder was diluted with 100 mL of distilled water and shaken for about 1 minute, and then the dilution was analyzed with a UV spectrophotometer system (VWR UV-3100PC) at a wavelength of 260 nm.

[0152] pH analysis: pH measurements were performed using a calibrated Mettler Toledo® Seven compact pH / Ion S220 system equipped with a Mettler Toledo® InLab Expert Pro electrode. Each pouch was placed in a beaker containing 25 mL of distilled water and stirred for 30 minutes using a magnet and magnetic stirrer. After 30 minutes, the magnet and pouch were removed and the pH was measured.

[0153] result Nicotine Analysis: 100% of the added nicotine was recovered in the samples.

[0154] pH analysis: The pH results are summarized in Table 1 below. [Table 1]

[0155] Nils Cortado contains bamboo fiber and microcrystalline cellulose (MCC) as fillers. Zyn® Cool Mint Slim uses MCC and vegetable fiber as fillers. Volt® uses MCC as fillers. On!® uses MCC and maltitol as fillers. Nordic Spirit® uses Polyacrilex, a gum base that contains nicotine. Lyft® uses MCC as a filler.

[0156] It can be concluded that the pH of the chemically bonded ceramic system is consistent with the commercial product.

[0157] Example 5 - Filled Powder for Nicotine Pouches Below is shown a representative buccal formulation containing a nicotine-loaded powder made according to the methods of the present invention. [Table 2]

[0158] method Nicotine loaded base powders were made using BP and DAB grade calcium sulfate hemihydrate (CaSH) and nicotine in the form of USP grade nicotine bitartrate dihydrate as follows: 170.4 g of nicotine bitartrate was dissolved in 1215.7 g of deionized water in a household blender. 1519.6 g of CaSH was added in small portions. The mixture was blended for about 3 minutes using medium speed in the blender. The blend was then poured onto a metal-walled silicone canvas and allowed to solidify, creating a plate of about 10 mm thickness. The plate was then placed on a metal plate with holes and allowed to dry at room temperature for about 24 hours. The molded plate was then broken into smaller pieces using a pestle and mortar, and finally ground in a household flour mill. The resulting powder was then sieved using a Retsch® AS 200 Basic sieve shaker stack to obtain particles in the range of 50-500 μm. The resulting powder ("nicotine loaded base powder") was then mixed with the rest of the components according to Table 2 above. Mixing was performed by weighing the components into a glass container with a lid and mixing in a WAB Turbula® mixer at 60 rpm for 1 hour. After mixing, a portion of the powder mixture was filled and sealed into three separate non-woven pouches using a pouching machine. Each pouch was filled with approximately 0.3 g of powder.

[0159] analysis The pouches were suspended in a steel wire "cage" in a beaker containing 50 mL of deionized water. A magnet was added to the beaker, which was placed directly above a magnetic stirrer.

[0160] pH pH measurements were performed using a calibrated Mettler Toledo® Seven Compact pH / Ion S220 system equipped with a Mettler Toledo® InLab Expert Pro electrode. The pH meter was set to automatic measurement and pH was measured once every minute.

[0161] Nicotine Release A pipette was used to manually collect the samples, which were then analyzed with a UV spectrophotometer (VWR UV-3100PC) at a wavelength of 260 nm. A standard curve was obtained using a defined solution with nicotine base.

[0162] result The curves obtained from the nicotine release and pH measurements can be seen for each of the three pouches in Figures 4a and 4b.

[0163] Example 6 - Moist Nicotine Pouch A wet formulation was made by mixing the powder formulation from Example 5 with 17% by weight propylene glycol (PG). 0.6 g of the powder from Example 5 was mixed with 0.1 g of PG in a beaker using a spatula. The resulting mixture had a texture and viscosity similar to the commercially available wet product.

[0164] analysis Nicotine release and pH were tested according to the methods of Example 5.

[0165] result The results for nicotine release and pH are shown in Figures 5a and 5b, comparing this "wet" formulation to the dry formulation of Example 5. The data show that nicotine release rates are comparable for both the dry and wet formulations, confirming that both dry and wet formulations are capable of providing sustained release of nicotine over a meaningful time frame.

[0166] Example 7 - Taste evaluation A small-scale subjective evaluation was conducted with nicotine pouch users (n=4). Each user was given a can containing a pouch produced according to Example 5 with two different flavors, one citrus and one mint (Powder 1 and Powder 2), as shown in Table 3: [Table 3]

[0167] For comparison, each subject was also given one can of a dry commercial competitive product containing mint flavoring and one can of a wet commercial competitive product (Zyn® Mini dry and Zyn® Slim, respectively). Subjects were asked to evaluate the odor in the can, the rate of nicotine release, the duration of nicotine release, the rate of flavor release, and the duration of flavor release.

[0168] The results are presented in terms of a comparison of dry and wet commercial products. 1. Smell when you open the can: Powders 1 and 2 had a better, fuller smell compared to the commercial dry product and similar to the commercial wet product. 2. Nicotine production: The commercial wet products had the fastest nicotine onset. Powders 1 and 2 were equal to or faster than the commercial dry products. 3. Duration of Nicotine Release: Powders 1 and 2 had a much longer nicotine release than the commercially available dry product, and a longer nicotine release than the commercially available wet product. 4.Flavoring: The flavors in Powders 1 and 2 were perceived and fully developed much faster than the commercial dry product. The performance of the commercial wet product was roughly between the dry commercial product and Powders 1 and 2. 5.Flavor duration The duration of flavor release for powders 1 and 2 was much longer than for both the dry and moist commercial products. The moist commercial products had a longer flavor duration than the dry products. Powders 1 and 2 release flavor for at least 45-60 minutes, long after the nicotine has been released. One subject even kept a pouch containing powder 1 in their mouth for as long as 3 hours and still had good flavor from the pouch. The dry commercial products typically lost all flavor within 10 minutes, and the moist commercial products within 15-20 minutes.

[0169] Example 8 - Storage stability The stability of the formulations of the present invention under humid conditions was assayed using the following method.

[0170] Test materials A test formulation of the present invention (referred to as "bioceramic powder") was made according to the method of Example 5. Commercially available dry and wet formulations were used for comparison. The formulations were provided in powder form for storage and then sealed in pouches made of non-woven cellulose prior to storage.

[0171] Storage conditions The sealed pouches were stored under the following conditions: Trial duration: 34 days. Tank / Container: In open pouch cans with no lid. The cans are placed inside larger sealed plastic containers of different humidity. Temperature: Room temperature. Typically varies between 20°C and 23°C. Humidity: Two different levels of relative humidity ("RH") were used: 33% and 60% RH. RH was controlled by having saturated salt solutions containing different salts in the bottom of the plastic container as described in Greenspan L., Journal of Research of the National Bureau of Standards, vol. 81A, No. 1, 1977, 89-96.

[0172] analysis Analysis of nicotine content before and after storage was performed using the UV spectrophotometric method of Example 5. pH measurements were performed using the method of Example 5.

[0173] result: Nicotine release and pH results are shown in Figures 6a-6d for 33% and 60% RH. In these figures, "bioceramic powder" refers to the test results for the pouches containing the test formulations of the invention. The results show that after 4 weeks of storage, the releasable nicotine from the nicotine pouches containing the formulations of the invention was high. This indicates that the formulations of the invention have storage stability properties that are as good as those of the dry commercial product (in terms of nicotine release under the conditions tested) and better than those of the wet commercial product.

[0174] Example 9 - Different Carriers and pH Adjusters This example demonstrates the use of calcium silicate, Portland cement, and sodium carbonate as pH adjusting agents added to a calcium sulfate based nicotine powder.

[0175] material USP Grade Nicotine Bitartrate Dihydrate Deionized water (CSH) BP, DAB grade calcium sulfate hemihydrate (CS) Calcium silicate powder (CaO / SiO2=1 / 1) (PC) Portland Cement (SC) Sodium Carbonate

[0176] method Nicotine loaded base powders were made using BP and DAB grade calcium sulfate hemihydrate (CaSH) and nicotine in the form of USP grade nicotine bitartrate dihydrate as follows: 170.4 g of nicotine bitartrate was dissolved in 1215.7 g of deionized water in a domestic blender. 1519.6 g of CaSH was added in small portions. The mixture was blended for about 3 minutes using medium speed in the blender. The blend was then poured onto a metal-walled silicon canvas and allowed to solidify, creating a plate of about 10 mm thickness. The plate was then placed on a metal plate with holes and allowed to dry at room temperature for about 24 hours. The molded plate was then broken into smaller pieces using a pestle and mortar, and finally ground in a domestic flour mill. The resulting powder was then sieved using a Retsch® AS 200 Basic sieve shaker stack to obtain particles in the range of 50-500 μm. The resulting powder ("nicotine loaded base powder") was then mixed with CS and PC, respectively, to produce two different powders. Additionally, one powder, powder 3, was made in which the alkaline agent used was the standard drug sodium carbonate. Powder 1: 1 g of nicotine-loaded base powder was mixed with 5 wt% CS. Powder 2: 1 g of nicotine-loaded base powder was mixed with 3.5 wt% PC. Powder 3: 1 g of nicotine-loaded base powder was mixed with 3.5 wt% SC.

[0177] The powders were mixed by hand using a spatula in a beaker to create a homogenous blend. 0.3 g of the resulting powder was placed in each standard size pouch made of non-woven material for analysis.

[0178] analysis pH and nicotine release were performed according to the methods described in Example 9.

[0179] result The resulting nicotine release and pH profiles can be seen in Figures 7 and 8, respectively.

[0180] Example 10 - Real-time stability of CBC-based nicotine pouches The nicotine content of nicotine pouches containing the powder of the present invention was measured after storage under different conditions.

[0181] Sample preparation Three different types of samples were tested according to Table 4. They differ in the preparation, storage and analysis methods. [Table 4] *The can containing the pouch was kept in a handbag carried by the user and was occasionally opened.

[0182] The manufacturing process involves first producing a nicotine-containing chemically bonded ceramic (CBC) powder, mixing the resulting powder with additional ingredients, and filling the pouches.

[0183] Step 1 42.6 g of USP grade nicotine bitartrate dihydrate was dissolved in 312 g of deionized water. 380.2 g of BP, Dab grade calcium sulfate hemihydrate was weighed into a bowl. The water-nicotine salt solution was added to the calcium sulfate hemihydrate and manually stirred into a homogenous paste. The proportions of water-nicotine salt solution and calcium sulfate hemihydrate were selected to produce a dry powder with a nicotine (free base) content of approximately 25-30 mg per gram of powder. The paste was poured onto an aluminum foil sheet and allowed to set for approximately 10 minutes. The set material was then dried in a convection oven at 24°C for approximately 24 hours. The set material was then manually crushed using a pestle and mortar, and the crushed material was then sieved to obtain a powder in the particle size range of 50-500 μm.

[0184] Step 2 The nicotine-containing CBC powder from step 1 was mixed with other ingredients to produce a finished formulation according to Table 5. Blending of the components was accomplished by dry blending in a Turbula® dry mixer. [Table 5]

[0185] Step 3 Lab Pouching: A pouch of a non-woven heat sealable material designed for use as a pouch was filled with 0.3 g of powder. The pouch was sealed using a standard heat sealer.

[0186] Pouching at CMO: The finished powder was sent to a contract manufacturing organization (CMO) to be filled into pouches using a pouching machine designed for filling nicotine pouches. The pouch material used was a non-woven, heat sealable material designed for use as pouches. Each pouch was filled with approximately 0.3 g of the final nicotine formulation.

[0187] analysis To measure nicotine release, each pouch was suspended in a metal mesh cage in 100 ml of distilled water in a glass beaker containing a stirring magnet. The beaker was placed on a magnetic stirrer with a stirring speed of 360 rpm. Samples were taken after 30 minutes using a pipette and placed in sealable vials for analysis in either a UV spectrophotometer or an HPLC system.

[0188] UV spectrophotometer The absorbance of the analytes was measured using a UV spectrophotometer system (VWR UV-3100PC) at a wavelength of 260 nm. The absorbance of each analyte was calculated as a nicotine concentration using a calibration curve and the known powder weight in each pouch.

[0189] HPLC Samples were analyzed on a Shimadzu Prominence-I LC-2030 HPLC system equipped with a UV detector.

[0190] result The results are summarized in Table 6. The nicotine pouches had good stability over the time periods and conditions measured. [Table 6]

[0191] The analysis had several obvious sources of variability. - The analytical method itself has inherent variability. - The time period between the measurement calibration curve and the sample measurement may vary. The weight of the pouches filled by the CMO is not accurate. An accurate measurement requires the pouch to be emptied, so the weight is taken as an average of several pouches emptied from the same batch, not for the exact pouch measured.

[0192] Nevertheless, the results show minimal loss over the time periods and conditions studied.

[0193] Example 11 - Portland Cement Products Hardened Portland cement was used as a pH adjuster along with calcium nicotine phosphate granules.

[0194] method Sample preparation Step 1: Manufacturing of calcium phosphate nicotine granules 153g of USP grade nicotine bitartrate dihydrate was dissolved in 430ml of distilled water. 1973g of DAB / BP grade calcium sulfate hemihydrate was weighed into the steel drum of an intensive mixer type granulator. The granulator was started at a speed of 20m / s and the nicotine / water solution was poured in during 15 seconds. The granulator was turned on for another 15 seconds, then reduced to half speed and run for another 120 seconds, then turned off and the material examined. The granulator was turned on again at a speed of 20m / s, another 100ml of water was added, the machine was run for 15 seconds and turned off. The granulator was started again, another 150ml of water was added and the granulator was turned on for 15 seconds. The resulting granules were poured into aluminum trays and dried at room temperature for 24 hours. The dried granules were sieved using a Retsch® AS 200 Basic sieve shaker stack to obtain particles in the range of 50-500 μm. The resulting nicotine content in the powder was approximately 6 mg nicotine / 0.3 g powder.

[0195] Step 2: Production of hardened Portland cement powder. 10 g Portland cement and 4 g water were mixed manually into a homogenous paste in a glass beaker. The paste was then allowed to set and harden on aluminum foil for at least 1 hour at ambient room conditions. The material was then manually ground using a pestle and mortar. The ground granules were sieved using a Retsch® AS 200 Basic sieve shaker stack to obtain particles in the range of 50-500 μm.

[0196] Step 3: Mixture of hardened Portland cement with nicotine containing calcium phosphate granules. 20 g of granules from step 1 were mixed with four different amounts of hardened Portland cement powder according to Table 7. Mixing was done in a Turbula® dry mixer for 30 minutes at 50 rpm. [Table 7]

[0197] Step 4 Filling the pouch with powder 0.3 g of powder was filled into a pouch of non-woven heat sealable material designed for use as a nicotine pouch. Three pouches were made for Powders 2, 3, and 4 in Table 7.

[0198] analysis Three different sets of measurements were performed using different samples, two different pH measurements, and one dissolution experiment.

[0199] pH method 1: 0.3 g of powders 1, 2, and 4 according to Table 7 were added to 100 ml of deionized water in a glass beaker equipped with a stirring magnet. The beaker was placed on a magnetic stirrer at 360 rpm. After 30 minutes, the pH was measured using a calibrated Mettler Toledo Seven compact pH / Ion S220 system equipped with a Mettler Toledo InLab Expert Pro electrode. Three samples of each powder were analyzed.

[0200] pH method 2: The filled pouches containing powders 2, 3, and 4 were suspended in a metal mesh cage in 100 ml of deionized water in a glass beaker containing a stirrer magnet. The beaker was placed on a magnetic stirrer with a stirrer speed of 360 rpm. After 30 minutes, the pH was measured using a calibrated Mettler Toledo Seven compact pH / Ion S220 system with a Mettler Toledo InLab Expert Pro electrode. Three samples of each powder were analyzed.

[0201] Melting: A pouch filled with 0.3 g of powder 3 according to Table 7 was suspended in a metal mesh cage in 100 ml of deionized water in a glass beaker containing a stirrer magnet. The beaker was placed on a magnetic stirrer with a stirrer speed of 360 rpm. For dissolution analysis, samples were taken after 30 minutes using a pipette and placed in a sealable vial for analysis. The samples were then analyzed by measuring absorbance using a UV spectrophotometer system (VWR UV-3100PC) at a wavelength of 260 nm. The absorbance of each analyte was calculated as a nicotine concentration using a calibration curve and known powder weight. Three pouches were analyzed.

[0202] result The results of the pH measurements are shown as the average of the three samples in Table 8. The desired pH of 8 or higher could be achieved with powders 3 and 4. [Table 8]

[0203] The results from the dissolution experiments can be seen in Table 9. It was determined that at least 6 mg of nicotine was dissolved from each sample, confirming that the addition of hardened PC powder does not interfere with nicotine release. [Table 9]

[0204] Example 12 - Nicotine concentration in nicotine pouches after human use Pouches containing nicotine-loaded bioceramic (chemically bonded ceramic) powder were generated and compared to commercially available nicotine pouches to evaluate the amount of nicotine remaining after 20 minutes of human use.

[0205] material USP Grade Nicotine Bitartrate Dihydrate Distilled water (CSH) BP, DAB grade calcium sulfate hemihydrate

[0206] Manufacturing of CBC-based nicotine pouches The manufacture involved first producing nicotine-containing chemically bonded ceramic (CBC) granules, mixing the resulting granules with additional ingredients, and then placing the mixture into a pouch.

[0207] Step 1: 153 g of nicotine bitartrate dihydrate was dissolved in 430 ml of distilled water. 1973 g of calcium sulfate hemihydrate was weighed into the steel drum of an intensive mixer type granulator. The granulator was started at a speed of 20 m / s and the nicotine / water solution was poured in during 15 seconds. The granulator was turned on for another 15 seconds, then reduced to half speed and run for another 120 seconds, then turned off and the material examined. The granulator was turned on again at a speed of 20 m / s, another 100 ml of water was added, the machine was run for 15 seconds and turned off. The granulator was started again, another 150 ml of water was added and the granulator was turned on for 15 seconds. The resulting granules were poured into aluminum trays and dried at room temperature for 24 hours. The dried granules were sieved using a Retsch® AS 200 Basic sieve shaker stack to obtain particles in the range of 50-200 μm.

[0208] Step 2: The nicotine-containing CBC granules from step 1 were mixed with other ingredients to obtain the finished formulation according to Table 10. Blending of the components was achieved by dry blending in a Turbula® dry mixer. [Table 10]

[0209] After mixing, the powders were allowed to stand in a closed jar for at least 24 hours to allow the flavoring to homogenize.

[0210] Step 3: Pouches of a nonwoven heat sealable material designed for use as pouches were filled with either 0.33 g or 0.15 g of the finished formulation. The pouches were sealed using a standard heat sealer. The pouch containing 0.15 g was half the length of the pouch containing 0.33 g, which is the same size as the commercially available ZYN® product.

[0211] The molecular structure of the chemically bonded ceramic system obtained from this method was subjected to X-ray powder diffraction analysis and found to be the same as that obtained in Example 5. For both hardened ceramics obtained from the hydration of calcium sulfate hemihydrate, the following X-ray diffraction peaks of high intensity were observed: 11.5, 20.7, and 29.2° 2θ (using X-rays with a wavelength of 1.5406 Å), which are also the most intense peaks observable for calcium sulfate dihydrate.

[0212] Human Use Testing Two users ("User 1" and "User 2") who currently use different brands of nicotine pouches were permitted to use the different nicotine pouches according to the following method. The pouches used are listed in Tables 11A and 11B. Zonnic is an approved nicotine replacement therapy (NRT) product and is not a product for recreational use. [Table 11] [Table 12]

[0213] To test the pouches, the user placed the pouch between the upper lip and gums and held it in place for 20 minutes without touching the pouch with the tongue. After 20 minutes, the pouches were removed and immediately placed in plastic vials and frozen to -20°C awaiting analysis. The users tested the pouches according to Table 12. A washout period of at least 1 hour was mandatory between uses of the pouches. [Table 13]

[0214] analysis Before analysis, each pouch used was thawed at room temperature. The pouch was then suspended in a steel mesh cage in a beaker containing 100 ml of distilled water and a stirrer magnet. The assembly was immediately placed on a magnetic stirrer set at 360 rpm. After 60 minutes, samples were collected and analyzed using a UV spectrophotometer system (VWR UV-3100PC) at a wavelength of 260 nm to obtain absorbance values. Using a calibration curve based on a calibration solution of nicotine bitartrate dissolved in distilled water, the corresponding nicotine concentration could be calculated, and then the amount of nicotine remaining in the pouch after use could be calculated.

[0215] result The results from the analysis are shown in Figure 9. The results clearly show that the CBC pouch had significantly less nicotine remaining in the pouch after use compared to the other products.

Claims

1. An oral preparation comprising a solid, porous, chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjuster, The chemically bonded ceramic system contains calcium and is formed in the absence of the pH adjusting agent. The chemically bonded ceramic system is formed in the presence of nicotine or a salt thereof, and as a result, the nicotine or salt thereof is located within the pores of the chemically bonded ceramic system. Oral preparation.

2. The chemically bonded ceramic system is based on calcium phosphate, calcium sulfate, calcium silicate, calcium aluminate, or a mixture thereof. The formulation according to claim 1.

3. The chemically bonded ceramic system is formed from alpha-tricalcium phosphate, tetracalcium phosphate, or calcium sulfate. The formulation according to claim 2.

4. The aforementioned preparation is prepared using a nicotine salt such as nicotine dihydrate bitartarate. A preparation according to any one of claims 1 to 3.

5. The pH adjusting agent is a carbonate, bicarbonate, or phosphate compound. A preparation according to any one of claims 1 to 3.

6. The aforementioned formulation, upon contact with saliva, yields a pH of at least 8. A preparation according to any one of claims 1 to 3.

7. The pH adjusting agent is mainly located on the outside of the pores of the chemically bonded ceramic system. A preparation according to any one of claims 1 to 3.

8. The chemically bonded ceramic system is present in an amount of 40% to 98% by weight of the oral preparation. A preparation according to any one of claims 1 to 3.

9. A permeable sealed bag containing a solid, porous, chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjuster, The chemically bonded ceramic system contains calcium and is formed in the absence of the pH adjusting agent. The chemically bonded ceramic system is formed in the presence of nicotine or a salt thereof, and as a result, the nicotine or salt thereof is located within the pores of the chemically bonded ceramic system. Permeable sealed bag.

10. The bag comprises a cavity surrounded by a permeable material, and the pH adjusting agent is associated with the permeable material. The bag according to claim 9.

11. An oral preparation according to any one of claims 1 to 3, and a bioadhesive and / or mucosal adhesion promoter, Sublingual tablets, buccal tablets, wafers, or lozenges.

12. A method for forming an oral preparation comprising a solid, porous, chemically bonded ceramic system, nicotine or a salt thereof, and a pH adjuster, The method includes forming the chemically bonded ceramic system in the absence of the pH adjusting agent and in the presence of nicotine or a salt thereof. The chemically bonded ceramic system contains calcium. method.

13. For use in treating nicotine dependence, treating one or more symptoms of nicotine dependence, assisting in smoking cessation, or improving symptoms associated with a disease or condition selected from the group consisting of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression, An oral preparation according to any one of claims 1 to 3.

14. In the non-therapeutic oral administration of nicotine to humans, the oral preparation according to any one of claims 1 to 3, use.

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