Multilayered nicotine-containing pharmaceutical composition

Abstract

To provide alternative compositions capable of delivering or administering nicotine via an oral route for therapeutic purposes to aid in smoking cessation.SOLUTION: The invention provides a multi-layered pharmaceutical composition comprising two or more formulations with varying properties. In some embodiments, the pharmaceutical compositions provide combinations of different organoleptic properties within the same product. In certain embodiments, these combinations allow for a controlled release profile of active ingredients as the user enjoys the pharmaceutical composition. The invention further provides methods for making and using the pharmaceutical composition.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to compositions containing nicotine, particularly nicotine-containing pharmaceutical compositions intended to be administered to provide a pharmacological effect or otherwise used for therapeutic purposes.

Background Art

[0002] Symptoms, diseases or disorders of the central nervous system (CNS) can be drug-induced; can be caused by genetic factors, infections or psychological trauma; or can be of unknown origin. These include neuropsychiatric disorders, neurological disorders and mental diseases; including neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive-emotional disorders. The clinical pathologies of multiple CNS symptoms, diseases or disorders are due to dysfunctions of the CNS (i.e., disorders resulting from inappropriate amounts of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and / or inappropriate interactions between neurotransmitters and neurotransmitter receptors).

[0003] Nicotinic compounds such as nicotine can affect nicotinic acetylcholine-activated receptors (nAChRs). Subtypes of nAChRs are present in both the CNS and the peripheral nervous system (PNS), but the distribution of subtypes is non-uniform. For example, certain subtypes are abundant in the brains of vertebrates, others are abundant in autonomic ganglia, and still others are abundant at the neuromuscular junction. Activation of nAChRs by nicotinic compounds leads to neurotransmitter release. See, for example, Dwoskin et al., Exp. Opin. Ther. Patents, 10:1561-1581 (2000); Schmitt et al., Annual Reports in Med. Chem. 35:41-51 (2000); Huang et al., J. Am. Chem. Soc., 127:14401-14414 (2006); Arneric et al., Biochem. Pharmacol., 74:1092-1101 (2007) and Millar, Biochem. Pharmacol., 78:766-776 (2009), which are hereby incorporated by reference.

[0004] It has been suggested that the administration of nicotine and other nicotinic compounds may lead to a variety of pharmacological effects. For example, see U.S. Patent No. 5,583,140 to Bencherif et al.; No. 5,723,477 to McDonald et al.; No. 7,001,900 to Jacobsen et al.; No. 7,135,484 to Dart et al. and No. 7,214,686 to Bencherif et al.; and U.S. Patent Publication 2010 / 0004451 to Ahmad et al., which are incorporated herein by reference. As a result, it has been suggested that nicotine and other nicotinic compounds may be useful in treating a wide range of symptoms, diseases, and disorders, including those affecting the CNS. In addition, the administration of nicotine and nicotinic compounds has been proposed for the treatment of certain other symptoms, diseases, and disorders. See, for example, U.S. Patent No. 5,604,231 to Smith et al.; No. 5,811,442 to Bencherif et al.; No. 6,238,689 to Rhodes; and No. 6,489,349 to Bencherif et al., which are incorporated herein by reference. Furthermore, nicotine administration is used in attempts to help tobacco smokers quit smoking (i.e., as smoking cessation aids). For example, nicotine is the active ingredient in various types of so-called "nicotine replacement therapy" or "NRT" products. See, for example, the background art described in U.S. Patent Application No. 13 / 278,877 to Borschke et al., filed October 21, 2011, which is incorporated herein by reference.

[0005] One specific method used to provide oral administration of nicotine is through the use of nicotine-containing lozenges or tablet-type products. Nicotine-containing lozenges, tablets, and microtab-type products are marketed under the trademark names, for example, "Commit" (registered trademark), "Nicorette" (registered trademark), "Nicotinell" (registered trademark), and "NiQuitin" (registered trademark). See also, for example, U.S. Patent No. 5,110,605 to Acharya; No. 5,733,574 to Dam; No. 6,280,761 to Santus; No. 6,676,959 to Andersson et al.; and No. 6,248,760 to Wilhelmsen; and U.S. Patent Publication 2001 / 0016593 to Wilhelmsen, which are incorporated herein by reference.

[0006] It would be desirable to provide alternative compositions that can deliver or administer nicotine via the oral route for therapeutic purposes. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 5,583,140 [Patent Document 2] U.S. Patent No. 5,723,477 [Patent Document 3] U.S. Patent No. 7,001,900 [Patent Document 4] U.S. Patent No. 7,135,484 [Patent Document 5] U.S. Patent No. 7,214,686 [Patent Document 6] U.S. Patent Application Publication No. 2010 / 0,004,451 [Patent Document 7] U.S. Patent No. 5,604,231 [Patent Document 8] U.S. Patent No. 5,811,442 [Patent Document 9] U.S. Patent No. 6,238,689 [Patent Document 10] U.S. Patent No. 6,489,349 [Patent Document 11] U.S. Patent Application No. 13 / 278,877 [Patent Document 12] U.S. Patent No. 5,110,605 [Patent Document 13] U.S. Patent No. 5,733,574 [Patent Document 14] U.S. Patent No. 6,280,761 [Patent Document 15] U.S. Patent No. 6,676,959 [Patent Document 16] U.S. Patent No. 6,248,760 [Patent Document 17] U.S. Patent Application Publication No. 2001 / 0,016,593 [Non-patent literature]

[0008] [Non-Patent Document 1] Dwoskin et al., Exp. Opin. Ther. Patents, 10:1561-1581 (2000) [Non-Patent Document 2] Schmitt et al., Annual Reports in Med.Chem.35:41-51(2000) [Non-Patent Document 3] Huang et al., J.Am.Chem.Soc., 127:14401-14414(2006) [Non-Patent Document 4] Arneric et al., Biochem. Pharmacol., 74:1092-1101 (2007) [Non-Patent Document 5] Millar, Biochem.Pharmacol., 78:766-776(2009) [Overview of the project]

[0009] In one embodiment, the present invention relates to a nicotinic compound-containing composition intended for use for therapeutic purposes. The composition is typically a pharmaceutically acceptable form adapted for oral delivery of the composition. The composition generally comprises a series of two or more different formulations having different properties, which can be arranged in various ways. The different formulations, including the product, may be provided, for example, in a multilayer form. For example, a nicotinic compound-containing composition may comprise an inner core of one formulation and one or more coatings of another formulation, the coatings of which may be full or partial coatings. Thus, it is also possible to provide new compositions by combining formulations having different functional properties within the same product. In certain embodiments, such a multilayer composition allows for a controlled delivery profile during use. For example, one particular formulation may provide a rapid release of the nicotinic compound it contains, while another formulation may provide a prolonged release of the nicotinic compound it contains.

[0010] In one aspect of the present invention, a multilayer pharmaceutical composition is provided comprising two or more formulations having different functional properties, wherein the formulations are selected from the group consisting of: i) a soluble formulation comprising a sugar substitute and a sugar alcohol syrup in an amount of at least about 80% by weight; ii) a molten formulation comprising a lipid having a melting point of about 36°C to about 45°C; iii) a pastel formulation comprising a polysaccharide filler; iv) a pastel formulation comprising a sugar alcohol and a natural gum binder component; v) a chewable formulation comprising a binder, an emulsifier and a lipid having a melting point of about 36°C to about 45°C; and vi) a hard-coated formulation comprising a binder, a sugar substitute and a sugar alcohol syrup, wherein at least one formulation further comprises one or more nicotinic compounds. In certain embodiments, the entire formulation of the multilayer pharmaceutical composition may comprise one or more nicotinic compounds, which may be the same or different.

[0011] In some embodiments, one or more nicotinic compounds in the pharmaceutical composition of the present invention can independently be in the form of a free base, a salt, a complex or a solvate. The one or more nicotinic compounds can include, for example, nicotinopolacrex. In certain embodiments, the one or more nicotinic compounds include a nicotinic compound adsorbed on a porous particulate carrier containing, for example, microcrystalline cellulose.

[0012] The form of the nicotinic compound-containing pharmaceutical composition can be diverse. For example, in some embodiments, the form of the pharmaceutical composition is a core formulation surrounded by one or more continuous layers or a core formulation coated with one or more discontinuous (e.g., partial) layers so as to form a layered or parallel arrangement of two or more formulations. The number of layers can be diverse; for example, in some embodiments, the multilayer pharmaceutical composition can include between 2 and 10 layers, such as between 2 and 5 layers.

[0013] The components of the various formulations can be diverse. In some embodiments, the sugar substitute of the soluble formulation can include isomalt, and / or the sugar alcohol syrup of the soluble formulation can include maltitol syrup. In one exemplary embodiment, the soluble formulation includes a nicotinic compound; a sugar substitute in an amount of about 80% by weight or more; and a sugar alcohol syrup.

[0014] The meltable formulation, if present, in certain embodiments can include a lipid having a melting point of about 38°C to about 41°C. The lipid can be, for example, an animal or plant-derived fat, wax or oil. In one exemplary embodiment, the meltable formulation includes a nicotinic compound, a lipid having a melting point of about 36°C to about 45°C in an amount of about 10% to about 50% by weight; and a filler in an amount of about 20% to about 40% by weight. In another exemplary embodiment, the meltable formulation includes a nicotinic compound; a lipid having a melting point of about 36°C to about 45°C in an amount of about 30% by weight or more; and a filler in an amount of about 30% by weight or more.

[0015] Pastel formulation iii) may, if present, include polydextrose as a polysaccharide filler component in certain embodiments. In some embodiments, the polysaccharide filler component may be present in an amount of about 10% to about 25% by weight of the pastel formulation on a dry weight basis. In one exemplary embodiment, pastel formulation iii) includes a nicotinic compound; a polysaccharide filler in an amount of about 10% by weight or more; a wetting agent in an amount of about 20% by weight or more; a binder in an amount of about 10% by weight or more; and an emulsifier in an amount of about 1% by weight or more.

[0016] In one exemplary embodiment, pastel component iv) comprises a nicotinic compound; a wetting agent in an amount of about 0.5% by weight or more; a sugar alcohol filler in an amount of about 20% by weight or more; and a natural gum binder in an amount of about 10% or more.

[0017] Chewable formulations, if present, may, in certain embodiments, include gum arabic as a binder material. In one exemplary embodiment, the chewable formulation comprises a nicotinic compound, a binder material in an amount of about 30% by weight or more, and a lipid having a melting point of about 36°C to about 45°C in an amount of about 15% by weight or more.

[0018] If present, the rigid coating formulation may, in certain embodiments, contain carboxymethylcellulose as a binder component. If present, the rigid coating formulation may, in certain embodiments, contain isomalt as a sugar substitute. In one exemplary embodiment, the rigid coating formulation comprises a nicotinic compound; a binder; a sugar substitute in an amount of about 20% by weight or more; and a sugar alcohol syrup in an amount of about 5% by weight or more.

[0019] Any combination of two or more formulations described herein may be used in the multilayer pharmaceutical composition of the present invention. For example, in a particular embodiment, the product may comprise two different formulations, where the formulations comprise: formulations i) and ii), formulations i) and iii), formulations i) and iv), formulations i) and v), formulations i) and vi), formulations ii) and iii), formulations ii) and iv), formulations ii) and v), formulations ii) and vi), formulations iii) and iv), formulations iii) and v), formulations iii) and vi), or formulations iv) and vi), where the formulations may be arranged in any way. With respect to the foregoing, the listed formulations are intended to include their rearrangements, and each formulation can be constructed in a variety of ways. For example, “formulations i) and ii)” may also comprise formulations ii) and i), and “formulations iv) and vi)” may also comprise formulations vi) and iv). In other words, “Formulations i) and ii)” are intended to encompass embodiments in which formulation i) is the core and formulation ii) is a partial or complete layer thereon, and embodiments in which formulation ii) is the core and formulation i) is a partial or complete layer thereon.

[0020] In certain embodiments, a combination of three or more formulations described herein may be used in the multilayer pharmaceutical composition of the present invention. In certain embodiments, the product may include formulations i), ii), and iii); formulations i), ii), and iv); formulations i), ii), and v); formulations i), ii), and vi); formulations i), iii), and iv); formulations i), iii), and v); formulations i), iv), and v); formulations i), iv), and vi); formulations i), iv), and vi); formulations i), v), and vi); formulations i), iv), and vi); formulations i), iv), and vi); formulations i), iv), and vi); formulations ii), iii), and v); formulations ii), iv), and vi); formulations ii), iv), and vi); formulations ii), iv), and vi); formulations iii), iv), and vi); or formulations iii), v), where the formulations may be arranged in any way. With respect to the foregoing, the listed formulations are intended to include their rearrangements, and each formulation can be constructed in a variety of ways. For example, “formulations i), ii) and iii)” may also include formulations i), iii), and ii); formulations ii), iii), and i); formulations ii), i), and iii); formulations iii), i), and ii); and formulations iii), ii), and i).In other words, “formulations i), ii) and iii)” are embodiments in which formulation i) is the core, formulation ii) is a partial or complete layer on formulation i), formulation iii) is a partial or complete layer on formulation ii), and formulations i) is the core, formulation iii) is a partial or complete layer on formulation i), formulation ii) is a partial or complete layer on formulation iii), and formulations ii) is the core, formulation iii) is a partial or complete layer on formulation ii), and formulation i) is a partial or complete layer on formulation iii). The embodiments are intended to include the following forms of application, and embodiments in which formulation ii) is the core, formulation i) is a partial or complete layer on formulation ii), formulation iii) is a partial or complete layer on formulation ii), and embodiments in which formulation iii) is the core, formulation i) is a partial or complete layer on formulation iii), formulation ii) is a partial or complete layer on formulation i), and embodiments in which formulation iii) is the core, formulation ii) is a partial or complete layer on formulation iii), formulation i) is a partial or complete layer on formulation ii).

[0021] In another aspect of the present invention, a method is provided for preparing a multilayer pharmaceutical composition, the method comprising: preparing a first formulation by combining a nicotinic compound with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorings, sweeteners, emulsifiers, disintegration aids, wetting agents, buffers and mixtures thereof to form a first nicotinic compound-containing mixture, and forming the first nicotinic compound-containing mixture into a desired form; preparing a second formulation by combining a nicotinic compound with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorings, sweeteners, emulsifiers, disintegration aids, wetting agents, buffers and mixtures thereof to form a second nicotinic compound-containing mixture, and forming the second nicotinic compound-containing mixture into a desired form; and applying the second formulation to the first formulation, wherein the formulation is selected from formulations i), ii), iii), iv), v) and iv) described herein.

[0022] In certain embodiments, the first formulation can be formed into a desired form by pouring or otherwise introducing the first nicotinic compound-containing mixture into a mold, by injection molding the first nicotinic compound-containing mixture, or by other methods suitable for providing the formulation. In certain embodiments, the second formulation can be applied by spray coating, dipping coating, or by forming the second formulation into a sheet to be applied to the first formulation as a sandwich coating. Spray coating or dipping coating may be carried out at a temperature at which the first formulation is maintained substantially in its original form. In some embodiments, the method further includes applying a third formulation as a coating on the second formulation. The third nicotinic compound-containing formulation can be applied, for example, by spray coating, dipping coating, or by forming the third nicotinic compound-containing formulation into a sheet to be applied to the second formulation as a sandwich coating.

[0023] In a further embodiment, a method is provided for treating a human subject having a symptom, disease, or disorder that is responsive to stimulation of nicotinic acetylcholineergic receptors, the method comprising orally administering to the human subject an effective amount of a pharmaceutical composition according to any embodiment described herein. In one embodiment, the pharmaceutical composition is administered as a smoking cessation aid. [Modes for carrying out the invention]

[0024] The present invention will now be described in more detail. However, the present invention can be embodied in many different forms and should not be construed as being limited to the embodiments shown herein. Rather, these embodiments are provided so as to make this disclosure complete and perfect and fully convey the scope of the invention to those skilled in the art. Where used herein and in the claims, the singular forms "a," "an," and "the" include plural nouns unless the context makes it clear. When "percent dry weight" or "based on dry weight," it refers to the weight based on the dry components (i.e., all components except water).

[0025] The present invention provides a nicotinic compound pharmaceutical composition comprising at least two different formulations. Specifically, such compositions generally include formulations having various functional properties, such as multilayer pharmaceutical compositions in which two or more formulations are provided as a multilayer pharmaceutical composition. Each formulation in the nicotinic compound-containing composition may contain one or more nicotinic compounds. At least one formulation contained in the nicotinic compound-containing composition contains a nicotinic compound, but in certain embodiments, one or more other formulations (e.g., one or more layers) in the composition may not contain a nicotinic compound at all. The present invention further provides a method for preparing a multilayer nicotinic compound-containing pharmaceutical composition.

[0026] The structure of a multilayer pharmaceutical composition is generally described by the term "layered" as a structure in which a core is covered by one or more coating layers, which may be partial or complete layers. In other words, each coating layer may completely cover the core or the preceding layer, or only cover a portion of it. The core may be in any form, such as a flat sheet, or a given shape (e.g., square, circular, oval, elliptical, or rectangular), or a shape that can be generally described as spherical, cylindrical (e.g., ranging from the general shape of a flat disc to the general shape of a relatively long, slender rod), helical, elliptical, square, rectangular, etc. In some embodiments, the core and / or multilayer pharmaceutical composition may take the form of beads, powders, capsules, films, strips, gels, etc. In certain embodiments, the shape of the composition may resemble a wide variety of products of the type of pills, tablets, lozenges, capsules, and capsule-type tablets. Furthermore, side-by-side configurations are also included within the scope of the present invention, for example, in which the composition comprises two layers bonded to each other along one surface, and optionally additional layers bonded to one or both of those two layers. The number of layers constituting the pharmaceutical composition can vary, but is typically from about two to about ten layers, for example, two, three, four, five, six, seven, eight, nine, or ten layers. Although the pharmaceutical composition is described herein as "layered" or "multilayered," these layers may not be distinct layers of various formulations with clear boundaries between the layers. For example, there may be some degree of blending, including adjacent layers, between formulations of the product. However, in preferred embodiments, the pharmaceutical composition retains the characteristics and behavior of the individual formulations.

[0027] The functional properties of one or more formulations constituting a multilayer pharmaceutical composition are generally diverse. As used herein, the term "organoleptic" refers to all aspects of a pharmaceutical composition formulation that can be experienced by the user's five senses. Functional properties include, but are not limited to, taste, odor, texture (e.g., chewiness, solubility / melting, hardness, elasticity, crunchiness, biting), etc. For example, formulations within a given multilayer pharmaceutical composition may, in a particular embodiment, have functional properties independently selected from hard, soluble, chewy, mochi-like, melting, crunchy, and combinations thereof. Certain formulations useful as components of the pharmaceutical composition according to the present invention may be described as lozenge-like or pastel-like. The resulting multilayer pharmaceutical composition may, in a particular embodiment, include a unique combination of functional properties as a result of a combination of formulations having different functional properties. For example, in one particular embodiment, the pharmaceutical composition may have a rigid lozenge-like outer formulation and a soluble core formulation such that, upon being placed in the user's mouth, the user first experiences a dissolving effect, followed by a melting effect. This specification also encompasses numerous other combinations of formulations resulting in various combinations of functional properties.

[0028] As used herein, the terms “dissolve,” “dissolving,” and “dissolvable” refer to a formulation having water-soluble components that interact with oral moisture and transfer to a solution, thereby causing the product to be consumed gradually.

[0029] As used herein, “melt,” “melting,” and “meltable” refer to the ability of a formulation to change from a solid state to a liquid state. That is, melting usually occurs when a substance (e.g., a formulation in a pharmaceutical composition) changes from a solid to a liquid due to the application of heat. With respect to the pharmaceutical compositions of the present invention, the application of heat is brought about by the internal temperature of the user's mouth. Therefore, the term “meltable” refers to a formulation that is capable of liquefying in the user's mouth when the product changes phase from solid to liquid, and distinguishes between formulations and / or products that simply disintegrate in the oral cavity due to loss of binding properties within the formulation, or formulations that simply dissolve in the oral cavity when the water-soluble components of the formulation interact with water.

[0030] As used herein, the term “pastel” refers to a soluble oral formulation in which the final product is a hardened solid gel, prepared by solidifying a liquid or gel-like composition, such as a composition containing a gelling agent or binder. In certain embodiments, such formulations are characterized by sufficient binding to resist light chewing in the oral cavity without rapid disintegration. The pastel-like formulations of this disclosure do not typically exhibit the highly deformable chewability seen in conventional chewing gums.

[0031] As used herein, "chewable" means having a binding strength higher than that of pastels but generally lower than that of gum, and being easily deformable in the mouth. Such formulations may feature sufficient binding strength to withstand a greater degree of chewing than pastels. However, such compositions generally disintegrate in the oral cavity (unlike gum formulations).

[0032] As used herein, “hard coating-like” means a layer that exhibits some degree of hardness and / or crunchiness. It is generally a somewhat thin layer that can be easily broken by the user’s teeth and / or easily dissolved in the user’s mouth. Note that, although referred to herein as “coating,” this layer does not necessarily include an outer layer of the pharmaceutical composition and may include an inner layer of the product.

[0033] One or more "nicotinic compounds" in the pharmaceutical formulations of the present invention are natural or synthetic nicotine extracted from plant-based raw materials, which are at least partially purified and do not contain any plant structures such as tobacco leaves. Nicotine is naturally occurring and most preferably obtained as an extract from a species of the genus Nicotiana (e.g., tobacco). Various examples of tobacco and methods for processing tobacco are shown in U.S. Patent Application No. 13 / 240,500, filed September 22, 2011, incorporated herein by reference. See also nicotine-containing compositions shown in U.S. Patent Application Publication No. 2011 / 0268809, Publication No. 2011 / 0274628, and U.S. Patent Application No. 13 / 278,877, filed October 21, 2011, all incorporated herein by reference.

[0034] Nicotine may be enantiomerized S(-)-nicotine, R(+)-nicotine, or a mixture of S(-)-nicotine and R(+)-nicotine. It is most preferable that the nicotine be in the S(-)-nicotine form (e.g., a form that is virtually all S(-)-nicotine) or a racemic mixture consisting mainly or largely of S(-)-nicotine (e.g., a mixture consisting of about 95 parts by weight of S(-)-nicotine and about 5 parts by weight of R(+)-nicotine). It is most preferable that the nicotine be used in a virtually pure form or in a basically pure form. The very preferable nicotine used has a purity of more than about 95 percent by weight, more preferably more than about 98 percent, and most preferably more than about 99 percent. Despite the fact that nicotine can be extracted from species of the genus Nicotiana, it is very preferable that the nicotine (and the compositions and products produced according to the present invention) contain virtually or basically no other components of tobacco.

[0035] In embodiments where nicotine is derived from a plant of the genus Nicotiana, the plant or a part of the plant can be subjected to various types of processing conditions to supply nicotine. For example, the components can be separated from each other, or in other cases, fractionated into a chemical class or a mixture of individual compounds. Typical separation processes may include one or more processing steps (e.g., solvent extraction using polar solvents, organic solvents, or supercritical fluids), chromatography, distillation, filtration, recrystallization, and / or intersolvent partitioning. Examples of solvents or carriers for extraction and separation include water, alcohols (e.g., methanol or ethanol), hydrocarbons (e.g., heptane and hexane), diethyl ether, methylene chloride, and supercritical carbon dioxide.Techniques that are useful examples for extracting components from species of the genus Nicotiana are all incorporated herein by reference: Fiore's U.S. Patent No. 4,144,895; Osborne, Jr. et al.'s U.S. Patent No. 4,150,677; Reid's U.S. Patent No. 4,267,847; Wildman et al.'s U.S. Patent No. 4,289,147; Brummer et al.'s U.S. Patent No. 4,351,346; Brummer et al.'s U.S. Patent No. 4,359,059; Muller's U.S. Patent No. 4,506,682; Keritsis's U.S. Patent No. 4,589,428; S Specification No. 4,605,016 by oga et al.; Specification No. 4,716,911 by Poulose et al.; Specification No. 4,727,889 by Niven, Jr. et al.; Specification No. 4,887,618 by Bernasek et al.; Specification No. 4,941,484 by Clapp et al.; Specification No. 4,967,771 by Fagg et al.; Specification No. 4,986,286 by Roberts et al.; Specification No. 5,005,593 by Fagg et al.; Specification No. 5,018,540 by Grubbs et al.; Specification No. 5,060,669 by White et al.; Specification No. 5,005,593 by Fagg et al. Specification No. 65,775; White et al.'s Specification No. 5,074,319; White et al.'s Specification No. 5,099,862; White et al.'s Specification No. 5,121,757; Fagg's Specification No. 5,131,414; Munoz et al.'s Specification No. 5,131,415; Fagg's Specification No. 5,148,819; Kramer's Specification No. 5,197,494; Smith et al.'s Specification No. 5,230,354; Fagg's Specification No. 5,234,008; Smith's Specification No. 5,243,999; Raymond et al.'s Specification No. 5,3 This is described in specification No. 01,694; specification No. 5,318,050 by Gonzalez-Parra et al.; specification No. 5,343,879 by Teague; specification No. 5,360,022 by Newton; specification No. 5,435,325 by Clapp et al.; specification No. 5,445,169 by Brinkley et al.; specification No. 6,131,584 by Lauterbach; specification No. 6,298,859 by Kierulff et al.; specification No. 6,772,767 by Mua et al.; and specification No. 7,337,782 by Thompson.See also the various separation techniques described in Brandt et al., LC-GC Europe, pp. 2-5 (March, 2002) and Wellings, A Practical Handbook of Preparative HPLC (2006), which are incorporated herein by reference. In addition, plants or parts of plants are incorporated herein by reference in the following: Ishikawa et al., Chem. Pharm. Bull., 50, 501-507 (2002); Tienpont et al., Anal. Bioanal. Chem., 373, 46-55 (2002); Ochiai, Gerstel Solutions Worldwide, 6, 17-19 (2006); Coleman, III, et al., J. Sci. Food and Agric., 84, 1223-1228 (2004); Coleman, III et al., J. Sci. Food and Agric., 85, 2645-2654 (2005); Pawliszyn, ed., Applications of Solid Phase Microextraction, RSC Chromatography Monographs, (Royal Society of Chemistry, UK) (1999); Sahraoui et al., J. It can be subjected to various treatments as described in Chrom., 1210, 229-233 (2008); and U.S. Patent No. 5,301,694 by Raymond et al.

[0036] In certain embodiments, the isolation of nicotine from plants of the genus Nicotiana includes the step of removing high molecular weight components from the tobacco extract. In certain embodiments, high molecular weight components that are beneficial to remove according to the present invention include, but are not limited to, high molecular weight Maillard browning polymers, proteins, polysaccharides, certain pigments, and bacteria. For this purpose, a variety of methods can be used, including size exclusion chromatography, microfiltration, ultrafiltration, nanofiltration, reverse osmosis, and combinations thereof.

[0037] In one embodiment, ultrafiltration is used to remove high molecular weight components from tobacco raw materials. Ultrafiltration is typically applied to tobacco raw materials in the form of tobacco extracts (e.g., aqueous tobacco extracts). In ultrafiltration, the raw material to be filtered is brought into contact with a semipermeable membrane, as described in more detail in U.S. Patent Application No. 13 / 240,500, filed September 22, 2011, which is incorporated herein by reference. In such embodiments, the ultrafiltration step is designed to achieve a tobacco extract in which the level of suspended solids is reduced and therefore the level of clarity is increased.

[0038] Commercially available ultrafiltration systems are readily available and can be used in several embodiments for the ultrafiltration of tobacco extracts. For example, commercial suppliers such as Millipore, Spectrum® Labs, PAL Corporation, Whatman®, Porlex Corporation, and Snyder Filtration manufacture a variety of filtration membranes and cartridges and / or filtration systems (e.g., tangential flow filtration systems). Examples of membranes include, but are not limited to, Biomax® membranes and Ultracel® membranes and Pellicon® XL cassettes (from Millipore), Microkros® hollow fiber modules, Minikros® hollow fiber modules, and KrosFlo® hollow fiber modules (from Spectrum® Labs), and Microza filters and Centramate® tangential flow filtration membrane cassettes, Centrasette® tangential flow filtration membrane cassettes, Maximate® tangential flow filtration membrane cassettes, and Maxisette® tangential flow filtration membrane cassettes. Commercially available filtration systems include, but are not limited to, Millipore's Labscale® tangential flow filtration (TFF) systems and Spectrum® Labs' KrosFlo® tangential flow filtration systems and MiniKros® tangential flow filtration systems.

[0039] Filters and / or membranes that may be useful according to the present invention include those having molecular weight cutoffs of less than about 100,000 Da, less than about 75,000 Da, less than about 50,000, less than about 25,000 Da, less than about 20,000 Da, less than about 15,000 Da, less than about 10,000 Da, and less than about 5,000 Da. In certain embodiments, a multi-stage filtration process is used to supply an extract with improved clarity. Such embodiments use multiple filters and / or membranes having different (typically decreasing) molecular weight cutoffs. Any number of filters and / or membranes can be used sequentially according to the present invention. For example, a first filtration can be performed using a 50,000 Da molecular weight cutoff filter, and a second filtration can be performed using a 5,000 Da molecular weight cutoff filter. Thus, depending on the molecular weight cutoff of the filter, the ultrafiltered extract may contain only compounds having molecular weights of less than approximately 50,000, less than approximately 25,000, less than approximately 10,000 Da, less than approximately 7,500 Da, less than approximately 5,000 Da, less than approximately 2,500 Da, or less than approximately 1,000 Da. The ultrafiltered extract typically contains mainly sugars, nicotine, and amino acids. Ultrafiltration can be used in combination with other separation and purification methods to provide nicotine with an acceptable level of purity.

[0040] Ultrafiltered extracts may exhibit a greater degree of clarity improvement than unultrafiltered extracts. The clarity of extracts and compositions derived therefrom according to the present invention is typically defined in terms of translucency. As used herein, “translucent” or “translucent” refers to a material that allows a certain level of light to pass through it with diffusion. In various embodiments, certain materials of the present invention (e.g., certain tobacco extracts or nicotine obtained therefrom) may have a high degree of clarity such that the material or a portion thereof can be classified as “transparent” or “translucent,” which is defined as a material through which light can pass freely without significant diffusion. The clarity of an ultrafiltered extract is such that there is a certain level of translucency, as opposed to opacity (a material through which light cannot pass). In certain embodiments, the ultrafiltered extract is analyzed visually or by shining light on the extract and measuring the percentage of light that was not absorbed and / or scattered by the extract. This measurement may be performed, for example, using a standard spectrophotometer at a given wavelength. Spectrophotometers are typically calibrated with deionized water, assigning a 100% clarity value to deionized water. Ultrafiltered extracts may, in some embodiments, exhibit translucency exceeding about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 60%, 70%, 80%, or 90%. Typically, ultrafiltered extracts are not colorless and have a somewhat recognizable brown / black color. After ultrafiltration, the extract can be stored in a refrigerator or freezer, or it can be freeze-dried or spray-dried before use in the compositions of the present invention. In certain embodiments, it is provided in syrup form. Ultrafiltered extracts in some embodiments may be further processed to provide a sufficiently high level of purity of the nicotinic compound.

[0041] The nicotinic compounds of the present invention may contain nicotine in the form of a free base, a salt, a complex, or a solvated compound. See, for example, the discussion of nicotine in the form of a free base in Hansson's U.S. Patent Application Publication No. 2004 / 0191322, incorporated herein by reference. At least a portion of the nicotinic compounds may be used in the form of a nicotine resin complex, in which nicotine is bound in an ion exchange resin such as nicotine polarilex. See, for example, Lichtneckert et al.'s U.S. Patent No. 3,901,248, incorporated herein by reference. At least a portion of the nicotine may be used in the form of a salt. Salts of nicotine may be provided using various components and techniques as shown in Cox et al.'s U.S. Patent No. 2,033,909 and Perfetti, Beitrage Tabakforschung Int., 12, 43-54 (1983). Furthermore, nicotine salts are available from sources such as Pfalz & Bauer and K&K Laboratories, a subsidiary of ICN Biochemicals. Examples of pharmaceutically acceptable nicotine salts include nicotine salts of tartaric acid (e.g., nicotine tartrate and nicotine bitartrate), nicotine salts of chlorine (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine salts of sulfuric acid, nicotine salts of perchloric acid, nicotine salts of ascorbic acid, nicotine salts of fumaric acid, nicotine salts of citric acid, nicotine salts of malic acid, nicotine salts of lactic acid, nicotine salts of aspartic acid, nicotine salts of salicylic acid, nicotine salts of tosylic acid, nicotine salts of succinic acid, nicotine salts of pyruvate, etc.; and nicotine salt hydrates (e.g., zinc nicotine chloride monohydrate), etc. In certain embodiments, at least a portion of the nicotinic compound is in the form of a salt having an organic acid moiety containing levulinic acid, as discussed in Brinkley et al., U.S. Patent Application Publication No. 2011 / 0268809, which is incorporated herein by reference.

[0042] In one embodiment, the nicotinic compound is adsorbed onto a porous granular carrier material such as microcrystalline cellulose (MCC) before being incorporated into the composition of the present invention. In one embodiment, the MCC material used in the present invention has an average particle size in the range of about 15 to about 250 microns. Examples of MCC materials include various grades of AVICEL® and VIVACEL® materials. See, for example, Hansson U.S. Patent Application Publication 2004 / 0191322, which is incorporated herein by reference. In certain embodiments, nicotinic compounds in multiple forms, including any of the various combinations of nicotinic compounds considered herein, may be adsorbed onto the granular carrier. In some embodiments, the nicotinic compound and optionally the organic acid moiety may be adsorbed onto the granular carrier by, for example, dissolving the nicotinic compound (and optionally the organic acid moiety) in a hydrophilic solvent (e.g., water, alcohol, or a mixture thereof), mixing it with a solution containing the granular carrier, and then drying it to remove the solvent. The granular carrier material, which contains adsorbed nicotine and optionally an organic acid moiety, can be mixed with other carriers or excipients to provide a composition suitable for oral delivery of the active ingredient.

[0043] The compositions of the present invention are pharmaceutically effective and have a pharmaceutically acceptable form. That is, it is most preferable that the compositions do not incorporate, or intentionally incorporate, any tobacco components other than nicotine to any perceptible degree. Therefore, pharmaceutically effective and pharmaceutically acceptable compositions do not contain tobacco, processed tobacco components, or many of the tobacco components traditionally present in tobacco-containing cigarettes, cigars, pipes, or smokeless tobacco products. Highly preferred compositions contain less than 0.5 weight percent of non-nicotine tobacco components, more often less than about 0.25 weight percent of non-nicotine tobacco components, and are usually completely absent or lacking in non-nicotine tobacco components, processed tobacco components, or components derived from tobacco.

[0044] According to the present invention, one or more nicotinic compounds of various forms described herein are used in the preparation of a pharmaceutical composition. Specifically, a nicotinic compound can be mixed with one or more additional components to produce a formulation that is used in combination with other nicotinic compound-containing formulations or non-nicotinic compound-containing formulations to provide the multilayer pharmaceutical composition of the present invention. The types of formulations included in the pharmaceutical composition according to the present invention can vary and may include, but are not limited to, lozenge-type formulations, molten-type formulations, chewable-type formulations, rigid-coated formulations, and starch-molded and injection-molded formulations. Each formulation may contain one or more nicotinic compounds, or may not contain any nicotinic compounds. However, at least one component of a multilayer pharmaceutical composition usually contains a nicotinic compound.

[0045] The components of each formulation in a multilayer pharmaceutical composition can vary, and two or more formulations are independently selected so as to contain generally different combinations of other components. Individual components (including, optionally, one or more nicotinic compounds) can be processed, mixed, formulated, blended, and / or combined to produce a desired formulation.

[0046] Other components of the formulation may be artificial, or may be obtained from or derived from plant or biological sources. Examples of various components that may be incorporated into one or more formulations according to the present invention include salts (e.g., sodium chloride, potassium chloride, sodium citrate, potassium citrate, sodium acetate, potassium acetate, etc.), natural sweeteners (e.g., fructose, sucrose, glucose, maltose, vanillin, ethyl vanillin glucoside, mannose, galactose, lactose, etc.), artificial sweeteners (e.g., sucralose, saccharin, aspartame, asselfam K, neotame, etc.), organic and inorganic fillers (e.g., cereals, processed cereals, puffed cereals, maltodextrin, glucose, calcium carbonate, calcium phosphate, polycarbophil calcium, corn starch, lactose, isomalt, sugar alcohols such as mannitol, xylitol, or sorbitol, subdivided cellulose, hydroxypropyl cellulose, plant proteins, silicon dioxide, etc.), film-forming agents and binders (e.g., povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and other modified cellulose-type binders). Combination agent, sodium alginate, acacia gum, xanthan gum, starch-based binder (e.g., potato starch, corn starch, etc.), gum arabic, gellan gum, lecithin, etc.), gelling agent (e.g., fish gelatin), pH adjuster or buffer (e.g., metal hydroxide, preferably alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and metal carbonate, preferably potassium carbonate or sodium carbonate, or other alkali metal buffers such as metal bicarbonates such as sodium bicarbonate), emulsifier Colorants (e.g., dyes and pigments including caramel color, titanium dioxide, D&C Yellow No. 10, etc.), humectants (e.g., glycerin, propylene glycol, etc.), oral care additives (e.g., thyme oil, eucalyptus oil, and zinc), preservatives and antioxidants (e.g., potassium sorbate, sodium benzoate, ascorbyl palmitate, etc.), syrups (e.g., honey, high-fructose corn syrup, etc.), thickeners, disintegration aids or compressibility aids (e.g., microcrystalline cellulose, croscarmellose sodium,These include crospovidone, sodium starch glycolate, pregelatinized corn starch, etc.), lubricants or processing aids (e.g., magnesium stearate or calcium stearate), anti-tacks (e.g., talc), flow promoters (e.g., colloidal silica), surfactants (e.g., polysorbate 80), flavorings and flavoring mixtures, and mixtures thereof. Examples of various components may include, for example, those described in Gao et al., U.S. Patent Application Publication No. 2010 / 0291245, which is incorporated herein by reference.

[0047] The pharmaceutical compositions of the present invention may conveniently be available in the form of unit dosage forms, thereby allowing such formulations to be prepared by any of the methods commonly known in the field of pharmacy. Generally speaking, such preparation methods involve (by various means) combining an active agent with a suitable carrier or other adjuvant, which may consist of one or more components. The formulation of the active ingredient with one or more adjuvants is then physically processed to provide a formulation in a form suitable for delivery (e.g., by forming it into a tablet or by preparing an aqueous suspension).

[0048] The nicotine-containing pharmaceutical compositions of the present invention can incorporate a variety of pharmaceutically acceptable excipients. The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refer to carriers or excipients conventionally used in the art to facilitate storage, administration, and / or the therapeutic effect of an active agent (e.g., a nicotinic compound). The carrier must be pharmaceutically acceptable in that it has affinity with the other components of the formulation and is not excessively harmful to its recipient. The carrier can also reduce any undesirable side effects of the drug. See Wang et al. (1980) J. Parent. Drug Assn. 34(6):452-462, which is incorporated herein by reference in its entirety. Other examples of pharmaceutical excipients and / or additives suitable for use in compositions according to the present invention are described by reference in Remington: The Science & Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2006), Physician's Desk Reference, 64th edition, Thomson PDR (2010), and Handbook of Pharmaceutical Excipients, 6th edition, edited by Raymond C. Rowe et al., Pharmaceutical Press (2009).

[0049] Various excipients may change, and the selection and amount of each excipient may depend on factors such as the final shape and function of the desired product. For example, see U.S. Patent No. 5,512,306 by Carlsson et al.; No. 5,525,351 by Dam; No. 5,549,906 by Santus; No. 5,711,961 by Reiner et al.; No. 5,811,126 by Krishnamurthy; No. 5,939,100 by Albrechtsen et al.; No. 6,024,981 by Khankari et al.; No. 6,083,531 by Humbert-Droz et al.; Gow Specification No. 6,090,401 by an, Jr. et al.; Specification No. 6,110,495 by Dam; Specification No. 6,248,760 by Wilhelmsen; Specification No. 6,280,761 by Santus; Specification No. 6,426,090 by Ream et al.; Specification No. 6,569,463 by Patel et al.; Specification No. 6,583,160 by Smith et al.; Specification No. 6,585,997 by Moro et al.; Specification No. 6,676,959 by Andersson et al.; Specification No. 6,893,654 by Pinney et al.; Leung et al., Patent No. 7,025,983; Johnson et al., Patent No. 7,163,705; Andersson et al., Patent Publication No. 2003 / 0176467; Martino et al., Patent No. 2003 / 0235617; Vaya et al., Patent No. 2004 / 0096501; Liu et al., Patent No. 2004 / 0101543; Hansson, Patent No. 2004 / 0191322; Ek et al., Patent No. 2005 / 0053665; Chan et al., Patent No. 2005 / 012350 See the various components, relative amounts and combinations of components, nicotine-containing formulations and preparation methods shown in Specification No. 2; Andersen et al.'s Specification No. 2008 / 0038209; Andersson et al.'s Specification No. 2008 / 0286341; Axelsson's Specification No. 2009 / 0023819; Andersen's Specification No. 2009 / 0092573; Axelsson et al.'s Specification No. 2010 / 0004294; and Axelsson et al.'s Specification No. 2010 / 0061940 for details on nicotine-containing products.

[0050] The aforementioned components may be provided in powder or granular form for mixing with one or more nicotinic compounds, or in other cases in liquid form. When provided in powder or granular form, the components are most preferably used in the form of parts or components having an average particle size of less than about 50 microns. According to some embodiments, the average particle size of the components may be about 25 microns or less. The moisture content of the components provided in powder or granular form may vary. Most preferably, the moisture content of the components provided in powder or granular form is less than about 10 weight percent, may be less than about 5 percent, and in many cases less than about 2.5 weight percent. These components may be mixed with nicotine, for example, in a Hobart mixer with paddles, before the addition of any liquid components. In instances where liquid components are provided, the resulting mixture may still have a relatively low moisture content of less than about 10 weight percent, may be less than about 5 percent, and in many cases less than about 2.5 weight percent. The relative amounts of various added components in the pharmaceutical composition may vary.

[0051] The various components described above may be used together (e.g., as a component formulation) or separately (e.g., individual components may be added at various stages involved in the preparation of nicotinic compound-containing formulations and final pharmaceutical products). The relative amounts of the various components in a nicotinic compound-containing formulation may vary and are usually selected to impart desired sensory and performance characteristics to the pharmaceutical composition. Furthermore, the various components described above may be encapsulated when provided in the final product or final composition. Examples of encapsulated components are described, for example, in Atchley's International Publication No. 2010 / 132444(A2), which is incorporated herein by reference.

[0052] As used herein, “flavoring” or “flavoring agent” refers to any flavoring or aromatic substance that can alter the sensory characteristics associated with a pharmaceutical composition. Examples of sensory characteristics that can be altered by flavorings include taste, texture, moisture, coolness / heat, and / or aroma / smell. Flavorings may be natural or synthetic, and these flavor characteristics may be described as, but are not limited to, refreshing, sweet, herbal, confectionery, floral, fruity, or spicy. Certain various flavors include, but are not limited to, vanilla, coffee, chocolate, cream, mint, spearmint, menthol, peppermint, wintergreen, lavender, cardamom, nutmeg, cinnamon, clove, cascarilla, sandalwood, honey, jasmine, ginger, anise, sage, licorice, lemon, orange, apple, peach, lime, cherry, and strawberry. Flavorings utilized in this invention may also include components considered to be humectants, cooling agents, or lubricants, such as eucalyptus. These flavors may be served raw (i.e., individually) or in combination (e.g., spearmint and menthol, or orange and cinnamon). In some cases, flavorings may be served in spray-dried form. Flavorings are typically present in amounts of about 0.5 to about 10 percent dry weight, often in amounts of about 1 to about 6 percent dry weight, and most often in amounts of about 2 to about 5 percent dry weight.

[0053] Sweeteners may be natural or artificial, or used as a combination of artificial and natural sweeteners. In one embodiment, sucralose, sucrose, or a combination thereof is the primary sweetener component. When present, whether artificial or natural, a typical amount of sweetener may be at least about 0.2 percent, at least about 1 percent, or at least about 5 percent of the total dry weight of the composition. Preferably, the amount of sweetener in the composition does not exceed about 40 percent of the total dry weight of the composition, often not exceeding about 35 percent, and frequently not exceeding about 30 percent.

[0054] Sucrose is thought to contribute to the chewability or "resilience" of the final product, and therefore may be a particularly favorable sweetener in certain embodiments (e.g., as a component of starch-based formulations). In addition, although granulated sucrose provides a considerably lower sweetness effect compared to sucralose, the presence of sucrose may be favorable as an additional filler component. When these two sweeteners are present together, sucralose is usually present in an amount of at least about 0.25% dry weight, often at least about 0.5% dry weight, and most often at least about 1.0% dry weight (e.g., about 0.25 to about 2.0% dry weight), and sucrose is usually present in an amount of at least about 2.0% dry weight, often at least about 3.0% dry weight, and most often at least about 4.0% dry weight (e.g., about 1.0 to about 6.0% dry weight).

[0055] In certain embodiments, some formulations (or entire pharmaceutical compositions) are sugar-free and contain one or more sugar substitutes. “Sugar-free,” as used herein, means a product containing less than about 1 / 15th by weight of sugar, or less than about 1 / 10th by weight of sugar. Sugar substitutes, when used, may be provided in their pure form in a solid form (e.g., granular or powder form). In certain embodiments, sugar substitutes are dry and contain a very low moisture content. For example, a sugar substitute may contain less than about 5% by weight of water, less than about 3% by weight of water, less than about 2% by weight of water, or less than about 1% by weight of water.

[0056] In some embodiments, a syrup (e.g., corn syrup) may be used in an amount sufficient to impart the desired flavor characteristics to the pharmaceutical composition, preferably. In some embodiments (e.g., in starch-based formulations), a syrup may be used in an amount sufficient to provide chewiness and to slow solubilization. A typical amount of syrup (e.g., high-fructose corn syrup) may be less than about 10 percent or less than about 5 percent of the total dry weight of the composition.

[0057] In certain embodiments, sugar syrup or sugar alcohol syrup is added to a lozenge-type formulation to influence the recrystallization of another component of the formulation (e.g., a molten sugar substitute) during preparation. Examples of sugar alcohol syrups for such purposes include maltitol syrup, xylitol syrup, mannitol syrup, glycerol syrup, erythritol syrup, treitol syrup, arabitol syrup, ribitol syrup, mannitol syrup, sorbitol syrup, dulcitol syrup, iditol syrup, isomalt syrup, lactitol syrup, and polyglycitol syrup. Other syrups, such as corn syrup, golden syrup, or molasses, can be used. The amount of sugar alcohol syrup can vary, but is usually in the range of about 0.1% to about 2% by weight of the pharmaceutical composition mixture, often in the range of about 0.5% to about 1.5% by weight, and in more cases, it can be about 1% by weight. In certain embodiments, the amount of sugar alcohol syrup is greater, for example, up to about 2% by weight of the mixture, up to about 5% by weight of the mixture, up to about 10% by weight of the mixture, or up to about 20% by weight of the mixture.

[0058] The pharmaceutical compositions of this disclosure may typically contain at least one filler component. When a polysaccharide filler component is present, any additional filler components may be provided. Such filler components in a composition often achieve multiple functions, such as improving certain sensory properties like chewiness and texture, or enhancing the binding or compressibility of the product. In certain embodiments (e.g., in starch-molded formulations), sugar alcohols are particularly favored as filler components because they provide some sweetness and do not impair the desired chewable properties of the final product. Sugar alcohols (e.g., isomalt) are polyols derived from monosaccharides or disaccharides in partially or fully hydrogenated forms. Examples of sugar alcohols have between about 4 and about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates). Sugar alcohols may be added in the form of aqueous solutions or suspensions, such as solutions or suspensions having a solids content of about 50 to about 90 weight percent. Mixtures of sugar alcohols with other filler components may also be used. When present, whether organic or inorganic fillers, a typical amount of filler may be at least about 10 percent, at least about 20 percent, or at least about 25 percent based on the total dry weight of the composition. Preferably, the amount of additional filler in the composition does not exceed about 50 percent of the total dry weight of the composition, and often does not exceed about 40 percent. In one embodiment, a sugar alcohol such as sorbitol is provided as an additional filler.

[0059] Salts (e.g., sodium chloride, flour salts) may be used in amounts sufficient to impart the desired sensory properties to the pharmaceutical composition. When present, a typical amount of salt is at least about 0.5 dry weight percent or at least about 1.0 dry weight percent or at least about 1.5 dry weight percent of the total dry weight of the composition, but is usually less than about 5 percent of the total dry weight of the composition (e.g., about 0.5 to about 4 dry weight percent). In some embodiments, when present, the salt is less than about 2 percent or less than 1 percent of the total dry weight of the composition.

[0060] A humectant (e.g., glycerin) may be used in an amount sufficient to impart the desired moisture properties to the pharmaceutical composition. Furthermore, in some examples, the humectant can impart desirable flow properties to the pharmaceutical composition (e.g., for placement in a starch mold). When present, a typical amount of humectant is usually at least about 1 percent, at least about 1.5 percent by dry weight, or at least about 2 percent by dry weight of the total dry weight of the composition. In certain embodiments, the amount of humectant is at least about 10 percent by dry weight or at least about 20 percent by dry weight. An example range of dry weight is about 1 to about 40 percent by dry weight, and in more cases, about 3 to about 35 percent by dry weight. In some embodiments, the humectant may be provided in an amount less than about 5 percent of the total dry weight of the composition (e.g., about 0.5 to about 4 percent by dry weight).

[0061] A binder (or combination of binders) may be used in an amount sufficient to impart the desired physical properties and material integrity to the pharmaceutical composition. When present, a typical amount of binder may be at least about 5 percent, at least about 10 percent, at least about 15 percent, at least about 20 percent, or at least about 25 percent of the total dry weight of the composition. Preferably, the amount of binder in the composition does not exceed about 35 percent, about 40 percent, or about 45 percent of the total dry weight of the composition. Often, the desired amount of binder in the composition does not exceed about 20 percent of the total dry weight of the composition, and frequently does not exceed about 15 percent of the total dry weight of the composition. In certain embodiments, the binder substance includes natural gum. As used herein, natural gum refers to a naturally occurring polysaccharide substance that is useful as a thickener or gelling agent. Typical natural gums derived from plants are usually water-soluble to some extent and include xanthan gum, guar gum, gum arabic, ghati gum, tragacanth gum, karaya gum, locust bean gum, gellan gum, and combinations thereof.

[0062] Emulsifiers can be used in amounts sufficient to impart the desired stabilizing properties to the pharmaceutical composition. When present, the typical amount of emulsifier is usually less than about 5 percent of the total dry weight of the composition.

[0063] Certain buffers exhibit buffering activity within a pH range of approximately 6 to approximately 10, and examples of buffers include metal hydroxides, metal carbonates, metal bicarbonates, or mixtures thereof. When present, buffers are typically present in amounts less than approximately 1 percent of the dry weight of the formulation. Various food buffers are known and can be used to adjust the pH of the product of the present invention. Suitable buffers include those selected from the group consisting of acetates, glycinates, phosphates, glycerophosphates, citrates such as alkali metal citrates, carbonates, bicarbonates, and borates, and mixtures thereof. In certain embodiments, the buffer is, for example, an amino acid taught in Andersson et al., U.S. Patent Application Publication No. 2008 / 0286341 and PCT Application No. 2008 / 040371, both of which are incorporated herein by reference. As described therein, various amino acids and their salts are useful for this purpose, and include, but are not limited to, arginine, asparagine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, valine, cysteic acid, N-glycylglycine, and ornithine. In certain embodiments, N-glycylglycine or L-lysine is added as a buffer. In some embodiments, one amino acid buffer is used in combination with another amino acid buffer, and / or with one or more non-amino acid buffers. In certain embodiments, any pH adjuster is a base (e.g., NaOH). In certain embodiments, L-lysine and NaOH are added to the composition of the present invention.

[0064] Nicotine is well known to be prone to oxidation, and therefore, it may be advantageous to incorporate one or more antioxidants, such as ascorbyl palmitate and / or sodium ascorbate, into the composition according to the present invention. These one or more antioxidants may be present in the pharmaceutical composition mixture at concentrations ranging from about 0.05% to about 0.3% by weight, for example, from about 0.1% to about 0.25%, or from about 0.15% to about 0.2%.

[0065] The formulations of the present invention may include short-acting formulations, rapid-acting formulations, controlled-release formulations, sustained-release formulations, delayed-release formulations, and pulsed-release formulations, provided that such formulations achieve the administration of nicotinic compounds as described herein. See Remington's Pharmaceutical Sciences (18th edition; Mack Publishing Company, Eaton, Pennsylvania, 1990), which is incorporated herein by reference in its entirety.

[0066] The composition of the present invention incorporates a pharmaceutically effective amount of nicotine. The dose of the active ingredient (i.e., all forms of nicotine) is preferably an amount effective in treating some symptoms of a medical condition, disease, or disorder afflicting the subject or patient, or effective in preventing the onset of those symptoms. “Effective dose,” “therapeutic dose,” or “effective dosage” means an amount sufficient to induce the desired pharmacological or therapeutic effect, thereby resulting in effective prevention or treatment of a medical condition, disease, or disorder. Therefore, the effective dose of the active ingredient is sufficient to enter the appropriate area of ​​the body (e.g., to cross the blood-brain barrier of the subject), sufficient to bind to the appropriate receptor sites in the CNS and PNS of the subject, and / or sufficient to induce a neuropharmacological effect (e.g., to induce the secretion of neurotransmitters, thereby resulting in effective prevention or treatment of a medical condition, disease, or disorder). Prevention of disorder manifests, for example, by delaying the onset of symptoms of a medical condition, disease, or disorder. Treatment of a disorder is manifested, for example, by a reduction in the symptoms of the illness, disease, or disorder, or by an improvement in the recurrence of those symptoms.

[0067] The amount of active ingredient in the overall composition can vary. For compositions intended for oral consumption by being placed in the mouth (e.g., lozenges), the amount of nicotine in each dose piece or dose unit is usually at least about 0.5 mg, generally at least 1 mg, often at least about 1.5 mg, and frequently at least about 2 mg, calculated on a nicotine basis, but the amount of nicotine in each piece usually does not exceed about 10 mg, generally not exceeding about 8 mg, often not exceeding about 6 mg, and frequently not exceeding about 5 mg, calculated on a nicotine basis. Various example products of this type can incorporate about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, and about 4.5 mg of nicotine per piece or unit, calculated on a nicotine basis. The amount of nicotine incorporated into any given formulation layer in a multilayer composition can vary and is usually selected so that the total nicotine content in each product unit falls within the ranges described above.

[0068] The specific components and their amounts in a given formulation depend on the desired characteristics of that formulation. For example, the components may vary depending on the desired flavor, texture, and other characteristics. Some specific example formulations are provided in more detail below. It should be noted that these are merely example formulations and are not intended to limit the invention.

[0069] For example, a typical lozenge formulation may comprise a nicotinic compound, a sugar substitute, and a sugar alcohol syrup. The sugar substitute (e.g., isomalt) is a non-hygroscopic sugar alcohol capable of forming a glassy substrate. In one particular embodiment of the present invention, the lozenge formulation comprises a nicotinic compound, a sugar substitute in an amount of at least about 80% by weight, and a sugar alcohol syrup. In a particular embodiment, the sugar substitute is present in an amount of at least about 85% by weight or at least about 90% by weight. In a particular embodiment, the lozenge formulation may comprise isomalt, maltitol syrup, a nicotinic compound, NaCl, and sucralose. In a particular embodiment, the formulation is translucent. For further details regarding a typical lozenge formulation, see U.S. Patent Application Publication No. 13 / 240,525, filed September 22, 2011, filed by Holton, Jr. et al., incorporated herein by reference.

[0070] Typical melt-type formulations generally contain nicotinic compounds and lipids. These lipids can be varied and may be, for example, fats, oils, or waxy substances (or combinations thereof), forming part of the formulation. The lipid components can be derived from animal or plant-based sources and typically consist mainly of triglycerides, along with smaller amounts of free fatty acids and monoglycerides or diglycerides. In certain embodiments, the lipids are plant-derived fatty substances that are solid or semi-solid at room temperature (i.e., about 25°C) and at least partially liquefy when exposed to the user's oral temperature. The melting point of these lipids can vary and, in certain embodiments, may be in the range of about 36°C to about 45°C (e.g., about 38°C to about 41°C).

[0071] Plant-derived fats are primarily composed of saturated or unsaturated fatty acid chains (most of which are linked within a triglyceride structure) with carbon lengths of approximately 10 to 26 carbon atoms, more typically 14 to 20 carbon atoms, and most often 14 to 18 carbon atoms. Examples of plant-derived fats that can be used include palm oil, palm kernel oil, soybean oil, cottonseed oil, and mixtures thereof. In some embodiments, the lipid substance may be hydrogenated, partially hydrogenated, or unhydrogenated. In some examples, the lipid substance may include a mixture of lipid components. For example, the lipid substance may include a mixture of palm oil and palm kernel oil.

[0072] In certain specific embodiments, a molten formulation is provided comprising a nicotinic compound, about 10 to about 50 percent of lipid components based on the total dry weight of the formulation, about 0 to about 1 percent of artificial sweeteners, about 20 to about 40 percent of fillers, up to about 10 percent of flavorings, and up to about 5 percent of salts. Further details regarding specific lipids and molten formulations containing lipids can be found in U.S. Patent Application Publication No. 13 / 330,929, filed December 20, 2011, which is incorporated herein by reference.

[0073] A typical chewable formulation usually contains a nicotinic compound, a natural gum (e.g., gum arabic), a lipid component, and an emulsifier. In one particular embodiment, the chewable formulation contains gum arabic, an emulsifier, a lipid component, glycerin, a nicotinic compound, sucralose, sodium chloride, sodium hydroxide, and a flavoring agent.

[0074] A typical rigid coating formulation usually contains a nicotinic compound, a binder, and a sugar alcohol syrup. In one particular embodiment, the rigid coating formulation contains a nicotinic compound, a binder, a sugar alcohol, isomalt, sodium hydroxide, sucralose, and a flavoring agent. While the rigid coating formulation according to the present invention usually contains such components, it should be noted that in certain embodiments, various other coatings may be applied, and in some embodiments, various other coatings may be applied in addition to the rigid coating formulation. For example, in certain embodiments, the entire multilayer pharmaceutical composition of the present invention and / or any of the component formulations described herein may include an outer coating, the outer coating may include components such as carnauba wax and / or shellac in a pharmaceutically acceptable form, which are a gloss composition and surface glossing agent. The application of the coating can be achieved using techniques such as airless spray coating, fluidized bed coating, and the use of a coating pan. Other materials used as coatings may include cellulose materials (e.g., cellulose butyrate phthalate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethylcellulose), and polymerizable materials such as polymers and copolymers of acrylic acid, methacrylic acid, and their esters. For example, such coatings may include film-forming polymers such as cellulosic polymers and any plasticizers. Other optional coating components may include flavorings, sweeteners, colorants, and salts.

[0075] A typical injection-molded formulation (i.e., pastel) may contain, for example, a nicotinic compound and about 10% to about 25% by weight of a polysaccharide filler component on a dry weight basis. The polysaccharide filler can vary, but in certain embodiments it contains polydextrose. Certain embodiments contain one or more components including sugar alcohol fillers (e.g., sorbitol), binders including water-soluble gums (e.g., gum arabic), and / or flavorings, binders, emulsifiers, disintegrants, humectants, and mixtures thereof. In one particular embodiment, the formulation contains a nicotinic compound, at least about 10% by dry weight of a polysaccharide filler component, at least about 10% by dry weight of at least one type of binder, at least about 20% by dry weight of at least one type of humectant, and at least about 1% by dry weight of at least one type of emulsifier. For further details regarding typical injection-molded formulations, see U.S. Patent Application Publication No. 12 / 957,838, filed December 1, 2010, by Cantrell et al., incorporated herein by reference.

[0076] A typical starch-based formulation (i.e., a pastel) may contain, for example, a nicotinic compound, at least one binder or gelling agent in the form of a natural gum, and at least one sugar alcohol as a filler component. In another embodiment, the starch-based formulation contains a nicotinic compound, at least one binder or gelling agent in the form of a natural gum, sucrose, and corn syrup. For example, in one embodiment, the starch-based formulation contains, based on the total dry weight of the pharmaceutical composition, at least about 10 percent of sugar alcohol fillers, at least about 10 percent of binders, about 0.1 to about 2 percent of artificial sweeteners, about 1 to about 5 percent of humectants, about 1 to about 5 percent of natural sweeteners, up to about 5 percent of flavorings, and up to about 3 percent of salts.

[0077] One particular starch-molded formulation comprises at least about 10 dry weight percent of sugar alcohol (e.g., sorbitol, isomalt, maltitol, and / or a combination thereof), at least about 10 or 15 dry weight percent of natural gum binder component (e.g., gum arabic), at least about 0.5 dry weight percent of humectant (e.g., glycerin), at least about 0.2 dry weight percent of sweetener (e.g., sucralose), and at least about 0.5 dry weight percent of flavoring. Another example composition comprises at least about 20 dry weight percent of sugar alcohol, at least about 25 dry weight percent of natural gum binder component, at least about 2 dry weight percent of humectant, at least about 1 dry weight percent of sweetener, and at least about 4 dry weight percent of flavoring. In a further embodiment, the composition comprises at least about 30 dry weight percent of sugar alcohol, at least about 40 dry weight percent of natural gum binder component, at least about 2 dry weight percent of humectant, and at least about 2 dry weight percent of salt (e.g., NaCl). Another embodiment comprises at least about 30 dry weight percent sucrose, at least about 40 dry weight percent natural gum binder component, at least about 2 dry weight percent syrup (e.g., corn syrup), at least about 2 dry weight percent humectant, and at least about 2 dry weight percent salt. For further details regarding typical starch-molding formulations, see U.S. Patent Application No. 12 / 957,821 of Cantrell et al., filed December 1, 2010, which is incorporated herein by reference.

[0078] The formulations constituting the pharmaceutical compositions of the present invention may have a variety of functional properties. For example, starch-molded formulations can, in certain embodiments, be characterized as soluble and lightly chewable, and generally in the form of a hardened solid gel (e.g., “pastel”). In certain embodiments, starch-molded formulations are characterized by sufficient binding to resist light chewing in the oral cavity without rapidly disintegrating. Such formulations of the present disclosure do not typically exhibit the highly deformable chewability found in conventional chewing gum. Meltable formulations can, in certain embodiments, be described as providing a smooth, creamy sensation (rather than a slippery, waxy, or slimy sensation) when in the user's mouth. Lozenge-type formulations are generally hard and soluble. Chewable formulations generally exhibit a chewiness between pastels and gum as described herein. Chewable formulations, like pastels, typically exhibit binding properties that resist light chewing in the mouth, but usually disintegrate more slowly than pastels, allowing for more chewing before the composition completely disintegrates. Hard-coated formulations generally provide some degree of crunchiness or crispness.

[0079] The structure and properties of formulations within a given multilayer pharmaceutical composition can vary. In certain embodiments, two-component and three-component pharmaceutical compositions are provided, as shown in Table 1, where the core may refer to the innermost component of a coated formulation, and the first and second layers are layers applied continuously to the core formulation. Alternatively, the core may refer to one component of a side-by-side configuration, where the first layer is applied so as to adhere to the core formulation on at least one side, and the second layer, if present, adheres to the first layer formulation on at least one side.

[0080] Table 1 lists various combinations of formulations that may include multilayer pharmaceutical compositions. Depending on the specific composition of each formulation, Table 1 represents example products of the present invention having various combinations of formulations. Preferably, each formulation provided in Table 1 is a formulation having a specific composition as described herein.

[0081] [Table 1-1]

[0082] [Table 1-2]

[0083] [Table 1-3]

[0084] [Table 1-4]

[0085] [Table 1-5]

[0086] [Table 1-6]

[0087] [Table 1-7]

[0088] The pharmaceutical composition according to the present invention has the advantage of being able to exhibit a variety of mixed sensory properties. In certain embodiments, such a pharmaceutical composition is multilayered, so that it can provide the user with a variety of sensory stimuli during use of the product. For example, the pharmaceutical composition can be adjusted to exhibit a certain range of sensory properties in a desired sequence of experiences (e.g., an initial hard and dissolving sensation followed by a chewy sensation).

[0089] Due to the multilayer structure of the pharmaceutical composition of the present invention, in certain embodiments, the flavor and / or nicotine release profile of the product as a whole can be tuned. In other words, the manner and / or rate at which nicotine is released can vary. Certain types of formulations typically exhibit a faster or slower nicotine release. Such formulations are conveniently located within the multilayer structure of the pharmaceutical composition so that the product exhibits a desired release profile. For example, in one particular embodiment, the outer formulation includes a formulation that exhibits a relatively fast nicotine release, while one or more inner formulations exhibit a more sustained nicotine release profile, providing a product that results in both an initial rapid release and a sustained release of nicotine. In certain embodiments, various flavorings and / or other components (e.g., sensory substances) can be incorporated into certain layers. By altering the flavor and / or sensory stimuli of different layers, a unique range of taste and / or sensory experiences can be provided to the user during use of the product.

[0090] The composition of the present invention incorporates a pharmaceutically effective amount of nicotine. The dose of the active ingredient (i.e., all forms of nicotine) is preferably an amount effective in treating some symptoms of a medical condition, disease, or disorder afflicting the subject or patient, or effective in preventing the onset of those symptoms. “Effective dose,” “therapeutic dose,” or “effective dosage” means an amount sufficient to induce the desired pharmacological or therapeutic effect, thereby resulting in effective prevention or treatment of a medical condition, disease, or disorder. Therefore, the effective dose of the active ingredient is sufficient to enter the appropriate area of ​​the body (e.g., to cross the blood-brain barrier of the subject), sufficient to bind to the appropriate receptor sites in the CNS and PNS of the subject, and / or sufficient to induce a neuropharmacological effect (e.g., to induce the secretion of neurotransmitters, thereby resulting in effective prevention or treatment of a medical condition, disease, or disorder). Prevention of disorder manifests, for example, by delaying the onset of symptoms of a medical condition, disease, or disorder. Treatment of a disorder is manifested, for example, by a reduction in the symptoms of the illness, disease, or disorder, or by an improvement in the recurrence of those symptoms.

[0091] For the compositions of the present invention, the intended daily dose of the active ingredient may vary. The total dose of the active ingredient may depend on factors such as the body weight of the subject ingesting the composition, the medical condition being treated, the state or severity of the disease or disorder being treated, the desired pharmacological effect, or other such factors. The amount of nicotine active ingredient administered to a subject per day, calculated on a nicotine basis, is usually at least about 2 mg, often at least about 4 mg, and frequently at least about 10 mg. The amount of nicotine active ingredient administered to a subject per day is usually not more than about 60 mg, often not more than about 50 mg, and frequently not more than about 40 mg. See also, for example, the various types of dosing plans and techniques described in Baker et al.'s U.S. Patent No. 5,593,684; Kyle et al.'s Patent No. 6,660,754; and Sachs' U.S. Patent Application Publication No. 2004 / 0006113; Pinney et al.'s Patent No. 2005 / 0214229; Andersen's Patent No. 2008 / 0124283; and Axelsson et al.'s Patent No. 2009 / 0293895, which are incorporated herein by reference.

[0092] Typical compositions incorporating nicotine as an active ingredient can have a variety of forms and compositions, and as a result, their characteristics, properties, behavior, hardness, shape, form, size, and weight can vary. Typical compositions can generally be spherical, cylindrical (for example, ranging from the common shape of a flat disc to the common shape of a relatively long, slender rod), spiral, elliptical, square, rectangular, etc. Alternatively, the composition may take the form of beads, granules, crystalline powder, capsules, films, strips, gels, etc. The form of the composition may resemble the wide variety of pills, tablets, lozenges, capsules, capsule tablets, pouches, and gum-type products that have traditionally been used for administering pharmaceutical-type products. Typical compositions can be soft to the touch, hard, or of intermediate softness or hardness, and therefore, the composition can be described as malleable, flexible, chewy, elastic, brittle, etc. When administered orally, the various components of a product may disperse readily or slowly, or they may dissolve at varying rates (e.g., relatively fast to relatively slow). As a result, for compositions ingested orally by human subjects, the rate of release of the active ingredient during use of the product can vary from relatively fast to relatively slow, depending on factors such as the product design and how the product is used by the target audience.The following are incorporated herein by reference: Ray et al. U.S. Patent No. 4,655,231; Place et al. No. 5,147,654; Carlsson et al. No. 5,543,424; Thompson No. 6,268,386; Yates No. 6,319,510; Halliday et al. No. 6,488,953; Zerbe et al. No. 6,709,671; Leung et al. No. 7,025,983; Rolling No. 7,105,173; Stillman No. 7,115,297; Knight No. 7,435,749. See also, for example, the various products proposed in the following publications: Leung et al. No. 7,491,406; Chan et al. No. 2006 / 0198873; Houze et al. No. 2006 / 0240087; Bess et al. No. 2006 / 0204559; Steen et al. No. 2007 / 0269492; Chau et al. No. 2008 / 0020050; Andersson et al. No. 2008 / 0286340; Sanghvi et al. No. 2008 / 0292683; and Bunick et al. No. 2009 / 0004248.

[0093] There can be a variety of methods for preparing multilayer nicotinic compound-containing pharmaceutical compositions. Generally, core formulations can be provided by any method for providing such formulations. While exemplary methods for providing a particular type of formulation are provided herein, it should be noted that other methods can be used without departing from the present invention. Typically, a core formulation is prepared and one or more additional layers are applied thereto. The core can be formed into a desired shape (e.g., by roll molding or press molding) by, for example, pouring the formulation mixture directly into a mold, or by extrusion molding. In some embodiments, the mixture can be extruded, starched, or injection molded.

[0094] In certain embodiments, the method for forming one or more additional layers may require some adjustment to facilitate the application of the formulation to the core or previous layers of the pharmaceutical composition. For example, the second and subsequent layers of the pharmaceutical composition are often applied by coating means (e.g., by dip coating, spray coating, or by preparing separate sheets of the formulation that can be used to wrap the core formulation or to adhere to one or more surfaces of the core formulation, as in a side-by-side configuration).

[0095] Typical conditions related to the manufacture of food products, such as those described herein, include control of heat and temperature (i.e., the temperature of the heat to which the various components are exposed during manufacture, and the temperature of the manufacturing environment), moisture content (e.g., the amount of moisture present in individual components and in the final composition), humidity in the manufacturing environment, control of the atmosphere (e.g., nitrogen atmosphere), airflow experienced by the various components during the manufacturing process, and various other similar factors. Furthermore, the various processing steps involved in the manufacture of the product may involve the selection of specific solvents and processing aids, the use of heat and radiation, cooling conditions and cryogenic storage conditions, component mixing rates, etc. Manufacturing conditions can also be controlled by the selection of the form of the various components (e.g., solid, liquid, or gas), particle size or crystallinity of components in solid form, concentration of components in liquid form, etc. Components can be processed into the desired composition by techniques such as extrusion, compression, spraying, etc.

[0096] In certain embodiments, molten formulations may be prepared by mixing components (e.g., a nicotinic compound and one or more additional components) with molten lipids to form a molten pharmaceutical formulation slurry, which can then be placed in a mold or used to coat another formulation.

[0097] In certain embodiments, lozenge-type formulations can be prepared by heating a mixture of components containing a high percentage of isomalt to about 143°C. Once all components have dissolved, the temperature is raised beyond the hard cracking stage (e.g., to about 166°C), and then the mixture is removed from the heat and allowed to cool. Various components can be added at certain stages (e.g., they may be added to the isomalt mixture at room temperature, when the mixture reaches 143°C or 166°C, or at a given temperature during the cooling process).

[0098] In certain embodiments, injection-molded formulations may be prepared by mixing components (e.g., nicotinic compounds, binders, and polysaccharide filler components) to form a pharmaceutical formulation mixture, injection molding the pharmaceutical formulation mixture (e.g., by compressing the mixture using a compressive force of at least about 75,000 kPa or at least about 100,000 kPa), and then cooling the pharmaceutical formulation mixture (e.g., to a temperature of about 20°C to about 25°C) to form a solidified pharmaceutical formulation.

[0099] There can be various methods for preparing a formulation, and a particular method for producing a particular type of formulation may need to be adapted depending on the composition of a given pharmaceutical composition. For example, if a formulation includes an outer layer formed by traditional techniques, the method may need to be modified so that the formulation can be coated with another formulation. For example, such a formulation may be wet-sprayed or dry-sprayed onto another surface, or it may be coated onto another surface by dipping it in the formulation. The coating method may need to be modified from traditional spray coating techniques depending on the properties of the formulation. For example, to spray-coat a lozenge-type formulation onto another formulation, it may be necessary to raise and maintain the temperature of the formulation and the spray coating equipment during the process. In certain embodiments, temperature control is important to avoid changes in the properties of the other formulation. For example, care must be taken to avoid melting of a molten formulation in the core of the pharmaceutical composition during the application of an additional layer.

[0100] In certain embodiments, at least a portion of the pharmaceutical composition is transparent or translucent as defined herein. Transparency / translucency can be determined by any technique commonly used in the art. However, it is generally measured by spectrophotometric light transmittance over a certain range of wavelengths (e.g., up to about 400–700 nm). The transmittance measurement of certain pharmaceutical compositions of the present invention may be higher than that of conventional nicotine-containing pharmaceutical compositions. Translucency may also be confirmed by visual inspection, which involves simply holding the pharmaceutical composition towards a light source and determining whether light passes through the product while diffusing.

[0101] Aspects of the present invention are more adequately illustrated by the following embodiments, which are provided to illustrate certain particular aspects of the invention and should not be construed as limiting the invention. [Examples]

[0102] Example 1: Preparation of lozenge-type formulation A nicotinic compound-containing formulation suitable for use as a lozenge component in a pharmaceutical composition for oral use is provided by the following method: Mix isomalt, NaCl, and vanillin in a pot and bring the temperature of the mixture to 143°C. Maintain the mixture at 143°C until the isomalt melts, then raise the temperature to 166°C. In a separate container, mix nicotine, maltitol syrup, H2O, sucralose, and optionally L-lysine to form a solution. Optionally, in a second separate container, mix water and sodium hydroxide to form a solution.

[0103] Stop heating the isomalt mixture and allow it to cool to 132°C. Combine the remaining components (i.e., the nicotine-containing solution and, if desired, the sodium hydroxide solution) and add one or more flavorings, if desired, to the combined solution. Pour the combined solution into the hot isomalt mixture and mix.

[0104] Pour the resulting mixture into the mold. If the mixture is too viscous to pour, it may be heated in a microwave oven at high heat (for example, for about 7 seconds). Typical pharmaceutical formulation mixtures are listed below. Mixture 1 below contains no base, while mixtures 2 and 3 contain different amounts of sodium hydroxide.

[0105] [Table 2]

[0106] [Table 3]

[0107] Other acceptable excipients for lozenge formulations are provided, for example, in U.S. Patent Application No. 13 / 240,500 to Holton, Jr., filed September 22, 2011, which is incorporated herein by reference.

[0108] Example 2: Preparation of a molten formulation a) Meltable preparation 1 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry components are prepared, including a filler (isomalto), a salt (sodium chloride), a sweetener (sucralose), and a flavoring (vanillin, spray-dried peppermint, spray-dried menthol). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0109] A lipid substance having a melting point of approximately 38°C to 42°C is prepared (available from AarhusKarlshamn USA Inc. as 108-24-B). The lipid substance is a non-hydrogenated lauric coating fat containing a mixture of palm kernel oil and palm oil. The lipid substance is melted in a mixing vessel. While maintaining the heat of the mixing vessel containing the molten lipid substance, the mixed dry formulation is added while mixing, thereby creating a fluid slurry of a nicotinic compound-containing composition with a water content of less than approximately 10 percent. The slurry is placed in a mold to obtain approximately 1 gram-weight of pharmaceutical composition per piece. The slurry is dried and cured in ambient air for approximately 45 minutes, after which each piece of the molten nicotinic compound-containing formulation is removed from the mold. The mixture of nicotinic compound-containing compositions consists of approximately 53.0 parts lipids, 39.8 parts fillers, 0.2 parts nicotine, 0.8 parts salt, 0.7 parts sweeteners, and 5.5 parts flavorings.

[0110] b) Meltable preparation 2 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry components are prepared, including a filler (isomalto), a salt (sodium chloride), a sweetener (sucralose), and a flavoring (vanillin, spray-dried peppermint, spray-dried menthol). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0111] A lipid substance having a melting point of approximately 38°C to 42°C is prepared (available from Earl's Karlsham, USA, as 108-24-B). The lipid substance is a non-hydrogenated lauric coating fat containing a mixture of palm kernel oil and palm oil. The lipid substance is melted in a mixing vessel. While maintaining the heat of the mixing vessel containing the molten lipid substance, the mixed dry formulation is added while mixing, thereby creating a fluid slurry of a nicotinic compound-containing composition with a water content of less than approximately 10 percent. The slurry is placed in a mold to obtain a pharmaceutical composition of approximately 1 gram by weight per piece. The slurry is dried and cured in ambient air for approximately 45 minutes, after which each piece of the molten nicotinic compound-containing formulation is removed from the mold. The mixture of the nicotinic compound-containing composition consists of approximately 53.0 parts lipid substance, 38.2 parts filler, 0.2 parts nicotine, 0.8 parts salt, 0.7 parts sweetener, and 7.1 parts flavoring.

[0112] c) Meltable preparation 3 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry components are prepared, including a filler (isomalto), a salt (sodium chloride), a sweetener (sucralose), and a flavoring (vanillin, spray-dried peppermint, spray-dried menthol). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0113] A lipid substance having a melting point of approximately 38°C to 42°C is prepared (available from Earl's Karlsham, USA as 108-24-B). The lipid substance is a non-hydrogenated lauric coating fat containing a mixture of palm kernel oil and palm oil. The lipid substance is melted in a mixing vessel. While maintaining the heat of the mixing vessel containing the molten lipid substance, the mixed dry formulation is added while mixing, thereby creating a fluid slurry of a nicotinic compound-containing composition with a water content of less than approximately 10 percent. The slurry is placed in a mold to obtain a nicotinic compound-containing formulation of approximately 1 gram by weight per piece. The slurry is dried and cured in ambient air for approximately 45 minutes, after which each piece of the molten nicotinic compound-containing formulation is removed from the mold. The mixture of the nicotinic compound-containing composition consists of approximately 53.0 parts lipid substance, 36.6 parts filler, 0.2 parts nicotine, 0.8 parts salt, 0.7 parts sweetener, and 8.7 parts flavoring.

[0114] d) Meltable formulation 4 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry materials are prepared, including a filler (isomalto), a sweetener (sucralose), and a flavoring (vanillin). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0115] A lipid substance having a melting point of approximately 38°C to 42°C is prepared (available from Earl's Karlsham, USA as 108-24-B). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. The lipid substance is melted in a mixing vessel. While maintaining the heat of the mixing vessel containing the molten lipid substance, the mixed dry formulation is added while mixing, thereby creating a fluid slurry of a nicotinic compound-containing composition with a water content of less than approximately 10 percent. The slurry is placed in a mold to obtain a nicotinic compound-containing formulation of approximately 1 gram by weight per piece. The slurry is dried and hardened in ambient air for approximately 45 minutes, after which each piece of the nicotinic compound-containing formulation is removed from the mold. The mixture of the nicotinic compound-containing composition consists of approximately 52.9 parts lipid substance, 46.1 parts filler, 0.2 parts nicotine, 0.7 parts sweetener, and 0.1 parts flavoring.

[0116] e) Meltable formulation 5 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry components are prepared, including fillers (isomalto), additives (sodium chloride, wheat flour), sweeteners (sucralose), and flavorings (vanillin). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0117] A lipid substance having a melting point of approximately 38°C to 42°C is prepared (available from Earl's Karlsham, USA as 108-24-B). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. The lipid substance is melted in a mixing vessel. While maintaining the heat of the mixing vessel containing the molten lipid substance, the mixed dry formulation is added while mixing, thereby creating a fluid slurry of a nicotinic compound-containing composition with a water content of less than approximately 10 percent. The slurry is placed in a mold to obtain a nicotinic compound-containing formulation of approximately 1 gram by weight per piece. The slurry is dried and cured in ambient air for approximately 45 minutes, after which each piece of the nicotinic compound-containing formulation is removed from the mold. The mixture of the nicotinic compound-containing composition consists of approximately 53.0 parts lipid substance, 45.2 parts filler, 0.2 parts nicotine, 0.8 parts additives, 0.7 parts sweetener, and 0.1 parts flavoring.

[0118] f) Meltable preparation 6 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry components are prepared, including fillers (isomalto), additives (sodium chloride, wheat flour), sweeteners (sucralose), and flavorings (vanillin). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0119] A lipid substance having a melting point of approximately 39°C to 41°C is prepared (available from Earl's Karlsham, USA as 108-48-B). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. The lipid substance is melted in a mixing vessel. While maintaining the heat of the mixing vessel containing the molten lipid substance, the mixed dry formulation is added while mixing, thereby creating a fluid slurry of a nicotinic compound-containing composition with a water content of less than approximately 10 percent. The slurry is placed in a mold to obtain a pharmaceutical composition of approximately 1 gram by weight per piece. The slurry is dried and cured in ambient air for approximately 45 minutes, after which each piece of the nicotinic compound-containing composition is removed from the mold. The mixture of the nicotinic compound-containing composition consists of approximately 53.0 parts lipid substance, 45.2 parts filler, 0.2 parts nicotine, 0.8 parts additives, 0.7 parts sweetener, and 0.1 parts flavoring.

[0120] g) Meltable preparation 7 A nicotinic compound-containing formulation suitable for use as a soluble component in a pharmaceutical composition for oral use is provided by the following method: Various dry components are prepared, including a filler (isomalto), a salt (sodium chloride), a sweetener (sucralose), and two flavorings (vanillin and mint). All of the dry components, in powder form, are added together with a nicotinic compound (e.g., nicotine) and thoroughly mixed in a Hobart mixer with paddles at approximately 120 rpm for approximately 3 minutes.

[0121] A lipid substance having a melting point of approximately 38°C to 42°C is prepared (available from Earl's Karlsham, USA as 108-24-B). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. The lipid substance is melted in a mixing container using a microwave oven. The molten lipid is slowly added to the dry mixture while stirring. While maintaining the heat of the mixing container containing the molten lipid substance, the entire molten lipid component is added to create a fluid slurry of the nicotinic compound-containing composition. The slurry is placed in a mold to obtain approximately 1 gram by weight of the nicotinic compound-containing composition per piece. The slurry is dried and cured in ambient air for approximately 45 minutes, after which each piece of the nicotinic compound-containing formulation is removed from the mold. The mixture of the nicotinic compound-containing composition consists of approximately 53.0 parts lipid substance, 45.2 parts filler, 0.2 parts nicotine, 0.8 parts additives, 0.7 parts sweetener, and 0.1 parts flavoring.

[0122] Other acceptable excipients for molten formulations are provided, for example, in U.S. Patent Application No. 13 / 330,929 to Cantrell, filed December 20, 2011, which is incorporated herein by reference.

[0123] Example 3: Preparation of starch-molded formulation (pastel) a) Starch-molded preparation 1 A nicotinic compound-containing formulation suitable for use as a starch-forming component in pharmaceutical compositions for oral use is provided by the following method: Prepare an aqueous mixture. Hydrate a binder material (gum arabic) with water, and then mix the hydrated gum with a filler (isomalto), an additional filler (maltitol; available as lycasin from Roquette Freres SA) and a salt in a high-shear mixer to form an aqueous mixture. The aqueous mixture consists of approximately 33 parts binder material, 29 parts isomalt, 4.1 parts maltitol, 2 parts salt and 33 parts water.

[0124] The aqueous mixture is mixed with a sweetener (sucralose) and nicotine in a Hobart mixing bowl to form a nicotinic compound-containing composition. The mixture of the nicotinic compound-containing composition consists of approximately 99.3 parts aqueous mixture, 0.2 parts nicotine, and 0.5 parts sucralose.

[0125] The nicotinic compound-containing composition is heated to approximately 54°C and then placed in a starch mold. The nicotinic compound-containing composition is left in the starch mold at approximately 60°C for approximately 19 hours. The nicotinic compound-containing composition is allowed to cool and then removed from the starch mold. The nicotinic compound-containing composition is then cured at ambient room temperature for approximately 24 hours.

[0126] b) Starch-molded preparation 2 A nicotinic compound-containing formulation suitable for use as a starch-forming component in pharmaceutical compositions for oral use is provided by the following method: A binder material (gum arabic) is hydrated with water, and then sodium hydroxide is added to adjust the pH of the mixture to 8.0 to prepare an aqueous mixture. The mixture is heated to about 82°C. Separately, isomalt and maltitol syrup are combined, heated to about 166°C, cooled to about 132°C, and added to the aqueous mixture. Flavoring, salt, sucralose, glycerin, and nicotine are added and mixed. The mixture of the nicotinic compound-containing composition consists of about 64.2 parts aqueous mixture (32 parts water, 32 parts binder, 0.2 parts buffer), 0.2 parts nicotine, 2.4 parts glycerin, 29.0 parts isomalt, 1.3 parts maltitol syrup, 0.3 parts sucralose, 2 parts salt, and 0.6 parts flavoring.

[0127] The nicotinic compound-containing composition is placed in a starch mold at a temperature of approximately 71°C (the placement temperature should be above approximately 66°C). The nicotinic compound-containing composition is left in the starch mold at approximately 60°C for approximately 72 hours. The nicotinic compound-containing composition is allowed to cool, and then removed from the starch mold. The nicotinic compound-containing composition is then cured at ambient room temperature for approximately 24 hours.

[0128] Other acceptable excipients for starch-based formulations are provided, for example, in U.S. application 12 / 957,821 to Cantrell et al., filed December 1, 2010, which is incorporated herein by reference.

[0129] Example 4: Preparation of injection-molded formulation (pastel) a) Injection molded formulation 1 A nicotinic compound-containing formulation suitable for use as an injection-molded component of pharmaceutical compositions for oral use is provided by the following method: A humectant (available from Corn Products International as HYSTAR 3375), an emulsifier (available from Loders Croklaan as DUR-EM117), corn syrup, glycerin, and a flavoring agent are mixed and heated to form a liquid mixture.

[0130] Nicotine is mixed with salt, sucralose, a binder (gum arabic), and polydextrose powder (available as LITESSE from Danisco A / S) in a Hobart mixing bowl. The liquid mixture is added to the Hobart mixing bowl containing the nicotine mixture, binder, and polydextrose powder, and the components are mixed in a Hobart mixer (model N-50) at approximately 120 rpm for approximately 4-5 minutes to form a nicotinic compound-containing composition. The nicotinic compound-containing composition is passed through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in the Hobart mixer to form powder granules. The mixture of nicotinic compound-containing compositions consists of approximately 21.4 parts binder material, 0.2 parts nicotine, 42.7 parts humectant, 1.5 parts emulsifier, 21.4 parts polydextrose, 5.3 parts corn syrup, 3.2 parts glycerin, 2.8 parts salt, 0.3 parts sucralose, and 1.2 parts flavoring.

[0131] The granulated nicotinic compound-containing composition is transferred to an injection molding mold and compressed at approximately 103,500 kPa for 1 minute. The mold is a two-piece stainless steel block filled with the nicotinic compound-containing composition, and is then compressed in conjunction with a hydraulic press unit (Wabach Hydraulic Press, Model 12-102T, Serial 2201). After cooling at ambient temperature for approximately 60 minutes, the nicotinic compound-containing composition is removed from the injection molding mold.

[0132] b) Injection molded formulation 2 A nicotinic compound-containing composition suitable for use as a pharmaceutical composition for oral use is provided by the following method: A filler (maltitol; available as licacin from Rocket Frères SA), an emulsifier (available as DUR-EM117 from Rodders Crocran), corn syrup, glycerin, and a flavoring are mixed and heated to form a liquid mixture.

[0133] Nicotine is mixed with salt, sucralose, a binder (gum arabic), and a polysaccharide (maltodextrin; available from Grain Processing Corporation as MALTRIN M100) in a Hobart mixing bowl. The liquid mixture is added to the Hobart mixing bowl containing the nicotine mixture, binder, and polysaccharide, and the components are mixed in a Hobart mixer (Model N-50) at approximately 120 rpm for approximately 4-5 minutes to form a nicotinic compound-containing composition. The nicotinic compound-containing composition is passed through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed back into the Hobart mixer to form powder granules. The mixture of nicotinic compound-containing compositions consists of approximately 21.4 parts binder material, 0.2 parts nicotine, 21.4 parts polysaccharide, 42.7 parts filler, 1.5 parts emulsifier, 5.3 parts corn syrup, 3.2 parts glycerin, 2.9 parts salt, 0.3 parts sucralose, and 1.2 parts flavoring.

[0134] The granulated nicotinic compound-containing composition is transferred to an injection molding mold and compressed at approximately 103,500 kPa for 1 minute. The mold is a two-piece stainless steel block filled with the nicotinic compound-containing composition, and is then compressed by engaging it with a hydraulic press unit (Wobuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for approximately 60 minutes, the nicotinic compound-containing composition is removed from the injection molding mold.

[0135] c) Injection molded formulation 3 A nicotinic compound-containing composition suitable for use as a pharmaceutical composition for oral use is provided by the following method: A filler (maltitol; available as licacin from Rocket Frères SA), an emulsifier (available as DUR-EM117 from Rodders Crocran), corn syrup, glycerin, and a flavoring are mixed and heated to form a liquid mixture.

[0136] Nicotine is mixed with salt, sucralose, a binder (gum arabic), and polysaccharide (pullulan powder) in a Hobart mixing bowl. The liquid mixture is added to the Hobart mixing bowl containing the nicotine mixture, binder, and polysaccharide, and the ingredients are mixed in a Hobart mixer (model N-50) at approximately 120 rpm for approximately 4-5 minutes to form a nicotinic compound-containing composition. The nicotinic compound-containing composition is passed through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in the Hobart mixer to form powder granules. The mixture of nicotinic compound-containing compositions consists of approximately 21.4 parts binder material, 0.2 parts nicotine, 21.4 parts polysaccharide, 42.6 parts filler, 1.5 parts emulsifier, 5.3 parts corn syrup, 3.2 parts glycerin, 2.8 parts salt, 0.3 parts sucralose, and 1.3 parts flavoring.

[0137] The granulated nicotinic compound-containing composition is transferred to an injection molding mold and compressed at approximately 103,500 kPa for 1 minute. The mold is a two-piece stainless steel block filled with the nicotinic compound-containing composition, and is then compressed by engaging it with a hydraulic press unit (Wobuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for approximately 60 minutes, the nicotinic compound-containing composition is removed from the injection molding mold.

[0138] d) Injection molding formulation 4 A nicotinic compound-containing composition suitable for use as a pharmaceutical composition for oral use is provided by the following method: A humectant (available from Corn Products International as HYSTAR3375), an emulsifier (available from Rodders Crocran as DUR-EM117), corn syrup, glycerin, and a flavoring are mixed and heated to form a liquid mixture.

[0139] Nicotine is mixed with salt, sucralose, a binder (gum arabic), and polydextrose powder (available from Danisco A / S as LITESSE) in a Hobart mixing bowl. The liquid mixture is added to the Hobart mixing bowl containing the nicotine mixture, binder, and polydextrose powder, and the components are mixed in a Hobart mixer (model N-50) at approximately 120 rpm for approximately 4-5 minutes to form a nicotinic compound-containing composition. The nicotinic compound-containing composition is passed through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in the Hobart mixer to form powder granules. The mixture of the nicotinic compound-containing composition consists of approximately 22.4 parts binder material, 0.2 parts nicotine, 40 parts humectant, 1.6 parts emulsifier, 22.4 parts polydextrose, 5.6 parts corn syrup, 3.4 parts glycerin, 2.8 parts salt, 0.3 parts sucralose, and 1.3 parts flavoring.

[0140] The granulated nicotinic compound-containing composition is transferred to an injection molding mold and compressed at approximately 103,500 kPa for 1 minute. The mold is a two-piece stainless steel block filled with the nicotinic compound-containing composition, and is then compressed by engaging it with a hydraulic press unit (Wobuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for approximately 60 minutes, the nicotinic compound-containing composition is removed from the injection molding mold. e) Injection molding formulation 5 A nicotinic compound-containing composition suitable for use as a pharmaceutical composition for oral use is provided by the following method: A humectant (available from Corn Products International as HYSTAR3375), an emulsifier (available from Rodders Crocran as DUR-EM117), corn syrup, glycerin, and a flavoring are mixed and heated to form a liquid mixture.

[0141] Nicotine is mixed with salt, sucralose, a binder (gum arabic), and polydextrose powder (available from Danisco A / S as LITESSE) in a Hobart mixing bowl. The liquid mixture is added to the Hobart mixing bowl containing the nicotine mixture, binder, and polydextrose powder, and the components are mixed in a Hobart mixer (model N-50) at approximately 120 rpm for approximately 4-5 minutes to form a nicotinic compound-containing composition. The nicotinic compound-containing composition is passed through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in the Hobart mixer to form powder granules. The mixture of nicotinic compound-containing compositions consists of approximately 26 parts binder material, 0.2 parts nicotine, 31.5 parts humectant, 1.2 parts emulsifier, 26 parts polydextrose, 6.2 parts corn syrup, 4.1 parts glycerin, 2 parts salt, 0.2 parts sucralose, and 0.9 parts flavoring.

[0142] The nicotinic compound-containing composition is transferred to an injection molding mold and compressed at approximately 103,500 kPa for 1 minute. The mold is a two-piece stainless steel block filled with the nicotinic compound-containing composition, and is then compressed by engaging it with a hydraulic press unit (Wobuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for approximately 60 minutes, the nicotinic compound-containing composition is removed from the injection molding mold.

[0143] Other acceptable excipients for injection-molded formulations are provided, for example, in U.S. Patent Application No. 12 / 957,838, filed December 1, 2010, to Cantrell et al., which is incorporated herein by reference.

[0144] Example 5: Preparation of a chewable formulation A nicotinic compound-containing formulation suitable for use as a chewable component in a pharmaceutical composition for oral use is provided by the following method: Prepare an aqueous mixture. Nicotine is added and a binder material (gum arabic) is hydrated with water to form an aqueous mixture. The aqueous mixture consists of approximately 49.7 parts binder, approximately 0.6 parts nicotine, and approximately 49.7 parts water. The aqueous mixture is mixed with salt (NaCl), buffer (sodium hydroxide), sweetener (sucralose), glycerin, and emulsifier (sunflower lecithin) to dissolve the added components. The mixture is heated to approximately 49°C. The heated mixture is combined with a lipid substance (available from Earl's Karl Sham, USA as 108-24-B) that has a melting point of approximately 38°C to 42°C and is heated until it becomes a melt and flavoring. The mixture of the nicotinic compound-containing composition consists of approximately 36 parts aqueous mixture, 24 parts lipid substance, 6 parts glycerin, 0.2 parts emulsifier component, 0.2 parts sucralose, 0.6 parts salt, 0.3 parts buffer, 0.6 parts flavoring, and 32 parts water.

[0145] Nicotine compound-containing compositions are formed by various methods. In one embodiment, the composition is placed in a mold, left in the mold under ambient conditions until dry, and then removed from the mold. In another embodiment, it is poured onto a tabletop, air-dried to a semi-moist state, and then formed into the desired shape using a drop roller.

[0146] Example 6: Preparation of a rigid coating formulation An aqueous mixture is prepared by adding sodium hydroxide, nicotine, and a binder (CMC-15), and the mixture is heated to approximately 57°C. The aqueous mixture consists of approximately 0.3 parts sodium hydroxide, approximately 2 parts nicotine, approximately 13 parts CMC-15, and approximately 84.7 parts water. A mixture of sorbitol, isomalt, maltitol syrup, and sucralose is melted until liquid, cooled to approximately 135°C, and added to the aqueous mixture. Flavorings and colorants (to provide a pearly appearance) are added to obtain a nicotinic compound-containing composition consisting of approximately 10 parts aqueous mixture (approximately 0.2 parts nicotine), approximately 7 parts sorbitol, approximately 26.2 parts isomalt, approximately 0.2 parts sucralose, approximately 8.2 parts maltitol syrup, approximately 0.2 parts flavorings, and approximately 48.2 parts water.

[0147] The resulting formulation can be cast into a sheet (for example, by casting it into a sheet on a stainless steel plate), or it can be immersed or spray-coated onto the composition described in this embodiment. If the formulation is cast into a sheet, it can be cut (for example, using a casting knife) and applied as a sandwich coating material onto the composition described in this embodiment. If the formulation is immersed or spray-coated, it should be maintained at a temperature above approximately 66°C, applied as a liquid, and then cooled until cured.

[0148] Example 7: Preparation of a two-layer product a) Lozenges / Flat Prepare the lozenge-type formulation as described in Example 1, pour it into a mold, and let it cool. Prepare the molten formulation as described in Example 2. However, instead of pouring the fluid slurry into a mold, apply it directly to the surface of the cooled lozenge-type formulation. For example, immerse the molded lozenge-type formulation in the fluid slurry, dry and cure at room temperature to provide a two-layer product containing a lozenge-type core and a molten coating.

[0149] b) Lozenges / Chewables Prepare the lozenge-type formulation as described in Example 1, pour it into a mold, and let it cool. Prepare the chewable formulation as described in Example 5. Pour the formulation onto a tabletop and air dry it to a semi-moist state, forming it around the surface of the lozenge-type formulation, providing a two-layer product including a lozenge-type core and a chewable-type coating.

[0150] c) Lozenges / Hard coating A lozenge-type formulation is prepared as described in Example 1, poured into a mold, and cooled. A hard-coated formulation is prepared as described in Example 6. The coated formulation is cast into a sheet, cut, and directly applied to the surface of the lozenge-type product as a sandwich coating to provide a two-layer product containing a lozenge-type core and a hard-coated coating.

[0151] d) Meltability / Lozenge The molten formulation is prepared as described in Example 2. The lozenge-type formulation is prepared as described in Example 1, except that the hot mixture is applied directly to the surface of the molten formulation instead of being poured into a mold. For example, the hot mixture may be introduced into a spray coating apparatus adapted to maintain a temperature of approximately 132°C and sprayed onto the cooled surface of the molten formulation. As described in Example 1, the mixture must be kept at a high temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape. Since the molten formulation may melt to some extent at such high temperatures, steps must be taken to avoid or limit the melting of the molten formulation during the application of the lozenge-type formulation. For example, the molten formulation may be frozen before application of the lozenge-type formulation to limit the degree of melting.

[0152] e) Meltable / rigid coatings A molten formulation is prepared as described in Example 2. A hard-coated formulation is prepared as described in Example 6. The coated formulation is cast into a sheet, cut, and directly applied to the surface of the molten product as a sandwich coating to provide a two-layer product containing a molten core and a hard-coated coating.

[0153] f) Starch molding / meltability Prepare the starch mold formulation as described in Example 3, pour it into a mold, and let it cool. Prepare the molten formulation as described in Example 2. However, instead of pouring the fluid slurry into the mold, apply it directly to the surface of the cooled starch mold formulation. For example, immerse the starch mold formulation in the fluid slurry, dry and cure at room temperature to provide a two-layer product containing a starch mold core and a molten coating.

[0154] g) Starch molding / lozenges Prepare the starch moldable formulation as described in Example 3, pour it into a mold, and let it cool. Prepare the lozenge-type formulation as described in Example 1, except that the hot mixture is applied directly to the surface of the starch moldable formulation instead of being poured into a mold. For example, the hot mixture may be introduced into a spray coating apparatus adapted to maintain a temperature of approximately 132°C and sprayed onto the surface of the cooled starch moldable formulation. As described in Example 1, the mixture must be kept at a high temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape.

[0155] h) Injection molding / meltable Prepare the injection mold formulation as described in Example 4, injection mold it to the desired size and shape, and let it cool. Prepare the molten mold formulation as described in Example 2. However, instead of pouring the fluid slurry into a mold, apply it directly to the surface of the cooled injection mold formulation. For example, immerse the injection mold formulation in the fluid slurry, dry and cure it at room temperature to provide a two-layer product containing an injection mold core and a molten mold coating.

[0156] i) Injection molding / lozenges Prepare the injection-molded formulation as described in Example 4, injection-molde it to the desired size and shape, and let it cool. Prepare the lozenge-type formulation as described in Example 1, except that the hot mixture is applied directly to the surface of the injection-molded formulation rather than being poured into a mold. For example, the hot mixture may be introduced into a spray coating apparatus adapted to maintain a temperature of approximately 132°C and sprayed onto the surface of the cooled injection-molded formulation. As described in Example 1, the mixture must be kept at a high temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape.

[0157] Example 8: Preparation of a three-layer product a) Lozenges / Fusable / Hard coatings A two-layer product including a lozenge-type core and a molten coating material is prepared as described above in Example 7a. A hard-coated formulation is prepared as described in Example 6. The coated formulation is cast into a sheet, cut, and directly applied as a sandwich coating material to the surface of a two-layer lozenge / molten composition to provide a three-layer product including a lozenge-type core, a molten first coating material, and a hard-coated second coating material.

[0158] b) Starch molding / lozenges / meltable A two-layer product comprising a starch molded core and a lozenge-type coating is prepared in Example 7g as described above. A molten formulation is prepared as described in Example 2. However, instead of pouring the fluid slurry into a mold, it is applied directly to the surface of the cooled two-layer starch molded / lozenge composition. For example, the two-layer composition is immersed in a fluid slurry and dried and cured at room temperature to provide a three-layer product comprising a starch molded core, a lozenge-type first coating, and a molten second coating.

[0159] Using the teachings presented in the aforementioned specification, many modifications and other embodiments relating to the present invention will come to mind for those skilled in the art to which the invention relates. It will be understood, therefore, that the present invention is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the accompanying claims. Specific terms are used herein, but they are used only in a generic and descriptive sense and not for limiting purposes.

Claims

1. A multilayer pharmaceutical composition comprising two or more formulations having different functional properties, wherein the formulations are: iii) Pastel preparations containing polysaccharide fillers; and v) The multilayer pharmaceutical composition comprising a chewable formulation containing a binder, an emulsifier, and a lipid having a melting point of 36°C to 45°C, wherein at least one formulation further comprises one or more nicotinic compounds.

2. The multilayer pharmaceutical composition according to claim 1, wherein both formulations of the multilayer pharmaceutical composition contain one or more nicotinic compounds.

3. The multilayer pharmaceutical composition according to claim 1, wherein one or more nicotinic compounds are independently in the form of a free base, salt, complex, or solvent compound.

4. The multilayer pharmaceutical composition according to claim 3, wherein one or more nicotinic compounds include nicotinic poracrylex.

5. The multilayer pharmaceutical composition according to claim 1, comprising a nicotinic compound in which one or more nicotinic compounds are adsorbed on a porous microparticle carrier.

6. The multilayer pharmaceutical composition according to claim 5, wherein the porous microparticle carrier comprises microcrystalline cellulose.

7. The multilayer pharmaceutical composition according to claim 1, wherein the multilayer pharmaceutical composition includes a layer between 2 and 10.

8. The multilayer pharmaceutical composition according to claim 7, wherein the multilayer pharmaceutical composition includes a layer between 2 and 5.

9. The multilayer pharmaceutical composition according to claim 1, wherein the form of the pharmaceutical composition is a core formulation surrounded by one or more continuous layers or a core formulation covered by one or more discontinuous layers, so as to form a layered or parallel arrangement of two or more formulations.

10. The multilayer pharmaceutical composition according to claim 1, wherein the polysaccharide filler of the pastel formulation iii) contains polydextrose.

11. The multilayer pharmaceutical composition according to claim 1, wherein the polysaccharide filler of the pastel formulation iii) is present in an amount of about 10% to about 25% by weight of the pastel formulation on a dry weight basis.

12. The multilayer pharmaceutical composition according to claim 1, wherein the pastel component iii) comprises a nicotinic compound; a polysaccharide filler in an amount of about 10% by weight or more; a wetting agent in an amount of about 20% by weight or more; a binder in an amount of about 10% by weight or more; and an emulsifier in an amount of about 1% by weight or more.

13. The multilayer pharmaceutical composition according to claim 1, wherein the binder material of the chewable formulation is gum arabic.

14. The multilayer pharmaceutical composition according to claim 1, wherein the chewable formulation comprises a nicotinic compound, a binder material in an amount of about 30% by weight or more, and a lipid having a melting point of 36°C to 45°C in an amount of about 15% by weight or more.

15. A method for preparing a multilayer pharmaceutical composition, comprising: A first formulation is prepared by combining one or more nicotinic compounds with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorings, sweeteners, emulsifiers, disintegration aids, wetting agents, buffering agents, and mixtures thereof to form a first nicotinic compound-containing mixture, and then forming the first nicotinic compound-containing mixture into a desired form; A second formulation is prepared by combining one or more nicotinic compounds with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorings, sweeteners, emulsifiers, disintegration aids, wetting agents, buffering agents, and mixtures thereof to form a second nicotinic compound-containing mixture, and then forming the second nicotinic compound-containing mixture into a desired form; Furthermore, the second formulation is applied to the first formulation, wherein the formulation is: iii) Pastel preparations containing polysaccharide fillers; and v) The method comprising a chewable formulation containing a binder, an emulsifier, and a lipid having a melting point of 36°C to 45°C.

16. The method according to claim 15, wherein the first nicotinic compound-containing mixture is poured into a mold or the first nicotinic compound-containing mixture is injection molded to form the first formulation into a desired shape.

17. The method according to claim 15, wherein the second formulation is applied by spray coating, immersion coating, or by forming the second formulation on a sheet to which the first formulation is applied as a sandwich coating material.

18. The method according to claim 17, wherein the spray coating or immersion coating is carried out at a temperature such that the first formulation is maintained in substantially the same form.

19. The method according to claim 15, further comprising applying the third formulation as a coating material on the second formulation.

20. The method according to claim 19, wherein the third formulation is applied by spray coating, immersion coating, or by forming the third formulation on a sheet to be applied to the second formulation as a sandwich coating material.

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