Multi-layer 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 that contain nicotine, and in particular to pharmaceutical compositions containing nicotine that are intended to be administered to provide a pharmacological effect or otherwise used for therapeutic purposes. [Background technology]

[0002] Central nervous system (CNS) symptoms, diseases or disorders may be drug-induced; may be due to genetic predisposition, infection or trauma; or may be of unknown etiology. They encompass neuropsychiatric, neurological and psychiatric disorders; including neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive-affective disorders. The clinical pathology of several CNS symptoms, diseases or disorders results from CNS dysfunction (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 acetylcholinesteric receptors (nAChRs). Subtypes of nAChRs are present in both the CNS and the peripheral nervous system (PNS), but the distribution of subtypes is heterogeneous. For example, certain subtypes are abundant in the vertebrate brain, others in autonomic ganglia, and still others at the neuromuscular junction. Activation of nAChRs by nicotinic compounds leads to neurotransmitter release. See, e.g., 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 incorporated herein by reference.

[0004] It has been proposed that administration of nicotine and other nicotinic compounds can lead to various pharmacological effects.See, for example, 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 No. 2010 / 0004451 to Ahmad et al., which are incorporated herein by reference.As a result, it has been proposed that nicotine and other nicotinic compounds can show utility in the treatment of a wide variety of symptoms, diseases and disorders, including those that affect the CNS.In addition, administration of nicotine and other 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. Additionally, administration of nicotine has been utilized in attempts to help tobacco smokers quit smoking (i.e., as a smoking cessation aid). 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 particular method that has been utilized to provide oral administration of nicotine is through the use of nicotine-containing lozenge or tablet-type products. Nicotine-containing lozenges, tablets and microtab-type products are commercially available, for example, under the trade names "Commit®", "Nicorette®", "Nicotinell®" and "NiQuitin®". See, for example, U.S. Patent Nos. 5,110,605 to Acharya; 5,733,574 to Dam; 6,280,761 to Santus; 6,676,959 to Andersson et al.; and 6,248,760 to Wilhelmsen; and U.S. Patent Publication No. 2001 / 0016593 to Wilhelmsen, which are incorporated herein by reference.

[0006] It would be desirable to provide alternative compositions capable of delivering or administering 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. Pat. 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] US Patent Application Publication No. 2010 / 0,004,451 [Patent Document 7] U.S. Pat. No. 5,604,231 [Patent Document 8] U.S. Pat. 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 Serial No. 13 / 278,877 [Patent Document 12] U.S. Patent No. 5,110,605 [Patent Document 13] U.S. Pat. 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] US 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) Summary of the Invention

[0009] In one aspect, the present invention relates to a nicotinic compound-containing composition intended to be used for therapeutic purposes. The composition is typically in a pharma- ceutically acceptable form adapted for oral delivery of the composition. The composition generally comprises a series of two or more different formulations with different properties, which may be arranged in various ways. The different formulations comprising the product may be provided, for example, in a multi-layered form. For example, a nicotinic compound-containing composition may comprise an inner core of one formulation and one or more coatings of another formulation, said coatings may be full or partial coatings. In this way, it is also possible to combine formulations with different sensory properties in the same product to provide a new composition. In certain embodiments, such a multi-layered composition allows for a controlled delivery profile during use. For example, certain formulations may provide a fast release of the nicotinic compound contained therein, while other formulations may provide an extended release of the nicotinic compound contained therein.

[0010] In one aspect of the present invention, a multi-layered pharmaceutical composition is provided comprising two or more formulations having different sensory properties, said formulations being 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 meltable formulation comprising a lipid having a melting point of about 36°C to about 45°C; iii) a pastille formulation comprising a polysaccharide filler; iv) a pastille 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, all formulations of the multi-layered 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 be in the form of free base, salt, complex or solvate independently.One or more nicotinic compounds can include, for example, nicotine polacrilex.In certain embodiments, one or more nicotinic compounds include nicotinic compounds adsorbed on a porous particulate carrier, which can include, for example, microcrystalline cellulose.

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

[0013] The components of the various formulations may vary. In some embodiments, the sugar substitute of the soluble formulation may include isomalt, and / or the sugar alcohol syrup of the soluble formulation may 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, may in certain embodiments include a lipid having a melting point of about 38°C to about 41°C. The lipid may be, for example, an animal or vegetable 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 bulking agent 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 bulking agent in an amount of about 30% by weight or more.

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

[0016] In one exemplary embodiment, the pastel composition iv) comprises a nicotinic compound; a humectant 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% by weight or more.

[0017] The chewable formulation, when present, may in certain embodiments include gum arabic as a binder material. In one exemplary embodiment, the chewable formulation includes 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] The hard coat formulation, if present, may in certain embodiments include carboxymethylcellulose as a binder component. The hard coat formulation, if present, may in certain embodiments include isomalt as a sugar substitute. In one exemplary embodiment, the hard coat formulation includes 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 multi-layered pharmaceutical composition of the present invention. For example, a product may, in certain embodiments, include two different formulations, where the formulations include: 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), formulations iv) and v), or formulations iv) and vi), where the formulations may be arranged in any manner. In regard to the foregoing, the listed formulations are intended to include permutations thereof, and each formulation may be constructed in various ways. For example, "formulations i) and ii)" may also include formulations ii) and i), and "formulations iv) and vi)" may also include formulations vi) and iv). That is, "formulations i) and ii)" is 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 as described herein may be used in the multi-layered 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), v) and vi); formulations ii), iii) and iv); formulations ii), iii) and v); formulations ii), iii) and vi); formulations ii), iv) and v); formulations ii), iv) and vi); formulations ii), v) and vi); formulations iii), iv) and v); formulations iii), iv) and vi); or formulations iii), v) and vi), where the formulations may be arranged in any manner. With respect to the foregoing, the listed formulations are intended to include permutations thereof, and each formulation may be constructed in various ways. For example, "formulations i), ii) and iii)" can include formulations i), iii), and ii); formulations ii), iii) and i); formulations ii), i) and iii); formulations iii), i) and ii), as well as formulations iii), ii) and i).That is, "formulations i), ii) and iii)" refers to the embodiments in which formulation i) is the core, formulation ii) is a partial or complete layer on formulation i), and formulation iii) is a partial or complete layer on formulation ii), as well as the embodiments in which formulation i) is the core, formulation iii) is a partial or complete layer on formulation i), and formulation ii) is a partial or complete layer on formulation iii), and the embodiments in which formulation 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). This is intended to encompass embodiments in which formulation ii) is the core, formulation i) is a partial or complete layer on formulation ii), and 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), and 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), and formulation i) is a partial or complete layer on formulation ii).

[0021] In another aspect of the invention, there is provided a method of preparing a multi-layered pharmaceutical composition, the method comprising: preparing a first formulation by combining a nicotinic compound with one or more ingredients selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorants, sweeteners, emulsifiers, disintegration aids, humectants, 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 ingredients selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorants, sweeteners, emulsifiers, disintegration aids, humectants, 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, injection molding the first nicotinic compound-containing mixture, or other methods suitable for providing a formulation. In certain embodiments, the second formulation can be applied by spray coating, dip coating, or by forming the second formulation into a sheet that is applied to the first formulation as a sandwich coating. Spray coating or dip coating can be performed at a temperature at which the first formulation remains substantially intact. In some embodiments, the method further includes applying a third formulation onto the second formulation as a coating. The third nicotinic compound-containing formulation can be applied, for example, by spray coating, dip coating, or by forming the third nicotinic compound-containing formulation into a sheet that is applied to the second formulation as a sandwich coating.

[0023] In a further aspect, a method is provided for treating a human subject having a condition, disease or disorder responsive to stimulation of a nicotinic acetylcholine receptor, said method comprising orally administering to said human subject an effective amount of a pharmaceutical composition according to any of the embodiments described herein.In one embodiment, the pharmaceutical composition is administered as a smoking cessation aid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The present invention will now be described more fully. However, the present invention may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. References to "percent dry weight" or "dry weight basis" refer to weight based on dry ingredients (i.e., all ingredients except water).

[0025] According to the present invention, there is provided a nicotinic compound pharmaceutical composition comprising at least two different formulations. In particular, such compositions generally include formulations with different organoleptic properties, such as multi-layered pharmaceutical compositions in which two or more formulations are provided as a multi-layered pharmaceutical composition. Each formulation within a nicotinic compound-containing composition may comprise one or more nicotinic compounds. At least one formulation included within a nicotinic compound-containing composition may comprise a nicotinic compound, while in certain embodiments, one or more other formulations within the composition (e.g., one or more layers) may be essentially (including entirely) free of nicotinic compounds. The present invention further provides a process for preparing a multi-layered nicotinic compound-containing pharmaceutical composition.

[0026] The structure of the multi-layered pharmaceutical composition is generally represented by the term "layered" in that the 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 or only partially cover the core or previous layer. The core may be of any shape, such as a flattened sheet, or may be of a given shape (e.g., square, round, oval, elliptical, or rectangular), or may be of a shape that may be generally described as spherical, cylindrical (e.g., ranging from the general shape of a flattened disk to the general shape of a relatively long, slender rod), spiral, elliptical, square, rectangular, etc. In some embodiments, the core and / or the multi-layered pharmaceutical composition may be in the form of beads, granules, capsules, films, strips, gels, etc. The shape of the composition may resemble a wide variety of pill, tablet, lozenge, capsule, and capsule-tablet type products in certain embodiments. Side-by-side configurations are also contemplated within the scope of the present invention, for example, where the composition comprises two layers adhered to one another along one side, and optionally an additional layer adhered to one or both of the two layers. The number of layers that make up the pharmaceutical composition may vary, but typically ranges from about 2 to about 10 layers, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 layers. It is noted that although the pharmaceutical compositions are described herein as "layered" or "multi-layered," the layers may not be distinct layers of various formulations with distinct boundaries between layers. For example, there may be some intermixing, including adjacent layers, between the formulations of the product. However, in preferred embodiments, the pharmaceutical compositions retain the properties and behavior of the individual formulations.

[0027] The organoleptic properties of one or more of the formulations that make up a multi-layered pharmaceutical composition generally vary. As used herein, the term "organoleptic" refers to any aspect experienced by the user's senses that may relate to a pharmaceutical composition formulation. Organoleptic properties include, but are not limited to, taste, odor, texture (e.g., chewiness, solubility / meltability, hardness, springiness, crunchiness, chewiness), and the like. For example, the formulations within a given multi-layered pharmaceutical composition may, in certain embodiments, have organoleptic properties independently selected from hard, melting, crunchy, chewy, melting, crunchy, and combinations thereof. Certain formulations useful as components of pharmaceutical compositions according to the present invention may be described as lozenge-like or pastille-like. The resulting multi-layered pharmaceutical composition may, in certain embodiments, include a unique combination of organoleptic properties as a result of the combination of formulations with different organoleptic properties. For example, in one particular embodiment, the pharmaceutical composition may have a hard lozenge-like outer formulation and a meltable core formulation such that upon placement in the user's mouth, the user experiences a dissolving action first and a melting action later, although the present specification encompasses many other combinations of formulations that provide a variety of sensory property combinations.

[0028] As used herein, the terms "dissolve," "dissolving," and "dissolvable" refer to a formulation that has water-soluble components that interact with the moisture in the oral cavity and go into solution, thereby causing gradual consumption of the product.

[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 occurs when a substance (e.g., a formulation in a pharmaceutical composition) changes from solid to liquid, usually by the application of heat. For the pharmaceutical compositions of the present invention, the application of heat is brought about by the internal temperature of the user's mouth. Thus, the term "meltable" refers to a formulation that is capable of liquefying in the user's mouth as the product changes phase from solid to liquid, and is intended to distinguish formulations and / or products that simply disintegrate in the oral cavity due to loss of integrity within the formulation, or formulations that simply dissolve in the oral cavity when water-soluble components of the formulation interact with moisture.

[0030] As used herein, the term "pastel" refers to a dissolvable oral formulation made by solidifying a liquid or gel-like composition, such as a composition containing a gelling agent or binder, where the final product is a hardened solid gel. In certain embodiments, such formulations are characterized by sufficient integrity to resist mild chewing action in the oral cavity without rapidly disintegrating. Pastel-like formulations of the present disclosure do not usually exhibit the highly malleable chewability seen in conventional chewing gums.

[0031] As used herein, "chewable" means easily deformed in the mouth with greater integrity than that of a pastille, but generally less than that of a gum. Such formulations may be characterized by sufficient integrity to resist chewing to a greater extent than a pastille. However, such compositions generally disintegrate in the oral cavity (unlike gum formulations).

[0032] As used herein, "hard-coat-like" refers to a layer that exhibits a 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 a "coat," this layer does not necessarily include the outer layer of the pharmaceutical composition, and may include an inner layer of the product.

[0033] The one or more "nicotinic compounds" in the pharmaceutical formulation of the present invention refer to natural or synthetic nicotine extracted from plant material, which is at least partially purified and is not contained within plant structures such as tobacco leaves. Most preferably, the nicotine is naturally occurring and obtained as an extract from Nicotiana species (e.g., tobacco). Exemplary tobacco and tobacco processing methods are set forth in U.S. Patent Application No. 13 / 240,500, filed September 22, 2011, to Holton, Jr. et al., which is incorporated herein by reference. See also U.S. Patent Application Publication Nos. 2011 / 0268809 to Brinkley et al. and 2011 / 0274628 to Borschke, and the nicotine-containing compositions set forth in U.S. Patent Application No. 13 / 278,877, filed October 21, 2011, to Borschke et al., all of which are incorporated herein by reference.

[0034] Nicotine may have the enantiomeric forms S(-)-nicotine, R(+)-nicotine, or a mixture of S(-)-nicotine and R(+)-nicotine. Most preferably, nicotine is in the form of S(-)-nicotine (e.g., a form that is substantially all S(-)-nicotine) or a racemic mixture composed primarily or predominantly of S(-)-nicotine (e.g., a mixture composed of about 95 parts by weight of S(-)-nicotine and about 5 parts by weight of R(+)-nicotine). Most preferably, nicotine is used in a substantially pure form or in an essentially pure form. Highly preferably, the nicotine used has a purity of greater than about 95 percent by weight, more preferably greater than about 98 percent by weight, and most preferably greater than about 99 percent by weight. Despite the fact that nicotine may be extracted from Nicotiana species, it is highly preferred that the nicotine (and compositions and products produced in accordance with the present invention) be substantially or essentially free of other components of tobacco.

[0035] In embodiments where nicotine is derived from a plant of the Nicotiana species, the plant or plant parts can be subjected to various types of processing conditions to provide nicotine. For example, components can be separated from each other, or in other cases fractionated into mixtures of chemical classes or individual compounds. Typical separation processes can include one or more processing steps (e.g., solvent extraction using polar solvents, organic solvents, or supercritical fluids), chromatography, distillation, filtration, recrystallization, and / or solvent-solvent partitioning. Exemplary extraction and separation solvents or carriers include water, alcohols (e.g., methanol or ethanol), hydrocarbons (e.g., heptane and hexane), diethyl ether, methylene chloride, and supercritical carbon dioxide.Exemplary techniques useful for the extraction of components from Nicotiana species are described in U.S. Pat. Nos. 4,144,895 to Fiore; 4,150,677 to Osborne, Jr. et al.; 4,267,847 to Reid; 4,289,147 to Wildman et al.; 4,351,346 to Brummer et al.; 4,359,059 to Brummer et al.; 4,506,682 to Muller; 4,589,428 to Keritsis; and 4,589,428 to S. No. 4,605,016 to Oga et al.; No. 4,716,911 to Poulose et al.; No. 4,727,889 to Niven, Jr. et al.; No. 4,887,618 to Bernasek et al.; No. 4,941,484 to Clapp et al.; No. 4,967,771 to Fagg et al.; No. 4,986,286 to Roberts et al.; No. 5,005,593 to Fagg et al.; No. 5,018,540 to Grubbs et al.; No. 5,060,669 to White et al.; No. 5,0 No. 65,775 to White et al.; No. 5,074,319 to White et al.; No. 5,099,862 to White et al.; No. 5,121,757 to White et al.; No. 5,131,414 to Fagg; No. 5,131,415 to Munoz et al.; No. 5,148,819 to Fagg; No. 5,197,494 to Kramer; No. 5,230,354 to Smith et al.; No. 5,234,008 to Fagg; No. 5,243,999 to Smith; No. 5,3 No. 01,694; No. 5,318,050 to Gonzalez-Parra et al.; No. 5,343,879 to Teague; No. 5,360,022 to Newton; No. 5,435,325 to Clapp et al.; No. 5,445,169 to Brinkley et al.; No. 6,131,584 to Lauterbach; No. 6,298,859 to Kierulff et al.; No. 6,772,767 to Mua et al.; and No. 7,337,782 to Thompson.See also the various separation techniques presented in Brandt et al., LC-GC Europe, p. 2-5 (March, 2002) and Wellings, A Practical Handbook of Preparative HPLC (2006), which are incorporated herein by reference. In addition, plants or plant parts thereof may be used in the preparation of microbial compounds as described in 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. Chrom., 1210, 229-233 (2008); and Raymond et al., U.S. Pat. No. 5,301,694.

[0036] In certain embodiments, the isolation of nicotine from Nicotiana species plants comprises removing high molecular weight components from tobacco extract.In certain embodiments, the high molecular weight components that are beneficially removed 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, various 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 usually applied to tobacco raw materials in the form of tobacco extracts (e.g., tobacco aqueous extracts). In ultrafiltration, the raw material to be filtered is contacted with a semipermeable membrane, as described in more detail in US Patent Application No. 13 / 240,500, filed September 22, 2011, to Holton, Jr. et al., which is incorporated herein by reference. In such an embodiment, the ultrafiltration step is designed to achieve a tobacco extract with a reduced level of suspended solids and thus an increased level of clarity.

[0038] Commercially available ultrafiltration systems are readily available and may be used in some embodiments for ultrafiltration of tobacco extracts. For example, commercial suppliers such as Millipore, Spectrum® Labs, Pall 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). Exemplary 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), as well as 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) system and Spectrum® Labs' KrosFlo® tangential flow filtration system and MiniKros® tangential flow filtration system.

[0039] Filters and / or membranes that may be useful according to the present invention include those with 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 provide an extract with improved clarity. Such embodiments use multiple filters and / or membranes with different (typically decreasing) molecular weight cutoffs. Any number of filters and / or membranes can be used in succession 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 cut-off of the filter, the ultrafiltered extract may contain only compounds having a molecular weight of less than about 50,000, less than about 25,000, less than about 10,000 Da, less than about 7,500 Da, less than about 5,000 Da, less than about 2,500 Da, or less than about 1,000 Da. Ultrafiltered extracts usually contain primarily sugars, nicotine, and amino acids. Ultrafiltration may be used in conjunction with other separation and purification methods to provide nicotine with an acceptable purity level.

[0040] Ultrafiltered extracts may exhibit improved levels of clarity over non-ultrafiltered extracts. The clarity of extracts and compositions according to the invention made therefrom is usually defined in terms of translucency. As used herein, "translucent" or "translucency" refers to a material that allows a certain level of light to pass through it while being diffused. In various embodiments, certain materials of the present invention (e.g., certain tobacco extracts or nicotine obtained therefrom) may have such a high degree of clarity that the material or a portion thereof may be classified as "transparent" or exhibiting "transparency", which is defined as a material through which light can pass freely without significant diffusion. The clarity of ultrafiltered extracts is such that there is a level of translucency as opposed to opacity (which refers to a material through which light cannot pass). In certain embodiments, ultrafiltered extracts are analyzed by the naked eye or by shining light on the extract and measuring the percent of light that is not absorbed and / or scattered by the extract. The measurement may be performed, for example, using a standard spectrophotometer at a given wavelength. Spectrophotometers are usually calibrated with deionized water and assign a transparency value of 100% to deionized water. The ultrafiltered extract may, in some embodiments, exhibit a translucency of more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 60%, more than about 70%, more than about 80%, or more than about 90%. Usually, the ultrafiltered extract is not colorless and has some noticeable brown / black color. After ultrafiltration, the extract can be stored in a refrigerator or freezer, or the extract can be freeze-dried or spray-dried before use in the compositions of the present invention. In certain embodiments, it is provided in a syrup form. The ultrafiltered extract in some embodiments can be further processed to provide a sufficient level of purity of nicotinic compounds.

[0041] The nicotinic compound of the present invention may include nicotine in free base form, salt form, complex or solvate form.See, for example, the discussion of nicotine in free base form in US Patent Publication No. 2004 / 0191322 to Hansson, which is incorporated herein by reference.At least a portion of the nicotinic compound may be used in the form of a nicotine resin complex, in which nicotine is bound in an ion exchange resin, such as nicotine polacrilex.See, for example, US Patent No. 3,901,248 to Lichtneckert et al., which is 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 ingredients and techniques as shown in US Patent No. 2,033,909 to Cox et al. and Perfetti, Beitrage Tabakforschung Int., 12, 43-54 (1983). Additionally, salts of nicotine are available from sources such as Pfalz & Bauer, Inc., and K&K Laboratories, a division of ICN Biochemicals, Inc. Exemplary pharma- ceutically acceptable nicotine salts include nicotine tartrate salts (e.g., nicotine tartrate and nicotine bitartrate), nicotine chloride salts (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine sulfate salts, nicotine perchlorate salts, nicotine ascorbate salts, nicotine fumarate salts, nicotine citrate salts, nicotine malate salts, nicotine lactate salts, nicotine aspartate salts, nicotine salicylate salts, nicotine tosylate salts, nicotine succinate salts, nicotine pyruvic acid salts, and the like; nicotine salt hydrates (e.g., nicotine zinc chloride monohydrate); and the like. In certain embodiments, at least a portion of the nicotinic compound is in the form of a salt with an organic acid moiety, including but not limited to levulinic acid, as discussed in U.S. Patent Application Publication No. 2011 / 0268809 to Brinkley et al., 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) prior to incorporation into the compositions of the present invention. In one embodiment, the MCC material used in the present invention has an average particle size ranging from about 15 to about 250 microns. Exemplary MCC materials include various grades of AVICEL® and VIVACEL® materials. See, for example, US Patent Application Publication No. 2004 / 0191322 to Hansson, which is incorporated herein by reference. In certain embodiments, multiple forms of the nicotinic compound could be adsorbed onto the granular carrier, including any of the combinations of the various nicotinic compounds discussed herein. In some embodiments, the nicotinic compound and optionally the organic acid moiety can be adsorbed onto the granular carrier, for example, by dissolving the nicotinic compound (and optionally the organic acid moiety) in a hydrophilic solvent (e.g., water, alcohol, or mixtures thereof), mixing with a solution containing the granular carrier, followed by drying to remove the solvent. The particulate carrier material having adsorbed nicotine and optionally an organic acid moiety may be mixed with other carriers or excipients to provide a composition adapted for oral delivery of the active ingredient.

[0043] The compositions of the present invention are pharma- ceutically effective and have a pharma-ceutically acceptable form. That is, most preferably, the compositions do not incorporate or are not intentionally incorporated to any appreciable extent with tobacco components other than nicotine. Thus, pharma-ceutically effective and pharma-ceutically 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 forms of tobacco products. Highly preferred compositions contain less than 0.5 weight percent of tobacco components other than nicotine, more often less than about 0.25 weight percent of tobacco components other than nicotine, and usually are completely absent or devoid of tobacco components other than nicotine, processed tobacco components, or components derived from tobacco.

[0044] According to the present invention, the nicotinic compound in one or more of the various forms described herein is used in the preparation of pharmaceutical compositions.Specifically, the nicotinic compound can be mixed with one or more additional components to produce a formulation that is combined with other nicotinic compound-containing formulations or non-nicotinic compound-containing formulations to provide the multi-layered pharmaceutical composition of the present invention.The types of formulations included in the pharmaceutical composition according to the present invention can be various, including but not limited to lozenge-type formulations, melt-type formulations, chewable-type formulations, hard-coated formulations, and starch-molded formulations and injection-molded formulations.Each formulation can contain one or more nicotinic compounds or can be free of nicotinic compounds.However, at least one component of the multi-layered pharmaceutical composition usually contains a nicotinic compound.

[0045] The components of each formulation in a multi-layered pharmaceutical composition may vary and are independently selected such that two or more formulations contain generally different combinations of the other components. The individual components (optionally including one or more nicotinic compounds) may be processed, blended, formulated, compounded, and / or mixed to produce the desired formulation.

[0046] Other components of the formulation may be man-made or may be obtained or derived from plant or biological sources. Exemplary components that may be incorporated into one or more formulations according to the 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, aspartame K, neotame, etc.), organic and inorganic fillers (e.g., grains, processed grains, expanded grains, maltodextrin, glucose, calcium carbonate, calcium phosphate, calcium polycarbophil, corn starch, lactose, isomalt, sugar alcohols such as mannitol, xylitol, or sorbitol, comminuted cellulose, hydroxypropyl cellulose, vegetable proteins, silicon dioxide, etc.), film formers and binders (e.g., povidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and other modified cellulose types of binders). co-solvents, sodium alginate, gum acacia, xanthan gum, starch-based binders (e.g., potato starch, corn starch, etc.), gum arabic, gellan gum, lecithin, etc.), gelling agents (e.g., fish gelatin), pH adjusters or buffers (e.g., metal hydroxides, preferably alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and other alkali metal buffers such as metal carbonates, preferably potassium carbonate or sodium carbonate, or metal bicarbonates such as sodium hydrogen carbonate, etc.), emulsifiers , coloring agents (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 or compressibility aids (e.g., microcrystalline cellulose, croscarmellose sodium,Examples of suitable additives include, for example, crospovidone, sodium starch glycolate, pregelatinized corn starch, etc.), lubricants or processing aids (e.g., magnesium stearate or calcium stearate), anti-adherents (e.g., talc), glidants (e.g., colloidal silica), surfactants (e.g., polysorbate 80), flavorings and flavoring mixtures, and mixtures thereof. Exemplary components may include, for example, those described in U.S. Patent Application Publication No. 2010 / 0291245 to Gao et al., which is incorporated herein by reference.

[0047] The pharmaceutical composition of the present invention can be conveniently made available in the form of unit dosage form, whereby such preparations can be prepared by any of the methods generally known in the pharmaceutical field.Generally speaking, such preparation methods include (by various methods) combining active agent with suitable carrier or other adjuvants, which can consist of one or more ingredients.Then, the combination of active agent with one or more adjuvants is physically processed to provide the preparation in a suitable form for delivery (for example, forming into a tablet, or preparing an aqueous suspension).

[0048] The nicotine-containing pharmaceutical compositions of the present invention can incorporate various pharma- ceutically acceptable excipients. By the term "pharma- ceutically acceptable carrier" or "pharma- ceutically acceptable excipient" is intended a carrier or excipient conventionally used in the art for storing, administering, and / or promoting the therapeutic effect of an active agent (e.g., a nicotinic compound). A carrier must be pharma- ceutical acceptable in that it is compatible with the other ingredients of the formulation and is not appreciably harmful to its recipient. A carrier may also reduce any undesirable side effects of the agent. See Wang et al. (1980) J. Parent. Drug Assn. 34(6):452-462, which is incorporated herein by reference in its entirety. Other exemplary pharmaceutical excipients and / or additives suitable for use in the compositions according to the invention are described in Remington: The Science & Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2006), which are incorporated herein by reference; in Physician's Desk Reference, 64th Edition, Thomson PDR (2010); and in Handbook of Pharmaceutical Excipients, 6th Edition, edited by Raymond C. Rowe et al., Pharmaceutical Press (2009).

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

[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 the components are provided in powder or granular form, they are most preferably used in the form of parts or pieces having an average particle size of less than about 50 microns. According to some embodiments, the average particle size of the components may be less than about 25 microns. 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 often less than about 2.5 weight percent. The components may be mixed with nicotine, for example, in a Hobart mixer with a paddle, before the addition of any liquid components. In the event that a liquid component is 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 often less than about 2.5 weight percent. The relative amounts of the 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 the nicotinic compound-containing formulation and the final pharmaceutical product). The relative amounts of the various components in the nicotinic compound-containing formulation may vary and are usually selected to provide the pharmaceutical composition with the desired sensory and performance characteristics. Furthermore, the various components described above may be encapsulated when provided in the final product or composition. Exemplary encapsulation components are described, for example, in Atchley, International Publication No. WO 2010 / 132444(A2), which is incorporated herein by reference.

[0052] As used herein, a "flavoring agent" or "flavoring agent" is any flavorful or aromatic substance that can alter the sensory characteristics associated with a pharmaceutical composition. Exemplary sensory characteristics that can be modified by flavoring agents include taste, texture, moistness, coolness / heat, and / or aroma / odor. Flavoring agents can be natural or synthetic, and these flavor characteristics can be described as, but are not limited to, fresh, sweet, herbal, confectionery, floral, fruity, or spicy. Specific 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. Flavoring agents utilized in the present invention can also include ingredients that are considered humectants, cooling agents, or lubricants, such as eucalyptus. These flavors can be provided neat (i.e., alone) or in composites (e.g., spearmint and menthol, or orange and cinnamon). In some instances, the flavors can be provided in a spray-dried form. The flavors are typically present in an amount of about 0.5 to about 10 dry weight percent, often about 1 to about 6 dry weight percent, and most often about 2 to about 5 dry weight percent.

[0053] Sweeteners may be used in the form of natural or artificial sweeteners, or a combination of artificial and natural sweeteners. In one embodiment, sucralose, sucrose, or a combination thereof is the main sweetener component. When present, the representative amount of sweetener, whether artificial or natural sugar, 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. The amount of sweetener in the composition is preferably not more than about 40 percent, often not more than about 35 percent, and often not more than about 30 percent of the total dry weight of the composition.

[0054] Sucrose may be a particularly advantageous sweetener in certain embodiments (e.g., as a component of a starch molded formulation) because it is believed to contribute to the chew resistance or "resilience" of the final product. In addition, although granulated sucrose provides a significantly lower sweetening effect compared to sucralose, the presence of sucrose may be advantageous as an additional bulking ingredient. When these two sweeteners are present together, sucralose is usually present in an amount of at least about 0.25 dry weight percent, often at least about 0.5 dry weight percent, and most often at least about 1.0 dry weight percent (e.g., about 0.25 to about 2.0 dry weight percent), and sucrose is usually present in an amount of at least about 2.0 dry weight percent, often at least about 3.0 dry weight percent, and most often at least about 4.0 dry weight percent (e.g., about 1.0 to about 6.0 dry weight percent).

[0055] In certain embodiments, some formulations (or pharmaceutical compositions as a whole) are sugar-free and contain one or more sugar substitutes. "Sugar-free" as used herein is intended to include products with less than about 1 / 15th weight of sugar, or less than about 1 / 10th weight of sugar. Sugar substitutes, when used, can be provided in solid form (e.g., granular or powder form) as pure. In certain embodiments, sugar substitutes are dry and contain very low moisture content. For example, sugar substitutes can contain less than about 5% water by weight, less than about 3% water by weight, less than about 2% water by weight, or less than about 1% water by weight.

[0056] In some embodiments, syrup (e.g., corn syrup) may be used in an amount sufficient to provide desired flavor characteristics to the pharmaceutical composition. In some embodiments (e.g., in starch molded formulations), syrup may be used in an amount sufficient to provide chewiness and retard solubilization. A representative 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 the lozenge formulation to affect the recrystallization of another component of the formulation (e.g., molten sugar substitute) during preparation. Exemplary sugar alcohol syrups for such purposes include maltitol syrup, xylitol syrup, mannitol syrup, glycerol syrup, erythritol syrup, threitol 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 typically ranges from about 0.1% to about 2% by weight of the pharmaceutical composition mixture, often from about 0.5% to about 1.5% by weight, and more often 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 the present disclosure may typically include at least one filler component. When a polysaccharide filler component is present, optional filler components can be provided in addition to the polysaccharide filler component. Such filler components of the composition often perform multiple functions, such as improving certain sensory properties such as chewiness and texture, enhancing product cohesiveness or compressibility, etc. In certain embodiments (e.g., in starch molded formulations), sugar alcohols are particularly advantageous as filler components because they provide some sweetness and do not destroy the desired chewable properties of the final product. Sugar alcohols (e.g., isomalt) are polyols derived from mono- or disaccharides with partially or fully hydrogenated forms. Exemplary 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). The sugar alcohol may be added in the form of an aqueous solution or suspension, such as a solution or suspension having a solids content of about 50 to about 90 percent by weight. A mixture of sugar alcohol with other filler components may also be used. When present, a representative amount of filler, whether organic or inorganic, 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. The amount of additional filler in the composition preferably does not exceed about 50 percent, and often does not exceed about 40 percent, of the total dry weight of the composition. 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 an amount sufficient to impart desired sensory properties to the pharmaceutical composition. When present, a representative 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 typically will be less than about 5 percent (e.g., about 0.5 to about 4 dry weight percent) of the total dry weight of the composition. In some embodiments, when present, the salt will be less than about 2 percent or less than about 1 percent of the total dry weight of the composition.

[0060] Humectants (e.g., glycerin) may be used in an amount sufficient to provide the pharmaceutical composition with desired moisture characteristics. Additionally, in some instances, humectants can provide the pharmaceutical composition with desirable flow characteristics (e.g., for filling starch molds). When present, a representative amount of humectant will usually be at least about 1 percent, at least about 1.5 dry weight percent, or at least about 2 dry weight percent of the total dry weight of the composition. In certain embodiments, the amount of humectant is at least about 10 dry weight percent or at least about 20 dry weight percent. Exemplary dry weight ranges are from about 1 to about 40 dry weight percent, more often from about 3 to about 35 dry weight percent. In some embodiments, the humectant may be provided in an amount of less than about 5 percent (e.g., from about 0.5 to about 4 dry weight percent) of the total dry weight of the composition.

[0061] The binder (or combination of binders) may be used in an amount sufficient to provide the pharmaceutical composition with the desired physical properties and material integrity. When present, a representative 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. The amount of binder in the composition is preferably not more than about 35 percent, about 40 percent, or about 45 percent of the total dry weight of the composition. The amount of binder in the desired composition is often not more than about 20 percent of the total dry weight of the composition, and often not more than about 15 percent of the total dry weight of the composition. In certain embodiments, the binder material includes natural gums. As used herein, natural gums refer to naturally occurring polysaccharide materials that are useful as thickening or gelling agents. Representative natural gums derived from plants are usually water soluble to some extent and include xanthan gum, guar gum, gum arabic, gum ghatti, gum tragacanth, gum karaya, locust bean gum, gellan gum, and combinations thereof.

[0062] Emulsifying agents may be used in an amount sufficient to impart the desired stabilizing properties to the pharmaceutical composition. When present, a representative amount of emulsifying agent will usually be less than about 5 percent of the total dry weight of the composition.

[0063] Certain buffering agents exhibit buffering activity within a pH range of about 6 to about 10, and exemplary buffering agents include metal hydroxides, metal carbonates, metal bicarbonates, or mixtures thereof. When present, the buffering agent is typically present in an amount of less than about 1 percent based on the dry weight of the formulation. A variety of food grade buffering agents are known and may be used to adjust the pH of the products of the present invention. Suitable buffering agents 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 buffering agent is an amino acid, for example, as taught in U.S. Patent Application Publication No. 2008 / 0286341 to Andersson et al. and PCT Application No. 2008 / 040371 to Andersson et al., both of which are incorporated herein by reference. As described therein, various amino acids and their salts are useful for this purpose, including, but 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 buffering agent. In some embodiments, an amino acid buffering agent is used in combination with another amino acid buffering agent and / or in combination with one or more non-amino acid buffering agents. In certain embodiments, the optional pH adjusting agent is a base (e.g., NaOH). In certain embodiments, L-lysine and NaOH are added to the compositions of the present invention.

[0064] It is well known that nicotine is prone to oxidation, and therefore it may be advantageous to incorporate one or more antioxidants, such as, for example, ascorbyl palmitate and / or sodium ascorbate, into the composition according to the invention, which may be present in the pharmaceutical composition mixture at a concentration of from about 0.05% to about 0.3% by weight, such as, 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-term, immediate-release, controlled-release, sustained-release, delayed-release, and pulsed-release formulations, provided that the formulations achieve administration of the nicotinic compounds as described herein. See Remington's Pharmaceutical Sciences (18th ed.; Mack Publishing Company, Eaton, Pa., 1990), which is incorporated herein by reference in its entirety.

[0066] The compositions of the present invention incorporate a pharma- tically effective amount of nicotine. The dose of the active ingredient (i.e., all of the various forms of nicotine) is preferably an amount effective to treat some symptoms of the condition, disease, or disorder suffered by the subject or patient, or to prevent the onset of the symptoms. An "effective amount," "therapeutic amount," or "effective dose" refers to an amount sufficient to induce a desired pharmacological or therapeutic effect, thereby resulting in effective prevention or treatment of the condition, disease, or disorder. Thus, an effective amount of the active ingredient is an amount sufficient to enter the appropriate area of ​​the body (e.g., to cross the blood-brain barrier of the subject), to bind to the appropriate receptor sites of the CNS and PNS of the subject, and / or to induce a neuropharmacological effect (e.g., to induce the secretion of neurotransmitters, thereby resulting in effective prevention or treatment of the condition, disease, or disorder). Prevention of the disorder is manifested, for example, by delaying the onset of symptoms of the condition, disease, or disorder. Treatment of a disorder is manifested, for example, by a decrease in the symptoms of the condition, disease, or disorder, or an amelioration of the recurrence of the symptoms.

[0067] The amount of active ingredient in the overall composition may vary. For compositions intended for oral consumption by placing in the mouth of a subject (e.g., lozenges, etc.), the amount of nicotine in each dosage piece or dosage unit is usually at least about 0.5 mg, generally at least 1 mg, often at least about 1.5 mg, and often at least about 2 mg, calculated on a nicotine basis, while the amount of nicotine in each piece is usually not more than about 10 mg, generally not more than about 8 mg, often not more than about 6 mg, and often not more than about 5 mg, calculated on a nicotine basis. Exemplary various such products may 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 in any given formulation layer in a multi-layer composition may vary and is usually selected to bring the total nicotine content in each product unit into the ranges set forth above.

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

[0069] For example, a typical lozenge formulation may include 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 matrix. In one particular embodiment of the present invention, the lozenge formulation includes a nicotinic compound, a sugar substitute in an amount of at least about 80% by weight, and a sugar alcohol syrup. In certain embodiments, the sugar substitute is present in an amount of at least about 85% by weight or at least about 90% by weight. In particular embodiments, the lozenge formulation may include isomalt, maltitol syrup, a nicotinic compound, NaCl, and sucralose. In certain embodiments, the formulation is translucent. For further details regarding a representative lozenge formulation, see US Patent Application Publication No. 13 / 240,525, filed September 22, 2011, by Holton, Jr. et al., which is incorporated herein by reference.

[0070] A typical melt formulation generally comprises a nicotinic compound and a lipid. The lipid may vary and may be, for example, a fat, oil, or wax material (or a combination thereof) that forms part of the formulation. The lipid component may be derived from animal or vegetable sources and typically comprises primarily triglycerides with smaller amounts of free fatty acids and mono- or diglycerides. In certain embodiments, the lipid is a vegetable-derived fatty material that is solid or semi-solid at room temperature (i.e., about 25°C) and at least partially liquefies when exposed to the temperature of the user's mouth. The melting point of the lipid may vary and, in certain embodiments, may be within 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 (the majority of which are linked in triglyceride structures) having a carbon length of about 10 to about 26 carbon atoms, more typically about 14 to about 20 carbon atoms, and most often about 14 to about 18 carbon atoms. Exemplary plant-derived fats that can be used include palm oil, palm kernel oil, soybean oil, cottonseed oil, and mixtures thereof. According to some embodiments, the lipid material may be hydrogenated, partially hydrogenated, or non-hydrogenated. In some examples, the lipid material may include a mixture of lipid components. For example, the lipid material may include a mixture of palm oil and palm kernel oil.

[0072] In certain embodiments, melt-type formulations are provided that include a nicotinic compound, about 10 to about 50 percent lipid component, about 0 to about 1 percent artificial sweetener, about 20 to about 40 percent bulking agent, flavoring agent in an amount up to about 10 percent, and salt in an amount up to about 5 percent, based on the total dry weight of the formulation. Further details regarding specific lipids and melt-type formulations that include lipids can be found in U.S. Patent Application Publication No. 13 / 330,929, filed Dec. 20, 2011, to Cantrell et al., which is incorporated herein by reference.

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

[0074] A typical hard-coated formulation usually includes a nicotinic compound, a binder, and a sugar alcohol syrup. In one particular embodiment, the hard-coated formulation includes a nicotinic compound, a binder, a sugar alcohol, isomalt, sodium hydroxide, sucralose, and a flavoring. Although the hard-coated formulation according to the present invention usually includes such components, it is noted that in certain embodiments, various other coatings can be applied, and in some embodiments, various other coatings can be applied in addition to the hard-coated formulation. For example, the entire multi-layered pharmaceutical composition of the present invention and / or any of the component formulations described herein can, in certain embodiments, include an outer coating, which can include components such as a polish composition and surface polish carnauba wax and / or a pharma- ceutically acceptable form of shellac. Application of the coating can be accomplished using techniques such as airless spray coating, fluidized bed coating, use of a coating pan, and the like. Other materials used as coatings can be polymeric, such as cellulosic materials (e.g., cellulose butyrate phthalate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethyl cellulose), and polymers and copolymers of acrylic acid, methacrylic acid, and their esters. For example, such coatings can include a film-forming polymer, such as a cellulosic polymer, and an optional plasticizer. Other optional coating ingredients include flavorants, sweeteners, colorants, and salts.

[0075] A typical injection molded formulation (i.e., a pastille) may include, for example, a nicotinic compound, and about 10 weight percent to about 25 weight percent of a polysaccharide filler component on a dry weight basis. The polysaccharide filler may vary, but in certain embodiments includes polydextrose. Certain embodiments include one or more of the following components: a sugar alcohol filler (e.g., sorbitol), a binder including a water-soluble gum (e.g., gum arabic), and / or a flavoring agent, a binder, an emulsifier, a disintegration aid, a humectant, and mixtures thereof. In one particular embodiment, the formulation includes a nicotinic compound, at least about 10 dry weight percent of a polysaccharide filler component, at least about 10 dry weight percent of at least one binder, at least about 20 dry weight percent of at least one humectant, and at least about 1 dry weight percent of at least one emulsifier. For further details regarding representative injection molded formulations, see U.S. Patent Application Publication No. 12 / 957,838, filed Dec. 1, 2010, to Cantrell et al., which is incorporated herein by reference.

[0076] A typical starch molded formulation (i.e., pastilles) may, for example, comprise 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 molded formulation comprises 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 molded formulation comprises at least about 10 percent sugar alcohol filler, at least about 10 percent binder, about 0.1 to about 2 percent artificial sweetener, about 1 to about 5 percent humectant, about 1 to about 5 percent natural sweetener, up to about 5 percent flavoring, and up to about 3 percent salt, based on the total dry weight of the pharmaceutical composition.

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

[0078] The formulations constituting the pharmaceutical composition of the present invention may have various sensory properties. For example, starch molded formulations, in certain embodiments, can be characterized as soluble and lightly chewable, and are generally in the form of a hardened solid gel (e.g., "pastel"). In certain embodiments, starch molded formulations are characterized by sufficient integrity to resist mild chewing action in the oral cavity without rapid disintegration. Such formulations of the present disclosure do not usually exhibit the highly deformable chewiness seen in conventional chewing gums. Meltable formulations, in certain embodiments, can be described as providing a slippery and creamy sensation (rather than a slippery, waxy or slimy sensation) upon entry into the user's mouth. Lozenge-type formulations are generally chewy and soluble. Chewable formulations generally exhibit a chewiness between the pastilles and gums described herein. Like pastilles, chewable formulations usually exhibit integrity that resists mild chewing in the oral cavity, but usually disintegrate at a slower rate than pastilles, allowing for more chewing before complete disintegration of the composition. Hard-coated formulations generally provide some crunch or crunchiness.

[0079] The structure and nature of the formulations within a given multi-layered pharmaceutical composition may 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 the coated formulation, and the first and second layers are layers successively applied to the core formulation. Alternatively, the core may refer to one component of a side-by-side configuration, where the first layer is applied to the core formulation in at least one surface and the second layer, if present, is attached to the first layer formulation in at least one surface.

[0080] Table 1 describes various combinations of formulations that may comprise the multi-layered pharmaceutical composition. Depending on the specific composition of each formulation, Table 1 represents exemplary products of the present invention having various combinations of various formulations. Each formulation provided in Table 1 is preferably 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 that it can exhibit a mixture of sensory properties. In certain embodiments, such pharmaceutical compositions are multi-layered, so that they can provide the user with a variety of organoleptic sensations during the use of the product. For example, the pharmaceutical composition can be tailored to exhibit a certain range of sensory properties with a desired experience sequence (e.g., an initial hard and melting sensation followed by a chewy sensation).

[0089] Due to the multi-layered structure of the pharmaceutical composition of the present invention, certain embodiments can tailor the flavor and / or nicotine release profile of the product as a whole. In other words, the manner and / or speed at which nicotine is released can be varied. Certain types of formulations usually exhibit faster or slower release of nicotine. Such formulations are conveniently located within the multi-layered 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 release of nicotine, while one or more inner formulations exhibit a more sustained nicotine release profile, providing a product that provides both an initial fast release of nicotine and a sustained release of nicotine. In certain embodiments, various flavorants and / or other components (e.g., sensates) can be incorporated into certain layers. The flavor and / or organoleptic sensation of different layers can be varied to provide the user with a unique range of taste and / or sensory experiences during use of the product.

[0090] The compositions of the present invention incorporate a pharma- tically effective amount of nicotine. The dose of the active ingredient (i.e., all of the various forms of nicotine) is preferably an amount effective to treat some symptoms of the condition, disease, or disorder suffered by the subject or patient, or to prevent the onset of the symptoms. An "effective amount," "therapeutic amount," or "effective dose" refers to an amount sufficient to induce a desired pharmacological or therapeutic effect, thereby resulting in effective prevention or treatment of the condition, disease, or disorder. Thus, an effective amount of the active ingredient is an amount sufficient to enter the appropriate area of ​​the body (e.g., to cross the blood-brain barrier of the subject), to bind to the appropriate receptor sites of the CNS and PNS of the subject, and / or to induce a neuropharmacological effect (e.g., to induce the secretion of neurotransmitters, thereby resulting in effective prevention or treatment of the condition, disease, or disorder). Prevention of the disorder is manifested, for example, by delaying the onset of symptoms of the condition, disease, or disorder. Treatment of a disorder is manifested, for example, by a decrease in the symptoms of the condition, disease, or disorder, or an amelioration of the recurrence of the symptoms.

[0091] For the compositions of the present invention, the intended daily dose of active ingredient may vary. The total dose of active ingredient may depend on factors such as the body weight of the subject taking 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 is usually at least about 2 mg, often at least about 4 mg, and often at least about 10 mg, calculated on a nicotine basis. 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 often not more than about 40 mg. See, for example, the various types of dosing regimens and techniques set forth in U.S. Pat. No. 5,593,684 to Baker et al.; U.S. Pat. No. 6,660,754 to Kyle et al.; and U.S. Patent Application Publication No. 2004 / 0006113 to Sachs; U.S. Patent Application Publication No. 2005 / 0214229 to Pinney et al.; U.S. Patent Application Publication No. 2008 / 0124283 to Andersen; and U.S. Patent Application Publication No. 2009 / 0293895 to Axelsson et al., which are incorporated herein by reference.

[0092] Representative compositions incorporating nicotine as an active ingredient can have a wide variety of formats and configurations, and as a result, the characteristics, properties, behavior, firmness, shape, form, size, and weight of the compositions can vary. The shapes of representative compositions can be generally spherical, cylindrical (e.g., ranging from the general shape of a flattened disk to the general shape of a relatively long, slender rod), helical, elliptical, square, rectangular, etc., or the compositions can have the form of beads, granules, crystalline powders, capsules, films, strips, gels, etc. The shapes of the compositions can resemble a wide variety of pills, tablets, lozenges, capsules, capsule-type tablets, pouches, and gum-type products that have traditionally been used to administer pharmaceutical-type products. The general properties of representative compositions can be soft or firm to the touch, or of intermediate softness or firmness, and thus the compositions can be viewed as malleable, pliable, chewy, elastic, brittle, etc. When administered orally, the various components of the product may disperse readily or may appear to disperse slowly, or may dissolve at different rates (e.g., from relatively fast to relatively slow). As a result, for compositions that are ingested by placing in the mouth of a human subject, the release rate of the active ingredient during use of the product may vary from a relatively fast rate to a relatively slow rate, depending on factors such as the design of the product and the method of use of the product by the subject using the product.U.S. Patents Nos. 4,655,231 to Ray et al.; 5,147,654 to Place et al.; 5,543,424 to Carlsson et al.; 6,268,386 to Thompson; 6,319,510 to Yates; 6,488,953 to Halliday et al.; 6,709,671 to Zerbe et al.; 7,025,983 to Leung et al.; 7,105,173 to Rolling; 7,115,297 to Stillman; and 7,435,749 to Knight, all of which are incorporated herein by reference. see also, for example, the various products proposed in the specification; and Leung et al., U.S. Patent Application Publication No. 7,491,406; and Chan et al., U.S. Patent Application Publication No. 2006 / 0198873; Houze et al., U.S. Patent Application No. 2006 / 0240087; Bess et al., U.S. Patent Application No. 2006 / 0204559; Steen et al., U.S. Patent Application No. 2007 / 0269492; Chau et al., U.S. Patent Application No. 2008 / 0020050; Andersson et al., U.S. Patent Application No. 2008 / 0286340; Sanghvi et al., U.S. Patent Application No. 2008 / 0292683; and Bunick et al., U.S. Patent Application No. 2009 / 0004248.

[0093] The method by which the multi-layered nicotinic compound-containing pharmaceutical composition can be made may vary. Generally, the core formulation may be provided by any method for providing such a formulation. Note that although exemplary methods for providing certain types of formulations are provided herein, other methods may be used without departing from the present invention. Typically, a core formulation is made and one or more additional layers are applied thereto. The core may be molded (e.g., rolled or pressed) into a desired shape, for example, by pouring the formulation mixture directly into a mold, or extruded into a desired shape. In some embodiments, the mixture may be extruded, starch molded, or injection molded.

[0094] In certain embodiments, the method of forming one or more additional layers may require some adjustment to accommodate application of the formulation to the pharmaceutical composition core or to a previous layer. For example, second and subsequent layers of 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 encase the core formulation or adhere to one or more surfaces of the core formulation, such as in a side-by-side configuration).

[0095] Typical conditions involved in the manufacture of food grade products such as those described herein include the control of heat and temperature (i.e., the temperature of heat to which the various ingredients are exposed during manufacture, and the temperature of the manufacturing environment), moisture content (e.g., the degree of moisture present in the individual ingredients and in the final composition), humidity in the manufacturing environment, control of the atmosphere (e.g., nitrogen atmosphere), air flow experienced by the various ingredients during the manufacturing process, and other similar miscellaneous factors. Additionally, the various processing steps involved in the manufacture of the products may involve the selection of certain solvents and processing aids, the use of heat and radiation, cooling and cryogenic storage conditions, ingredient mixing rates, etc. The manufacturing conditions may also be controlled due to the selection of the shape (e.g., solid, liquid, or gas) of the various ingredients, the particle size or crystallinity of the ingredients in solid form, the concentration of the ingredients in liquid form, etc. The ingredients may be processed into the desired composition by techniques such as extrusion, compression, spraying, etc.

[0096] The melt formulations may, in certain embodiments, be prepared by mixing the components (e.g., the nicotinic compound and one or more additional components) with a molten lipid to form a molten pharmaceutical formulation slurry, which can then be cast into a mold or coated onto another formulation.

[0097] A lozenge formulation may be prepared, in certain embodiments, by heating a mixture of ingredients containing a high percentage of isomalt to about 143° C. Once all components are melted, the temperature is increased beyond the hard crack stage (e.g., to about 166° C.), and then removed from the heat and the mixture allowed to cool. The various components may be added at certain stages (e.g., they may be added to the isomalt mixture at room temperature, may be added when the mixture reaches 143° C. or 166° C., or may be added at a given temperature during the cooling process).

[0098] Injection molded formulations may, in certain embodiments, be prepared by mixing the components (e.g., a nicotinic compound, a binder, and a polysaccharide filler component) to form a pharmaceutical formulation mixture, injection molding the pharmaceutical formulation mixture (e.g., by compressing the mixture using a compression force of at least about 75,000 kPa or at least about 100,000 kPa), and 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] The method of preparing the formulation may vary, and a particular method of making a particular type of formulation may have to be adapted depending on the composition of a given pharmaceutical composition. For example, if the outer surface layer includes a formulation molded by traditional techniques, the method may require modification so that the formulation can be coated with another formulation. For example, such a formulation may be capable of being wet-sprayed or dry-sprayed onto another surface, or may be capable of being applied to another surface by immersing the surface in the formulation. The method of application may require modification of traditional spray coating techniques depending on the nature of the formulation. For example, to spray coat a lozenge-type formulation onto another formulation, it may be necessary to maintain an elevated temperature of the formulation and spray coating equipment during the process. In certain embodiments, temperature control is important to avoid altering the properties of the other formulation. For example, care must be taken to avoid melting of the molten-type formulation in the core of the pharmaceutical composition during the application of additional layers.

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

[0101] Aspects of the present invention will be more fully illustrated by the following examples, which are set forth to illustrate certain specific aspects of the invention and should not be construed as limiting the invention. EXAMPLES

[0102] Example 1: Preparation of a lozenge-type formulation A nicotinic compound-containing formulation suitable for use as a lozenge-type component of a pharmaceutical composition for oral use is provided by the following process: Isomalt, NaCl and vanillin are mixed in a pot and the temperature of the mixture is allowed to reach 143°C. The mixture is held at 143°C until the isomalt is melted and the temperature is then increased to 166°C. In a separate vessel, nicotine, maltitol syrup, H2O, sucralose and optionally L-lysine are mixed to form a solution. Optionally, in a second separate vessel, water and sodium hydroxide are mixed to form a solution.

[0103] Remove from heat the isomalt mixture and allow to cool to 132° C. Combine remaining ingredients (i.e., nicotine-containing solution and optional sodium hydroxide solution) and optionally add one or more flavorants to the combined solution. Pour combined solution into hot isomalt mixture and mix.

[0104] The resulting mixture is poured into a mold. If the mixture becomes too viscous to pour, it may be heated in a microwave oven using high heat (e.g., for about 7 seconds). Representative pharmaceutical formulation mixtures are listed below. Mixture 1 below does not contain any 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 melt-type formulation a) Meltable preparation 1 A nicotinic compound-containing formulation suitable for use as a meltable component of a pharmaceutical composition for oral use is provided by the following method: Various dry ingredients are prepared, including a filler (isomalt), salt (sodium chloride), sweetener (sucralose), and flavors (vanillin, spray-dried peppermint, spray-dried menthol). All dry ingredients in powder form, along with a nicotinic compound (e.g., nicotine), are added together and thoroughly mixed in a Hobart mixer equipped with a paddle at about 120 rpm for about 3 minutes.

[0109] A lipid material having a melting point of about 38° C. to about 42° C. is prepared (available as 108-24-B from AarhusKarlshamn USA Inc.). The lipid material is a non-hydrogenated lauric coating fat comprising a mixture of palm kernel oil and palm oil. The lipid material is melted in a mixing vessel. While maintaining heat to the mixing vessel with the molten lipid material, the mixed dry formulation is added with mixing, thereby creating a flowable slurry of the nicotinic compound-containing composition having a moisture content of less than about 10 percent. The slurry is placed in a mold to obtain a pharmaceutical composition weighing about 1 gram per piece. The slurry is dried and hardened in ambient air for about 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 is approximately 53.0 parts lipid material, 39.8 parts filler, 0.2 parts nicotine, 0.8 parts salt, 0.7 parts sweetener and 5.5 parts flavoring.

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

[0111] A lipid material having a melting point of about 38°C to about 42°C is prepared (available as 108-24-B from Earl Skarsham USA, Inc.). The lipid material is a non-hydrogenated lauric coating fat comprising a mixture of palm kernel oil and palm oil. The lipid material is melted in a mixing vessel. While maintaining heat to the mixing vessel with the molten lipid material, the mixed dry formulation is added with mixing, thereby creating a flowable slurry of nicotinic compound-containing composition having a moisture content of less than about 10 percent. The slurry is placed in a mold to obtain a pharmaceutical composition weighing about 1 gram per piece. The slurry is dried and allowed to harden in ambient air for about 45 minutes, after which each piece of the molten nicotinic compound-containing formulation is removed from the mold. The mixture of nicotinic compound-containing composition is about 53.0 parts lipid material, 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 meltable component of a pharmaceutical composition for oral use is provided by the following method: Various dry ingredients are prepared, including a filler (isomalt), salt (sodium chloride), sweetener (sucralose), and flavors (vanillin, spray-dried peppermint, spray-dried menthol). All dry ingredients in powder form, along with a nicotinic compound (e.g., nicotine), are added together and thoroughly mixed in a Hobart mixer equipped with a paddle at about 120 rpm for about 3 minutes.

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

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

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

[0116] e) Meltable preparation 5 A nicotinic compound-containing formulation suitable for use as a meltable component of a pharmaceutical composition for oral use is provided by the following method: Various dry ingredients are prepared, including a bulking agent (isomalt), additives (sodium chloride, flour), sweetener (sucralose) and flavoring (vanillin). All dry ingredients, in powder form, along with a nicotinic compound (e.g., nicotine), are added together and thoroughly mixed in a Hobart mixer equipped with a paddle at about 120 rpm for about 3 minutes.

[0117] A lipid material having a melting point of about 38°C to about 42°C is prepared (available as 108-24-B from Earl Skarsham USA, Inc.). The lipid material is a non-hydrogenated lauric coating fat that includes palm kernel oil and palm oil. The lipid material is melted in a mixing vessel. While maintaining heat to the mixing vessel with the molten lipid material, the mixed dry formulation is added with mixing, thereby creating a flowable slurry of the nicotinic compound-containing composition having a moisture content of less than about 10 percent. The slurry is placed in a mold to obtain a nicotinic compound-containing formulation weighing about 1 gram per piece. The slurry is dried and hardened in ambient air for about 45 minutes, after which each piece of the nicotinic compound-containing formulation is removed from the mold. The mixture of nicotinic compound-containing composition is about 53.0 parts lipid material, 45.2 parts filler, 0.2 parts nicotine, 0.8 parts additive, 0.7 parts sweetener, and 0.1 parts flavoring.

[0118] f) Meltable preparation 6 A nicotinic compound-containing formulation suitable for use as a meltable component of a pharmaceutical composition for oral use is provided by the following method: Various dry ingredients are prepared, including a bulking agent (isomalt), additives (sodium chloride, flour), sweetener (sucralose) and flavoring (vanillin). All dry ingredients, in powder form, along with a nicotinic compound (e.g., nicotine), are added together and thoroughly mixed in a Hobart mixer equipped with a paddle at about 120 rpm for about 3 minutes.

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

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

[0121] A lipid material having a melting point of about 38°C to about 42°C is prepared (available as 108-24-B from Earl Skarsham USA, Inc.). The lipid material is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. The lipid material is melted in a mixing vessel using a microwave oven. The molten lipid is slowly added to the dry mixture while stirring. While maintaining heat to the mixing vessel with the molten lipid material, the entire molten lipid component is added to create a flowable slurry of the nicotinic compound-containing composition. The slurry is placed in a mold to obtain a nicotinic compound-containing composition weighing about 1 gram per piece. The slurry is dried and hardened in ambient air for about 45 minutes, after which each piece of the nicotinic compound-containing formulation is removed from the mold. The mixture of nicotinic compound-containing composition is about 53.0 parts lipid material, 45.2 parts filler, 0.2 parts nicotine, 0.8 parts additive, 0.7 parts sweetener, and 0.1 parts flavor.

[0122] Other acceptable excipients for melt 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 formulation 1 A nicotinic compound-containing formulation suitable for use as a starch-formed component of a pharmaceutical composition for oral use is provided by the following process: An aqueous mixture is prepared. A binder material (gum arabic) is hydrated with water and the hydrated gum is then mixed in a high shear mixer with a filler (isomalt), additional filler (maltitol; available as LYCASIN from Roquette Freres SA) and salt to form an aqueous mixture. The aqueous mixture is 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 nicotinic compound-containing composition mixture is about 99.3 parts aqueous mixture, 0.2 parts nicotine, and 0.5 parts sucralose.

[0125] The nicotinic compound-containing composition is heated to about 54° C. and then placed into a starch mold. The nicotinic compound-containing composition is left in the starch mold at about 60° C. for about 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 allowed to harden at ambient room temperature for about 24 hours.

[0126] b) Starch formulation 2 A nicotinic compound-containing formulation suitable for use as a starch-formed component of a pharmaceutical composition for oral use is provided by the following process: An aqueous mixture is prepared by hydrating a binder material (gum arabic) with water and then adding sodium hydroxide to adjust the mixture to a pH of 8.0. 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 nicotinic compound-containing composition mixture is 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 into the starch mold at a temperature of about 71° C. (the placing temperature should be above about 66° C.). The nicotinic compound-containing composition is left in the starch mold at about 60° C. for about 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 allowed to harden at ambient room temperature for about 24 hours.

[0128] Other acceptable excipients for starch molded formulations are provided, for example, in U.S. Application No. 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 a pharmaceutical composition for oral use is provided by mixing and heating a humectant (available as HYSTAR 3375 from Corn Products International), an emulsifier (available as DUR-EM117 from Loders Croklaan), corn syrup, glycerin and flavorings to form a liquid mixture.

[0130] Nicotine is mixed with salt, sucralose, a binder material (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 material and polydextrose powder, where the ingredients are mixed in a Hobart Mixer (Model N-50) at about 120 rpm for about 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 ingredients into the dry ingredients. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in a Hobart Mixer to form a powder granule. The nicotinic compound-containing composition mixture is 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 mold and compressed at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel that is filled with the nicotinic compound-containing composition and then compressed by mating with a hydraulic press unit (Wabach Hydraulic Press, Model 12-102T, Serial 2201). After cooling at ambient temperature for about 60 minutes, the nicotinic compound-containing composition is removed from the injection 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 mixing and heating a bulking agent (maltitol; available as Lycasin from Roquette Frères SA), an emulsifier (available as DUR-EM117 from Roders Cloqueran), corn syrup, glycerin and flavorings to form a liquid mixture.

[0133] The nicotine is mixed with salt, sucralose, a binder material (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 material and polysaccharide, where the ingredients are mixed in a Hobart mixer (Model N-50) at about 120 rpm for about 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 ingredients into the dry ingredients. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in a Hobart mixer to form a powder granule. The mixture of nicotinic compound-containing compositions is 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 mold and compressed at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel that is filled with the nicotinic compound-containing composition and then mated and compressed with a hydraulic press unit (Wabuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, the nicotinic compound-containing composition is removed from the injection mold.

[0135] c) Injection Molding Formulation 3 A nicotinic compound-containing composition suitable for use as a pharmaceutical composition for oral use is provided by mixing and heating a bulking agent (maltitol; available as Lycasin from Roquette Frères SA), an emulsifier (available as DUR-EM117 from Roders Cloqueran), corn syrup, glycerin and flavorings to form a liquid mixture.

[0136] Nicotine is mixed with salt, sucralose, binder material (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 material and polysaccharide, where the ingredients are mixed in a Hobart mixer (Model N-50) at about 120 rpm for about 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 ingredients into the dry ingredients. The nicotinic compound-containing composition is extruded from the grinder. After extrusion, the nicotinic compound-containing composition is placed in a Hobart mixer to form a powder granule. The mixture of nicotinic compound-containing compositions is 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 mold and compressed at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel that is filled with the nicotinic compound-containing composition and then mated and compressed with a hydraulic press unit (Wabuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, the nicotinic compound-containing composition is removed from the injection 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 mixing and heating a humectant (available as HYSTAR 3375 from Corn Products International), an emulsifier (available as DUR-EM117 from Roders-Croquelant), corn syrup, glycerin and flavorings to form a liquid mixture.

[0139] Nicotine is mixed with salt, sucralose, binder material (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 material and polydextrose powder, where the ingredients are mixed in a Hobart mixer (Model N-50) at about 120 rpm for about 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 ingredients into the dry ingredients. 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 a powder granule. The nicotinic compound-containing composition mixture is 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 mold and compressed at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel that is filled with the nicotinic compound-containing composition and then mated and compressed with a hydraulic press unit (Wabuck hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, the nicotinic compound-containing composition is removed from the injection mold. e) Injection Molded Formulations 5 A nicotinic compound-containing composition suitable for use as a pharmaceutical composition for oral use is provided by mixing and heating a humectant (available as HYSTAR 3375 from Corn Products International), an emulsifier (available as DUR-EM117 from Roders-Croquelant), corn syrup, glycerin and flavorings to form a liquid mixture.

[0141] Nicotine is mixed with salt, sucralose, binder material (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 material and polydextrose powder, where the ingredients are mixed in a Hobart mixer (Model N-50) at about 120 rpm for about 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 ingredients into the dry ingredients. 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 a powder granule. The nicotinic compound-containing composition mixture is 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 mold and compressed at approximately 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel that is filled with the nicotinic compound-containing composition and then mated and compressed with a hydraulic press unit (Wabuck 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 mold.

[0143] Other acceptable excipients for injection molding type formulations are provided, for example, in U.S. Patent Application No. 12 / 957,838 to Cantrell et al., filed December 1, 2010, 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 of a pharmaceutical composition for oral use is provided by the following method: An aqueous mixture is prepared. Nicotine is added and a binder material (gum arabic) is hydrated with water to form an aqueous mixture. The aqueous mixture is about 49.7 parts binder, about 0.6 parts nicotine, and about 49.7 parts water. The aqueous mixture is mixed with salt (NaCl), buffer (sodium hydroxide), sweetener (sucralose), glycerin and emulsifier (sunflower lecithin) and the added ingredients are dissolved therein. The mixture is heated to about 49°C. The heated mixture is combined with a lipid material (available as 108-24-B from Earl Skarshamn, Inc., USA) heated until melted and flavorings having a melting point of about 38°C to about 42°C. The nicotinic compound-containing composition mixture is about 36 parts aqueous mixture, 24 parts lipid material, 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] The nicotinic compound-containing composition is formed in a variety of ways. In one embodiment, it is placed in a mold, left in the mold at ambient conditions until dry, and then removed from the mold. In another embodiment, it is poured onto a table top, air dried to a semi-damp state, and formed into the desired shape using a drop roller.

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

[0147] The resulting formulation can be cast into a sheet (e.g., by casting a sheet onto a stainless steel plate) or can be dip- or spray-coated onto the composition described above in this example. If the formulation is cast into a sheet, it can be cut (e.g., with a casting knife) and applied as a sandwich coating onto the composition described above in this example. If the formulation is dip- or spray-coated, it is maintained at a temperature above about 66° C., applied as a liquid, and then cooled until hardened.

[0148] Example 7: Preparation of a two-layered product a) Lozenge / meltable A lozenge formulation is prepared as described in Example 1, poured into a mold, and cooled. A melt formulation is prepared as described in Example 2. However, instead of pouring the flowable slurry into a mold, the flowable slurry is applied directly to the surface of the cooled lozenge formulation. For example, a molded lozenge formulation is dipped into the flowable slurry and allowed to dry and harden at room temperature to provide a two-layered product comprising a lozenge core and a melt coating.

[0149] b) Lozenges / chewables A lozenge formulation is prepared, poured into a mold, and cooled as described in Example 1. A chewable formulation is prepared as described in Example 5. The formulation is poured onto a table top, air dried to a semi-moist state, and formed around the surface of the lozenge formulation to provide a two-layered product comprising a lozenge core and a chewable coating.

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

[0151] d) Meltable / Lozenges The melt formulation is prepared as described in Example 2. The lozenge formulation is prepared as described in Example 1, except that the hot mixture is applied directly to the surface of the melt formulation, rather than poured into a mold. For example, the hot mixture can be introduced into a spray coating device adapted to maintain a temperature of about 132°C, and sprayed onto the surface of the cooled melt formulation. As noted in Example 1, the mixture must be kept at an elevated temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape. Because the melt formulation may exhibit some melting at such elevated temperatures, steps must be taken to avoid or limit melting of the melt formulation during application of the lozenge formulation. For example, the melt formulation may be frozen prior to application of the lozenge formulation to limit the extent of melting.

[0152] e) Meltable / hard coating materials A melt-form 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 sheets, cut, and applied directly to the surface of the melt-form product as a sandwich coating to provide a two-layered product containing a melt-form core and a hard-coated coating.

[0153] f) Starch moulding / melting properties A starch mold formulation is prepared as described in Example 3, poured into a mold, and cooled. A melt formulation is prepared as described in Example 2. However, instead of pouring the flowable slurry into a mold, the flowable slurry is applied directly to the surface of the cooled starch mold formulation. For example, the starch mold formulation is immersed in the flowable slurry and allowed to dry and harden at room temperature to provide a two-layered product that includes a starch mold core and a melt coating.

[0154] g) Starch Formings / Lozenges A starch mold formulation is prepared as described in Example 3, poured into a mold, and cooled. A lozenge formulation is prepared as described in Example 1, except that the hot mixture is applied directly to the surface of the starch mold formulation, rather than poured into a mold. For example, the hot mixture can be introduced into a spray coating device adapted to maintain a temperature of about 132°C, and sprayed onto the surface of the cooled starch mold formulation. As noted 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 / melt properties An injection molded formulation is prepared as described in Example 4, injection molded to the desired size and shape, and cooled. A melt molded formulation is prepared as described in Example 2. However, instead of pouring the flowable slurry into a mold, the flowable slurry is applied directly to the surface of the cooled injection molded formulation. For example, an injection molded formulation is immersed in the flowable slurry, dried and cured at room temperature to provide a two-layered product that includes an injection molded core and a melt molded coating.

[0156] i) Injection molding / lozenges An injection-molded formulation is prepared as described in Example 4, injection molded to the desired size and shape, and cooled. A lozenge-shaped formulation is prepared as described in Example 1, except that the hot mixture is applied directly to the surface of the injection-molded formulation rather than poured into a mold. For example, the hot mixture can be introduced into a spray coating device adapted to maintain a temperature of about 132°C and sprayed onto the surface of the cooled injection-molded formulation. As noted in Example 1, the mixture must be kept at an elevated temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape.

[0157] Example 8: Preparation of a Three-Layered Product a) Lozenge / meltable / hard coating A two-layered product comprising a lozenge core and a melt-type coating 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 applied directly to the surface of the two-layered lozenge / meltable composition as a sandwich coating to provide a three-layered product comprising a lozenge core, a melt-type first coating, and a hard-coated second coating.

[0158] b) Starch Forming / Lozenge / Meltable A two-layered product comprising a starch molded core and a lozenge-shaped coating is prepared as described above in Example 7g. A melt-type formulation is prepared as described in Example 2. However, instead of pouring the flowable slurry into a mold, it is applied directly to the surface of the cooled two-layered starch molded / lozenge composition. For example, the two-layered composition is immersed in the flowable slurry, and dried and hardened at room temperature to provide a three-layered product comprising a starch molded core, a lozenge-shaped first coating and a melt-type second coating.

[0159] Utilizing the teachings set forth in the foregoing specification, numerous modifications and other embodiments of the present invention will occur to those skilled in the art to which the present invention pertains. It is understood, therefore, that the 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 appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. 1. A multi-layered pharmaceutical composition comprising two or more formulations having different organoleptic properties, wherein said formulations comprise: 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 meltable formulation comprising a lipid having a melting point of about 36° C. to about 45° C.; iii) Pastille formulations containing polysaccharide fillers; iv) pastille formulations containing sugar alcohol and natural gum binder components; 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) hard-coated formulations comprising a binder, a sugar substitute and a sugar alcohol syrup, wherein at least one formulation further comprises one or more nicotinic compounds.

2. 10. The multi-layered pharmaceutical composition of claim 1, wherein all formulations of said multi-layered pharmaceutical composition comprise one or more nicotinic compounds.

3. 10. The multi-layered pharmaceutical composition of claim 1, wherein the one or more nicotinic compounds are independently in the form of a free base, a salt, a complex or a solvate.

4. 4. The multi-layered pharmaceutical composition of claim 3, wherein the one or more nicotinic compounds comprises nicotine polacrilex.

5. 10. The multi-layered pharmaceutical composition of claim 1, wherein said one or more nicotinic compounds comprise a nicotinic compound adsorbed onto a porous particulate carrier.

6. 6. The multi-layered pharmaceutical composition of claim 5, wherein the porous particulate carrier comprises microcrystalline cellulose.

7. 10. The multi-layered pharmaceutical composition of claim 1, wherein said multi-layered pharmaceutical composition comprises between 2 and 10 layers.

8. 8. The multi-layered pharmaceutical composition of claim 7, wherein said multi-layered pharmaceutical composition comprises between 2 and 5 layers.

9. 2. The multi-layered 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 coated with one or more discontinuous layers to form a layered or side-by-side arrangement of two or more formulations.

10. 2. The multi-layered pharmaceutical composition of claim 1, wherein the sugar substitute of the soluble formulation comprises isomalt and the sugar alcohol syrup of the soluble formulation comprises maltitol syrup.

11. 10. The multi-layered pharmaceutical composition of claim 1, wherein the soluble formulation comprises a nicotinic compound; a sugar substitute in an amount of about 80% by weight or more; and a sugar alcohol syrup.

12. 10. The multi-layered pharmaceutical composition of claim 1, wherein the lipid of the meltable formulation has a melting point of about 38°C to about 41°C.

13. 10. The multi-layered pharmaceutical composition of claim 1, wherein the meltable formulation comprises 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.

14. 10. The multi-layered pharmaceutical composition of claim 1, comprising: said meltable formulation 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.

15. 2. The multi-layered pharmaceutical composition of claim 1, wherein the polysaccharide filler component of the pastille formulation iii) comprises polydextrose.

16. 10. The multi-layered pharmaceutical composition of claim 1, wherein the polysaccharide filler component of the pastille formulation iii) is present in an amount of about 10 percent to about 25 percent by weight of the pastille formulation on a dry weight basis.

17. 2. The multi-layered pharmaceutical composition of claim 1, wherein the pastille constituents iii) comprise a nicotinic compound; a polysaccharide filler in an amount of about 10% by weight or more; a humectant 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.

18. 2. The multi-layered pharmaceutical composition of claim 1, wherein the pastille composition iv) comprises a nicotinic compound; a humectant 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 binder in an amount of about 10% by weight or more.

19. 2. The multi-layered pharmaceutical composition of claim 1, wherein the pastille composition iv) comprises a nicotinic compound; a humectant 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 binder in an amount of about 10% by weight or more.

20. 10. The multi-layered pharmaceutical composition of claim 1, wherein the binder material of the chewable dosage form is gum arabic.

21. 10. The multi-layered pharmaceutical composition of claim 1, wherein the chewable dosage form 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.

22. 10. The multi-layered pharmaceutical composition of claim 1, wherein the binder of the hard coat formulation comprises carboxymethylcellulose.

23. 10. The multi-layered pharmaceutical composition of claim 1, wherein the sugar substitute of the hard coat formulation comprises isomalt.

24. 10. The multi-layered pharmaceutical composition of claim 1, wherein the hard coat formulation comprises a nicotinic compound; 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.

25. 2. The multi-layered pharmaceutical composition of claim 1, wherein the product comprises: 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 ii) and vi); formulations iii) and iv); formulations iii) and v); formulations iii) and vi); formulations iv) and v); formulations iv) and vi); formulations i), ii) and iii); formulations i), ii) and iv); formulations i), ii) and v); formulations i), ii) and vi); formulations i), ii) and iii). and iv); formulations i), iii) and v); formulations i), iii) and vi); formulations i), iv) and v); formulations i), iv) and vi); formulations i), v) and vi); formulations ii), iii) and iv); formulations ii), iii) and v); formulations ii), iv) and vi); formulations ii), iv) and v); formulations ii), iv) and vi); formulations ii), v) and vi); formulations iii), iv) and v); formulations iii), iv) and vi); and formulations iii), v) and vi).

26. 1. A method for preparing a multi-layered pharmaceutical composition comprising: preparing a first formulation by combining one or more nicotinic compounds with one or more ingredients selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorants, sweeteners, emulsifiers, disintegration aids, humectants, buffers, and mixtures thereof to form a first nicotinic compound-containing mixture, and forming said first nicotinic compound-containing mixture into a desired form; preparing a second formulation by combining one or more nicotinic compounds with one or more ingredients selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorants, sweeteners, emulsifiers, disintegration aids, humectants, buffers, and mixtures thereof to form a second nicotinic compound-containing mixture and forming said second nicotinic compound-containing mixture into a desired form; and applying said second formulation to said first formulation, wherein said formulation comprises: 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 meltable formulation comprising a lipid having a melting point of about 36° C. to about 45° C.; iii) Pastille formulations containing polysaccharide fillers; iv) pastille formulations containing sugar alcohol and natural gum binder components; 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) hard coat formulations comprising binders, sugar substitutes and sugar alcohol syrups.

27. 27. The method of claim 26, wherein the first formulation is formed into a desired shape by pouring the first nicotinic compound-containing mixture into a mold or by injection molding the first nicotinic compound-containing mixture.

28. 27. The method of claim 26, wherein the second formulation is applied by spray coating, dip coating, or by forming the second formulation into a sheet which is applied to the first formulation as a sandwich coating.

29. 30. The method of claim 28, wherein the spray coating or dip coating is carried out at a temperature at which the first formulation remains substantially intact.

30. 27. The method of claim 26, further comprising applying a third formulation over the second formulation as a coating.

31. 31. The method of claim 30, wherein the third formulation is applied by spray coating, dip coating, or by forming the third formulation into a sheet which is applied to the second formulation as a sandwich coating.

32. 26. A method for treating a human subject having a condition, disease or disorder responsive to stimulation of a nicotinic acetylcholinesteric receptor, comprising orally administering to the human subject an effective amount of a pharmaceutical composition according to any one of claims 1 to 25.

33. 33. The method of claim 32, wherein the administering step comprises administering the pharmaceutical composition to a human subject as a smoking cessation aid.

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