Multi-layer nicotine-containing pharmaceutical composition

Abstract

To provide an oral administration formulation containing a nicotinic compound, having various organoleptic properties.SOLUTION: There is provided a multilayered nicotine-containing pharmaceutical composition comprising two or more formulations having different organoleptic properties, wherein the formulations are selected from the group consisting of: i) a dissolvable formulation comprising a sugar substitute and a sugar alcohol syrup in an amount of at least approximately 80 wt.%; ii) a meltable formulation comprising a lipid having a melting point of approximately 36 to 45°C; (iii) a pastel formulation comprising a polysaccharide filler; (iv) a pastel formulation comprising a sugar alcohol and a natural gum binder component; v) a chewable formulation comprising a binder, an emulsifier and a lipid having a melting point of approximately 36 to 45°C; and vi) a hard coating formulation comprising a binder, a sugar substitute and a sugar alcohol syrup; wherein at least one formulation further comprises one or more nicotinic compounds.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Symptoms, diseases or disorders of the central nervous system (CNS) can be drug-induced; can be caused by genetic factors, infections or psychological trauma; or can be of unknown cause. These include neuropsychiatric disorders, neurological disorders and mental diseases; including neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive-emotional disorders. The clinical pathologies of multiple CNS symptoms, diseases or disorders are due to 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 acetylcholine-activated receptors (nAChRs). Subtypes of nAChRs are present in both the CNS and the peripheral nervous system (PNS), but the distribution of subtypes is non-uniform. For example, certain subtypes are abundant in the brains of vertebrates, others are abundant in autonomic ganglia, and still others are abundant at the neuromuscular junction. Activation of nAChRs by nicotinic compounds leads to neurotransmitter release. See, for example, Dwoskin et al., Exp. Opin. Ther. Patents, 10:1561-1581 (2000); Schmitt et al., Annual Reports in Med. Chem. 35:41-51 (2000); Huang et al., J. Am. Chem. Soc., 127:14401-14414 (2006); Arneric et al., Biochem. Pharmacol., 74:1092-1101 (2007) and Millar, Biochem. Pharmacol., 78:766-776 (2009), which are incorporated herein by reference.

[0004] It has been proposed that the administration of nicotine and other nicotinic compounds can lead to various pharmacological effects. For example, see U.S. Patent No. 5,583,140 to Bencherif et al.; No. 5,723,477 to McDonald et al.; No. 7,001,900 to Jacobsen et al.; No. 7,135,484 to Dart et al. and No. 7,214,686 to Bencherif et al.; and U.S. Patent Publication No. 2010 / 0004451 to Ahmad et al., which are hereby incorporated by reference. As a result, it has been proposed that nicotine and other nicotinic compounds can be useful in the treatment of a wide variety of symptoms, diseases and disorders, including those that affect the CNS. In addition, the administration of nicotine and nicotinic compounds has been proposed for the treatment of certain other symptoms, diseases and disorders. For example, see 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 hereby incorporated by reference. Further, the administration of nicotine has been utilized in attempts to help tobacco smokers quit smoking (i.e., as smoking cessation aids). For example, nicotine is the active ingredient in various types of so-called "nicotine replacement therapy" or "NRT" products. See, for example, the background art described in U.S. Patent Application No. 13 / 278,877 to Borschke et al., filed October 21, 2011, which is hereby incorporated 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 lozenge, tablet and microtab-type products are commercially available, for example, under the trade names of "Commit®", "Nicorette®", "Nicotinell®" and "NiQuitin®". See, for example, U.S. Patent No. 5,110,605 to Acharya; No. 5,733,574 to Dam; No. 6,280,761 to Santus; No. 6,676,959 to Andersson et al.; and No. 6,248,760 to Wilhelmsen; as well as U.S. Patent Publication No. 2001 / 0016593 to Wilhelmsen, which are hereby incorporated 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

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

[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 composition containing a nicotinic compound intended for therapeutic use. The composition is typically in a pharmaceutically acceptable form adapted for oral delivery of the composition. The composition generally comprises two or more different formulations having different properties that can be arranged in various ways. The different formulations included in the product may be provided, for example, in a multilayered form. For example, the composition containing the nicotinic compound may include an inner core of one formulation and one or more coating materials of another formulation, and the coating material may be a complete or partial coating material. Thus, it is also possible to provide a new composition by combining formulations having different functional properties within the same product. In certain embodiments, such multilayered compositions enable a controlled delivery profile during use. For example, a particular formulation may provide rapid release of the nicotinic compound contained therein, while another formulation may provide prolonged release of the nicotinic compound contained therein.

[0010] In one aspect of the present invention, there is provided a multilayered pharmaceutical composition comprising two or more formulations having different functional 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 fusible formulation comprising a lipid having a melting point of about 36°C to about 45°C; (iii) a paste formulation comprising a polysaccharide filler; (iv) a paste 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 coating 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 of the formulations of the multilayered pharmaceutical composition may contain one or more nicotinic compounds, which may be the same or different.

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

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

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

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

[0015] Pastille formulation iii) may, in certain embodiments if present, 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 pastille formulation on a dry weight basis. In one exemplary embodiment, pastille 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, pastille composition iv) includes a nicotinic compound; a humectant in an amount of about 0.5 weight percent or more; a sugar alcohol filler in an amount of about 20 weight percent or more; and a natural gum binder in an amount of about 10% or more.

[0017] Chewable formulation may, in certain embodiments if present, 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 weight percent or more, and a lipid having a melting point of about 36°C to about 45°C in an amount of about 15 weight percent or more.

[0018] Hard-coated formulation may, in certain embodiments if present, include carboxymethylcellulose as a binder component. The hard-coated formulation may, in certain embodiments if present, include isomalt as a sugar substitute. In one exemplary embodiment, the hard-coated formulation includes a nicotinic compound; a binder; a sugar substitute in an amount of about 20 weight percent or more; and a sugar alcohol syrup in an amount of about 5 weight percent or more.

[0019] Any combination of two or more formulations described herein may be used within the multi-layered pharmaceutical composition of the present invention. For example, the product may, in certain embodiments, comprise two different formulations, where the formulations are: formulation i) and ii), formulation i) and iii), formulation i) and iv), formulation i) and v), formulation i) and vi), formulation ii) and iii), formulation ii) and iv), formulation ii) and v), formulation ii) and vi), formulation iii) and iv), formulation iii) and v), formulation iii) and vi), formulation iv) and v), or formulation iv) and vi), where the formulations may be arranged in any manner. In relation to the foregoing, the listed formulations are intended to include their permutations, and the formulations may each be constructed in various ways. For example, "formulation i) and ii)" may also include formulation ii) and formulation i), and "formulation iv) and vi)" may also include formulation vi) and formulation iv). That is, "formulation i) and ii)" is intended to encompass embodiments where formulation i) is the core and formulation ii) is a partial or complete layer thereon, and embodiments where formulation ii) is the core and formulation i) is a partial or complete layer thereon.

[0020] In certain embodiments, combinations of three or more formulations described herein may be used within the multilayer pharmaceutical compositions of the present invention. In certain embodiments, the product may comprise 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), 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), 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 their permutations, and the formulations may each be constructed in various ways. For example, "formulations i), ii) and iii)" may also include formulations i), iii), and ii); formulations ii), iii) and i); formulations ii), i) and iii); formulations iii), i) and ii), and formulations iii), ii) and i).That is, "formulations i), ii) and iii)" are intended to include embodiments where 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); embodiments where 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); embodiments where 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); embodiments where 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); embodiments where 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 where 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 present invention, there is provided a method for preparing a multilayer pharmaceutical composition, the method comprising: forming a first nicotine-containing compound mixture by combining a nicotine compound with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavoring agents, sweetening agents, emulsifying agents, disintegration aids, wetting agents, buffering agents and mixtures thereof, and preparing a first formulation by forming the first nicotine-containing compound mixture into a desired form; forming a second nicotine-containing compound mixture by combining a nicotine compound with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavoring agents, sweetening agents, emulsifying agents, disintegration aids, wetting agents, buffering agents and mixtures thereof, and preparing a second formulation by forming the second nicotine-containing compound mixture into a desired form; and applying the second formulation to the first formulation, wherein the formulations are 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 shape by pouring or otherwise introducing the first nicotine-containing compound mixture into a mold, injection molding the first nicotine-containing compound mixture, or by 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 material. The spray coating or dip coating can be carried out at a temperature at which the first formulation is maintained substantially in its original form. In some embodiments, the method further includes applying a third formulation as a coating material over the second formulation. The third nicotine-containing formulation can be applied, for example, by spray coating, dip coating, or by forming the third nicotine-containing formulation into a sheet that is applied to the second formulation as a sandwich coating material.

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

[0024] The invention will now be described more fully hereinafter. However, the invention can be embodied in many different forms and should not be construed as 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 herein and in the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The term "percent dry weight" or "dry weight basis" refers to the weight based on the dried components (i.e., all components excluding water).

[0025] According to the present invention, there is provided a pharmaceutical composition of a nicotinic compound comprising at least two different formulations. Specifically, such a composition generally comprises formulations having various functional properties, such as a multi-layered pharmaceutical composition in which two or more formulations are provided as a multi-layer pharmaceutical composition. Each formulation in the nicotinic compound-containing composition may contain one or more nicotinic compounds. At least one formulation contained in the nicotinic compound-containing composition contains a nicotinic compound, but in certain embodiments, one or more other formulations (e.g., one or more layers) in the composition may essentially (including completely) not contain a nicotinic compound. The present invention further provides a method for preparing a multi-layered nicotinic compound-containing pharmaceutical composition.

[0026] The structure of a multilayer pharmaceutical composition is generally represented by the term "layered" as a structure in which a core is covered by one or more coating layers that can be partial or complete layers. In other words, each coating layer may completely cover the core or the previous layer, or only cover a portion thereof. The core can be in any form such as a flat sheet, or a given shape (e.g., square, circular, oval, elliptical, or rectangular), or a structure of a shape that can generally be described as spherical, cylindrical (ranging from the general shape of a flat disk to a relatively long and slender rod), helical, ellipsoidal, square, rectangular, etc. In some embodiments, the core and / or the multilayer pharmaceutical composition can take the form of beads, granules, capsules, films, strips, gels, etc. The shape of the composition can, in certain specific embodiments, be similar to various types of products such as pills, tablets, lozenges, capsules, and capsule-shaped tablets. Note that a side-by-side configuration is also included within the scope of the present invention. For example, in such a configuration, the composition includes two layers adhered to each other along one surface, and optionally additional layers adhered to one or both of those two layers. The number of layers constituting the pharmaceutical composition can vary, but is usually from about 2 layers to about 10 layers, such as 2 layers, 3 layers, 4 layers, 5 layers, 6 layers, 7 layers, 8 layers, 9 layers, or 10 layers. Although the present pharmaceutical composition is described herein as "layered" or "multilayered", those layers may not be distinct layers of various formulations having a clear boundary between layers. For example, there may be some degree of mixing including adjacent layers between the formulations of the product. However, in a preferred embodiment, the present pharmaceutical composition retains the characteristics and behaviors of the individual formulations.

[0027] The organoleptic properties of one or more formulations that make up a multi-layered pharmaceutical composition are generally diverse. As used herein, the term "organoleptic" means any aspect experienced by the user's five senses that may be associated with a pharmaceutical composition formulation. Organoleptic properties include, but are not limited to, taste, odor, texture (e.g., mouthfeel, solubility / melting, hardness, elasticity, crunchiness, chewiness). For example, the formulations within a given multi-layered pharmaceutical composition may, in certain embodiments, have organoleptic properties independently selected from hard, dissolving, crushable, chewy, melting, crispy, and combinations thereof. Certain formulations useful as components of the pharmaceutical compositions according to the present invention may be described as lozenge-like or paste-like. The resulting multi-layered pharmaceutical composition may, in certain embodiments, include a unique combination of organoleptic properties as a result of a combination of formulations having 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 when placed in the user's mouth, the user first experiences a dissolving action and then a melting action. It should be noted that this specification encompasses numerous other combinations of formulations that result in various combinations of organoleptic properties.

[0028] As used herein, the terms "dissolve", "dissolving", and "dissolvable" refer to formulations having water-soluble components that interact with the moisture in the oral cavity and transfer into solution, thereby causing progressive 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 typically occurs when a substance (e.g., a formulation within a pharmaceutical composition) changes from a solid to a liquid upon the application of heat. With respect to the pharmaceutical compositions of the present invention, the application of heat is brought about by the internal temperature of the user's mouth. Thus, the term "meltable" refers to a formulation that is capable of liquefying in the user's mouth when the product changes phase from a solid to a liquid, and that differentiates formulations and / or products that simply disintegrate in the oral cavity due to loss of cohesiveness within the formulation, or formulations that simply dissolve in the oral cavity when the water-soluble components of the formulation interact with moisture.

[0030] As used herein, the term "pastille" refers to a soluble oral formulation in which the final product is a hardened solid gel, produced by solidifying a liquid composition or a gel-like composition, e.g., a composition containing a gelling agent or a binder. In certain embodiments, such formulations are characterized by a degree of cohesiveness sufficient to resist mild chewing action in the oral cavity without rapid disintegration. The pastille-like formulations of the present disclosure generally do not exhibit the very deformable chewability seen in conventional chewing gums.

[0031] As used herein, "chewable" means having a degree of cohesiveness that is higher than that of a pastille but generally lower than that of a gum, and being deformable in the mouth. Such formulations may be characterized by a degree of cohesiveness sufficient to resist a greater degree of chewing than a pastille. However, such compositions generally disintegrate in the oral cavity (unlike gum formulations).

[0032] As used herein, "coating-like" means a layer that exhibits a certain 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 can be easily dissolved in the user's mouth. Although referred to herein as a "coating", it should be noted that this layer does not necessarily include the outer layer of the pharmaceutical composition and may include an inner layer of the product.

[0033] One or more "nicotinic compounds" within the pharmaceutical formulations of the present invention are natural nicotine or synthetic nicotine extracted from plant-based raw materials, are at least partially purified, and mean compounds that are not contained within a plant structure such as a tobacco leaf. Nicotine is most preferably one that occurs naturally and is obtained as an extract from a species of the genus Nicotiana (e.g., tobacco). Exemplary various tobaccos and methods of processing tobacco are shown in the specification of U.S. Patent Application No. 13 / 240,500 to Holton, Jr. et al., filed on September 22, 2011, which is incorporated herein by reference. Also refer to the specifications of U.S. Patent Application Publication No. 2011 / 0268809 to Brinkley et al., U.S. Patent Application Publication No. 2011 / 0274628 to Borschke, both of which are incorporated herein by reference in their entirety, and the nicotine-containing compositions shown in the specification of U.S. Patent Application No. 13 / 278,877 to Borschke et al., filed on October 21, 2011.

[0034] Nicotine can have an enantiomeric form of 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 that is composed primarily or mostly 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 essentially pure form. A very preferred nicotine used has a purity higher than about 95 percent by weight, more preferably higher than about 98 percent by weight, and most preferably higher than about 99 percent by weight. Despite the fact that nicotine can be extracted from species of the genus Nicotiana, it is highly preferred that nicotine (and the compositions and products produced according to the present invention) be substantially or essentially free of other components of tobacco.

[0035] In embodiments where nicotine is derived from plants of the genus Nicotiana, the plant or a part of the plant can be subjected to various types of processing conditions to supply nicotine. For example, the components can be separated from each other, and in other cases fractionated into classes of chemicals or mixtures of individual compounds. Typical separation processes can include one or more processing steps (e.g., solvent extraction using a polar solvent, an organic solvent, or a supercritical fluid), chromatography, distillation, filtration, recrystallization, and / or partitioning between solvents. Exemplary solvents or carriers for extraction and separation include water, alcohols (e.g., methanol or ethanol), hydrocarbons (e.g., heptane and hexane), diethyl ether, methylene chloride, and supercritical carbon dioxide.Techniques that are useful examples for the extraction of components from species of the genus Nicotiana are incorporated herein by reference in their entirety: U.S. Patent No. 4,144,895 to Fiore; U.S. Patent No. 4,150,677 to Osborne, Jr. et al.; U.S. Patent No. 4,267,847 to Reid; U.S. Patent No. 4,289,147 to Wildman et al.; U.S. Patent No. 4,351,346 to Brummer et al.; U.S. Patent No. 4,359,059 to Brummer et al.; U.S. Patent No. 4,506,682 to Muller; U.S. Patent No. 4,589,428 to Keritsis; U.S. Patent No. 4,605,016 to Soga et al.; U.S. Patent No. 4,716,911 to Poulose et al.; U.S. Patent No. 4,727,889 to Niven, Jr. et al.; U.S. Patent No. 4,887,618 to Bernasek et al.; U.S. Patent No. 4,941,484 to Clapp et al.; U.S. Patent No. 4,967,771 to Fagg et al.; U.S. Patent No. 4,986,286 to Roberts et al.; U.S. Patent No. 5,005,593 to Fagg et al.; U.S. Patent No. 5,018,540 to Grubbs et al.; U.S. Patent No. 5,060,669 to White et al.; U.S. Patent No. 5,065,775 to Fagg; U.S. Patent No. 5,074,319 to White et al.; U.S. Patent No. 5,099,862 to White et al.; U.S. Patent No. 5,121,757 to White et al.; U.S. Patent No. 5,131,414 to Fagg; U.S. Patent No. 5,131,415 to Munoz et al.; U.S. Patent No. 5,148,819 to Fagg; U.S. Patent No. 5,197,494 to Kramer; U.S. Patent No. 5,230,354 to Smith et al.; U.S. Patent No. 5,234,008 to Fagg; U.S. Patent No. 5,243,999 to Smith; U.S. Patent No. 5,301,694 to Raymond et al.; U.S. Patent No. 5,318,050 to Gonzalez-Parra et al.; U.S. Patent No. 5,343,879 to Teague; U.S. Patent No. 5,360,022 to Newton; U.S. Patent No. 5,435,325 to Clapp et al.; U.S. Patent No. 5,445,169 to Brinkley et al.; U.S. Patent No. 6,131,584 to Lauterbach; U.S. Patent No. 6,298,859 to Kierulff et al.; U.S. Patent No. 6,772,767 to Mua; and U.S. Patent No. 7,337,782 to Thompson.Reference is also made to the various separation techniques shown 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 parts of the plants can be subjected to the various treatments shown 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, (The Royal Society of Chemistry, UK) (1999); Sahraoui et al., J. Chrom., 1210, 229-233 (2008); and U.S. Patent No. 5,301,694 to Raymond et al., all of which are incorporated herein by reference.

[0036] In certain embodiments, the isolation of nicotine from plants of the genus Nicotiana involves removing high molecular weight constituents from the tobacco extract. In certain embodiments, high molecular weight constituents 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 material. The ultrafiltration process is typically applied to tobacco material in the form of a tobacco extract (e.g., an aqueous tobacco extract). In ultrafiltration, the material to be filtered is contacted with a semi-permeable membrane as described in more detail in U.S. Patent Application No. 13 / 240,500 to Holton, Jr. et al., filed September 22, 2011, 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 transparency.

[0038] Commercially available ultrafiltration systems are readily available and can be used in some embodiments for the ultrafiltration of tobacco extracts. For example, commercial suppliers such as Millipore, Spectrum® Labs, Pall Corporation, Whatman®, Porrex 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), and Microza filters and Centramate,™ tangential flow filtration membrane cassettes, Centrasette™ tangential flow filtration membrane cassettes, Maximate™ tangential flow filtration membrane cassettes, and Maxisette™ tangential flow filtration membrane cassettes. Commercially available filtration systems include, but are not limited to, Millipore's Labscale™ tangential flow filtration (TFF) system and Spectrum® Labs' KrosFlo® tangential flow filtration system and MiniKros® tangential flow filtration system.

[0039] Filters and / or membranes that may be useful in accordance with the present invention include those having a molecular weight cut-off 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 having different (typically decreasing) molecular weight cut-offs. Any number of filters and / or membranes can be used successively in accordance with the present invention. For example, a first filtration can be performed using a 50,000 Da molecular weight cut-off filter, and a second filtration can be performed using a 5,000 Da molecular weight cut-off filter. Thus, the ultrafiltered extract, depending on the molecular weight cut-off of the filter, can 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. The ultrafiltered extract typically contains primarily saccharides, nicotine, and amino acids. Ultrafiltration can be combined with other separation and purification methods to provide nicotine having an acceptable purity level.

[0040] The ultrafiltered extract may exhibit a better level of transparency improvement than the non-ultrafiltered extract. The transparency of the extract and the composition 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 while being diffused. In various embodiments, certain materials of the present invention (e.g., certain tobacco extracts or nicotine obtained therefrom) may have a high degree of transparency such that the material or a portion thereof can be classified as "transparent" or exhibiting "transparency", which is defined as a material through which light can pass freely without significant diffusion. The transparency of the ultrafiltered extract is a transparency such that there is a level of translucency in contrast to opacity (which refers to a material through which light cannot pass). In certain embodiments, the ultrafiltered extract is analyzed visually or by shining light on the extract and measuring the percentage of light that was not absorbed and / or scattered by the extract. Such measurement can be performed, for example, using a standard spectrophotometer at a given wavelength. The spectrophotometer is typically calibrated with deionized water, which is assigned a transparency value of 100%. The ultrafiltered extract, in some embodiments, may exhibit 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 a somewhat recognizable brown / black color. After ultrafiltration, the extract can be stored in a refrigerator or freezer, or can be lyophilized or spray-dried before use in the composition 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 nicotine compounds.

[0041] The nicotine compound of the present invention may contain nicotine in the form of a free base, in the form of a salt, as a complex, or as a solvate. For example, see the discussion of nicotine in the free base form in Hansson U.S. Patent Application Publication No. 2004 / 0191322, which is incorporated herein by reference. At least a portion of the nicotine compound may be used in the form of a nicotine resin complex in which nicotine is bound within an ion exchange resin such as nicotine polacrillex. For example, see Lichtneckert et al. U.S. Patent No. 3,901,248, which is incorporated herein by reference. At least a portion of the nicotine may be used in the form of a salt. The salts of nicotine can be provided using various components and techniques shown in Cox et al. U.S. Patent No. 2,033,909 and Perfetti, Beitrage Tabakforschung Int., 12, 43-54 (1983). Further, the salts of nicotine are available from sources such as Fluka & Bauer, and K&K Laboratories, which is part of ICN Biochemicals. Examples of pharmaceutically acceptable nicotine salts include nicotine salts of tartaric acid (e.g., nicotine tartrate and nicotine bitartrate), nicotine salts of chlorine (e.g., nicotine hydrochloride and nicotine dihydrochloride), nicotine salts of sulfuric acid, nicotine salts of perchloric acid, nicotine salts of ascorbic acid, nicotine salts of fumaric acid, nicotine salts of citric acid, nicotine salts of malic acid, nicotine salts of lactic acid, nicotine salts of aspartic acid, nicotine salts of salicylic acid, nicotine salts of tosylate, nicotine salts of succinic acid, nicotine salts of pyruvic acid, etc.; nicotine salt hydrates (e.g., nicotine zinc chloride monohydrate), etc. In certain embodiments, at least a portion of the nicotine compound is in the form of a salt having an organic acid moiety including, but not limited to, levulinic acid, as discussed in Brinkley et al. U.S. Patent Application Publication No. 2011 / 0268809, which is incorporated herein by reference.

[0042] In one embodiment, the nicotine compound is adsorbed onto a porous granular carrier material, such as microcrystalline cellulose (MCC), before being incorporated into the compositions of the invention. In one embodiment, the MCC material used in the present invention has an average particle size in the range of about 15 to about 250 microns. Exemplary MCC materials include various grades of AVICEL® and VIVACEL® materials. See, for example, Hansson U.S. Patent Application Publication No. 2004 / 0191322, which is incorporated herein by reference. In certain embodiments, nicotine compounds of multiple shapes, including any of the various combinations of nicotine compounds contemplated herein, may be adsorbed onto the granular carrier. In some embodiments, the nicotine compound and optionally the organic acid moiety can be adsorbed onto the granular carrier by, for example, dissolving the nicotine compound (and optionally the organic acid moiety) in a hydrophilic solvent (such as water, alcohol, or a mixture thereof), mixing with a solution containing the granular carrier, and subsequently drying to remove the solvent. The granular carrier material having the adsorbed nicotine and optionally the organic acid moiety can be mixed with other carriers or excipients to provide a composition adapted for oral delivery of the active ingredient.

[0043] The compositions of the invention are pharmaceutically effective and have a pharmaceutically acceptable form. That is, it is most preferred that the composition does not incorporate, or is not intentionally incorporating, tobacco components other than nicotine to any appreciable extent. Thus, pharmaceutically effective and pharmaceutically acceptable compositions do not contain many of the tobacco components traditionally present in tobacco, processed tobacco components, or 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 typically no or negligible amounts of tobacco constituents, processed tobacco components, or components derived from tobacco are present or lacking.

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

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

[0046] Other components of the formulation can be artificial, or can be obtained from or derived from plant or biological sources. Examples of various components that can be incorporated into one or more formulations according to the present invention include salts (e.g., sodium chloride, potassium chloride, sodium citrate, potassium citrate, sodium acetate, potassium acetate, etc.), natural sweeteners (e.g., fructose, sucrose, glucose, maltose, vanillin, ethyl vanillin glucoside, mannose, galactose, lactose, etc.), artificial sweeteners (e.g., sucralose, saccharin, aspartame, acesulfame K, neotame, etc.), organic fillers and inorganic fillers (e.g., grains, processed grains, puffed grains, maltodextrin, glucose, calcium carbonate, calcium phosphate, polycarbophil calcium, corn starch, lactose, isomalt, mannitol, xylitol, or sugar alcohols such as sorbitol, microcrystalline cellulose, hydroxypropyl cellulose, plant proteins, silicon dioxide, etc.), film formers and binders (e.g., povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and other modified cellulose-type binders, sodium alginate, acacia gum, 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 metal carbonates, preferably other alkali metal buffers such as potassium carbonate or sodium carbonate, or metal bicarbonates such as sodium bicarbonate, etc.), emulsifiers, colorants (e.g., dyes and pigments including caramel pigments, titanium dioxide, D&C Yellow No. 10, etc.), humectants (e.g., glycerin, propylene glycol, etc.), oral care additives (e.g., thyme oil, eucalyptus oil, and zinc), preservatives and antioxidants (e.g., potassium sorbate, sodium benzoate, ascorbyl palmitate, etc.), syrups (e.g., honey, high fructose corn syrup, etc.), thickeners, disintegration aids or compressibility aids (e.g., microcrystalline cellulose, croscarmellose sodium,Cross povidone, sodium starch glycolate, pregelatinized starch, etc.), lubricants or processing aids (e.g., magnesium stearate or calcium stearate), anti-adhesives (e.g., talc), flow promoters (e.g., colloidal silica), surfactants (e.g., polysorbate 80), flavoring agents and flavoring mixtures, and mixtures thereof are included. The various exemplary components can 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 compositions of the present invention may conveniently be made available in unit dosage form, whereby such formulations can be prepared by any of the methods generally known in the pharmaceutical art. Generally speaking, such preparation methods involve (by various methods) combining the active pharmaceutical agent with a suitable carrier or other adjuvant which may consist of one or more components. The resulting formulation of the active ingredient with one or more adjuvants is then physically processed (e.g., formed into tablets or prepared as an aqueous suspension) to provide a formulation of a shape suitable for delivery.,

[0048] The nicotine-containing pharmaceutical composition of the present invention can incorporate various pharmaceutically acceptable excipients. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" are intended to mean carriers or excipients conventionally used in the art to facilitate storage, administration, and / or the healing effect of an active agent (e.g., a nicotine compound). The carrier must be pharmaceutically acceptable in that it is compatible with the other ingredients of the formulation and not unduly harmful to its recipient. The carrier can 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 examples of pharmaceutical excipients and / or additives suitable for use in the compositions according to the present invention are described in Remington: The Science & Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2006), Physician’s Desk Reference, 64th Edition, Thomson PDR (2010), and Handbook of Pharmaceutical Excipients, 6th Edition, Raymond C. Rowe et al., eds., Pharmaceutical Press (2009), each of which is incorporated herein by reference.

[0049] Various excipients may vary, and the choice and amount of each excipient can depend on factors such as the final shape and function of the desired product. See, for example, U.S. Patent No. 5,512,306 to Carlsson et al.; U.S. Patent No. 5,525,351 to Dam; U.S. Patent No. 5,549,906 to Santus; U.S. Patent No. 5,711,961 to Reiner et al.; U.S. Patent No. 5,811,126 to Krishnamurthy; U.S. Patent No. 5,939,100 to Albrechtsen et al.; U.S. Patent No. 6,024,981 to Khankari et al.; U.S. Patent No. 6,083,531 to Humbert-Droz et al.; U.S. Patent No. 6,090,401 to Gowan, Jr. et al.; U.S. Patent No. 6,110,495 to Dam; U.S. Patent No. 6,248,760 to Wilhelmsen; U.S. Patent No. 6,280,761 to Santus; U.S. Patent No. 6,426,090 to Ream et al.; U.S. Patent No. 6,569,463 to Patel et al.; U.S. Patent No. 6,583,160 to Smith et al.; U.S. Patent No. 6,585,997 to Moro et al.; U.S. Patent No. 6,676,959 to Andersson et al.; U.S. Patent No. 6,893,654 to Pinney et al.; U.S. Patent No. 7,025,983 to Leung et al.; and U.S. Patent No. 7,163,705 to Johnson et al.; U.S. Patent Application Publication No. 2003 / 0176467 to Andersson et al.; U.S. Patent Application Publication No. 2003 / 0235617 to Martino et al.; U.S. Patent Application Publication No. 2004 / 0096501 to Vaya et al.; U.S. Patent Application Publication No. 2004 / 0101543 to Liu et al.; U.S. Patent Application Publication No. 2004 / 0191322 to Hansson; U.S. Patent Application Publication No. 2005 / 0053665 to Ek et al.; U.S. Patent Application Publication No. 2005 / 0123502 to Chan et al.; U.S. Patent Application Publication No. 2008 / 0038209 to Andersen et al.; U.S. Patent Application Publication No. 2008 / 0286341 to Andersson et al.; U.S. Patent Application Publication No. 2009 / 0023819 to Axelsson; U.S. Patent Application Publication No. 2009 / 0092573 to Andersen; U.S. Patent Application Publication No. 2010 / 0004294 to Axelsson et al.; and U.S. Patent Application Publication No. 2010 / 0061940 to Axelsson et al. for various components of nicotine-containing products, relative amounts and combinations of components, nicotine-containing formulations, and methods of preparation shown therein.

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

[0051] The various components described above can be used together (e.g., as a component formulation) or separately (e.g., the individual components can be added at various stages involved in the preparation of nicotine compound-containing formulations and the final pharmaceutical). The relative amounts of the various components within the nicotine compound-containing formulation can vary and are typically selected to provide the desired sensory and performance characteristics to the pharmaceutical composition. Further, the various components described above can be encapsulated when provided in the final product or composition. Exemplary encapsulating components are described, for example, in the Atchley International Publication No. 2010 / 132444 (A2) pamphlet, which is incorporated herein by reference.

[0052] As used herein, "flavorant" or "fragrance" refers to any flavorful or aromatic substance that can alter the sensory characteristics associated with a pharmaceutical composition. Sensory characteristics that can be modified by exemplary flavorants include taste, texture, moisture, coolness / warmth, and / or aroma / odor. Flavorants can be natural or synthetic, and these flavor characteristics can be described as, but are not limited to, fresh, sweet, herbal, confectionary, 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, raspberry, and strawberry. The flavorants utilized in the present invention can also include components that are considered to be wetting agents, cooling agents, or lubricants, such as eucalyptus. These flavors can be provided raw (i.e., alone) or in a composite (e.g., spearmint and menthol, or orange and cinnamon). In some examples, the flavorant can be provided in a spray-dried form. Flavorants are typically present in an amount of about 0.5 to about 10 dry weight percent, often in an amount of about 1 to about 6 dry weight percent, and most often in an amount of about 2 to about 5 dry weight percent.

[0053] Sweeteners can be used in natural or artificial forms, or as a combination of artificial and natural sweeteners. In one embodiment, sucralose, sucrose, or a combination thereof is the primary sweetening component. When present, whether an artificial sweetener or a natural sugar, representative amounts of sweeteners can 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. It is preferred that the amount of sweetener in the composition does not exceed about 40 percent of the total dry weight of the composition, often does not exceed about 35 percent, and frequently does not exceed about 30 percent.

[0054] Sucrose can be a particularly convenient sweetener in certain embodiments (e.g., as a component of a starch matrix formulation) because it is thought to contribute to the chew resistance or "rebound" of the final product. In addition, granulated sucrose provides a considerably lower sweetening effect compared to sucralose, but the presence of sucrose can be convenient as an additional filler component. When these two types of sweeteners are present together, sucralose is typically present in an amount of at least about 0.25 percent by dry weight, often at least about 0.5 percent by dry weight, and most often at least about 1.0 percent by dry weight (e.g., from about 0.25 to about 2.0 percent by dry weight), and sucrose is typically present in an amount of at least about 2.0 percent by dry weight, often at least about 3.0 percent by dry weight, and most often at least about 4.0 percent by dry weight (e.g., from about 1.0 to about 6.0 percent by dry weight).

[0055] In certain embodiments, some formulations (or the entire pharmaceutical composition) do not contain sugar and contain one or more sugar substitutes. "Sugar-free," as used herein, includes products having less than about 1 / 15 of the weight of sugar, or less than about 1 / 10 of the weight of sugar. Sugar substitutes, when used, can be provided in pure form, in a solid form (e.g., granular or powdered form). In certain embodiments, the sugar substitute is dry and contains a very low content of moisture. For example, the sugar substitute can contain less than about 5 weight % water, less than about 3 weight % water, less than about 2 weight % water, or less than about 1 weight % water.

[0056] In some embodiments, syrup (e.g., corn syrup) can be used in an amount sufficient to preferably provide the desired flavor characteristics to the pharmaceutical composition. In some embodiments (e.g., in starch matrix formulations), the syrup can be used in an amount sufficient to provide chewiness and retard solubilization. Representative amounts of syrup (e.g., high fructose corn syrup) can be less than about 10 percent, or less than about 5 percent, of the total dry weight of the composition.

[0057] In certain embodiments, a sugar syrup or sugar alcohol syrup is added to the lozenge formulation to affect the recrystallization of another component of the formulation (e.g., a melted sugar substitute) during preparation. Examples of sugar alcohol syrups for such purposes include maltitol syrup, xylitol syrup, mannitol syrup, glycerol syrup, erythritol syrup, trehalose syrup, arabinitol syrup, ribitol syrup, mannitol syrup, sorbitol syrup, dulcitol syrup, iditol syrup, isomalt syrup, lactitol syrup, and polyglycitol syrup. Other syrups, such as corn syrup, golden syrup, or molasses, can be used. The amount of sugar alcohol syrup can vary, but is typically in the range of about 0.1% to about 2% by weight of the pharmaceutical composition mixture, often in the range of about 0.5% to about 1.5% by weight, and 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 composition of the present disclosure can usually contain at least one filler component. When a polysaccharide filler component is present, any filler component can be provided in addition to the polysaccharide filler component. Such filler components of the composition often achieve multiple functions, for example, improving certain sensory properties such as texture and mouthfeel, enhancing the binding or compressibility of the product, etc. In certain embodiments (e.g., in starch molding formulations), sugar alcohols are particularly convenient as filler components because they impart some sweetness and do not disrupt the desired chewable properties of the final product. A sugar alcohol (e.g., isomalt) is a polyol derived from a monosaccharide or disaccharide in a partially or fully hydrogenated form. Exemplary sugar alcohols have between about 4 and about 20 carbon atoms and include erythritol, arabinitol, ribitol, isomalt, maltitol, xylitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates). The sugar alcohol can 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 weight percent. Mixtures of sugar alcohols with other filler components can also be used. When present, whether an organic filler or an inorganic filler, a representative amount of the filler can 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. It is preferred that the amount of additional filler in the composition 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 salt) can be used in an amount sufficient to impart the desired sensory properties to the pharmaceutical composition. When present, a representative amount of the salt is at least about 0.5 dry weight percent or at least about 1.0 dry weight percent or at least about 1.5 dry weight percent of the total dry weight of the composition, but is usually less than about 5 percent (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 is less than about 2 percent or less than about 1 percent of the total dry weight of the composition.

[0060] Humectants (e.g., glycerin) can be used in an amount sufficient to impart the desired moisture properties to the pharmaceutical composition. Further, in some instances, the humectant can impart desirable flow properties to the pharmaceutical composition (e.g., for placement in a starch molding mold). When present, a representative amount of the humectant is usually 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 the 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 weight percent, and more often from about 3 to about 35 dry weight percent. In some embodiments, the humectant can be provided in an amount less than about 5 percent (e.g., about 0.5 to about 4 dry weight percent) of the total dry weight of the composition.

[0061] A binder (or combination of binders) can be used in an amount sufficient to impart the desired physical properties and substance integrity to the pharmaceutical composition. When present, representative amounts of binder can 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 preferably does not exceed 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 often does not exceed about 20 percent of the total dry weight of the composition and often does not exceed about 15 percent of the total dry weight of the composition. In certain embodiments, the binder material includes natural gums. As used herein, natural gum refers to a polysaccharide of natural origin that is useful as a thickening or gelling agent. Representative natural gums of plant origin are usually water-soluble to some extent and include xanthan gum, guar gum, gum arabic, ghatti gum, tragacanth gum, karaya gum, locust bean gum, gellan gum, and combinations thereof.

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

[0063] Certain buffers exhibit buffering action within a pH range of about 6 to about 10, and exemplary buffers include metal hydroxides, metal carbonates, metal bicarbonates, or mixtures thereof. When present, the buffer is typically present in an amount of less than about 1 percent, based on the dry weight of the formulation. Various food buffers are known and can be used to adjust the pH of the products of the present invention. Suitable buffers include those selected from the group consisting of acetates, glycinate salts, phosphates, glycerophosphates, citrates such as alkali metal citrates, carbonates, bicarbonates, and borates, and mixtures thereof. In certain embodiments, the buffer is an amino acid as taught, for example, in both 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 buffer. In some embodiments, one amino acid buffer is used in combination with another amino acid buffer and / or in combination with one or more non-amino acid buffers. In certain embodiments, any pH adjuster is a base (e.g., NaOH). In certain embodiments, L-lysine and NaOH are added to the composition of the present invention.

[0064] Nicotine is well known to be prone to oxidation, and thus it can be advantageous to incorporate one or more antioxidants, such as ascorbyl palmitate and / or sodium ascorbate, into the compositions according to the present invention. The one or more antioxidants can be present in the pharmaceutical composition mixture at a concentration from about 0.05 wt% to about 0.3 wt%, 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 can include short-term formulations, immediate-release formulations, controlled-release formulations, sustained-release formulations, delayed-release formulations, and pulsed-release formulations, provided that such formulations achieve the administration of a nicotinic compound as described herein. See Remington’s Pharmaceutical Sciences (18th Edition; Mack Publishing Company, Easton, Pennsylvania, 1990), which is incorporated herein by reference in its entirety.

[0066] The compositions of the present invention incorporate a pharmaceutically effective amount of nicotine. The dosage of the active ingredient (i.e., all of the various forms of nicotine) is preferably an amount effective to treat some of the symptoms of the condition, disease, or disorder that the subject or patient is suffering from, or effective to prevent the occurrence of such symptoms. An “effective amount,” “therapeutic amount,” or “effective dosage” means an amount sufficient to induce the desired pharmacological or therapeutic effect and thus result in an effective prevention or treatment of the condition, disease, or disorder. Accordingly, the effective amount of the active ingredient is an amount sufficient to enter the appropriate region of the body (e.g., to cross the blood-brain barrier of the subject), an amount sufficient to bind to the appropriate receptor sites in the CNS and PNS of the subject, and / or an amount sufficient to induce a neuropharmacological effect (e.g., to induce the secretion of neurotransmitters and thus result in an effective prevention or treatment of the condition, disease, or disorder). Prevention of a disorder is manifested, for example, by delaying the onset of the symptoms of the condition, disease, or disorder. Treatment of a disorder is manifested, for example, by a reduction in the symptoms of the condition, disease, or disorder, or an improvement in the recurrence of such symptoms.

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

[0068] The specific components and their amounts in a given formulation are dependent on the desired characteristics of that formulation. For example, the components can 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 present invention.

[0069] For example, a typical lozenge formulation can include a nicotine compound, a sugar substitute, and a sugar alcohol syrup. The sugar substitute (e.g., isomalt) is a non-hygroscopic sugar alcohol that can form a glassy matrix. In one particular embodiment of the present invention, the lozenge formulation includes a nicotine 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 a specific embodiment, the lozenge formulation can include isomalt, maltitol syrup, a nicotine compound, NaCl, and sucralose. In certain embodiments, the formulation is translucent. For further details regarding representative lozenge formulations, reference is made to U.S. Patent Application Publication No. 13 / 240,525 to Holton, Jr. et al., filed on September 22, 2011, which is incorporated herein by reference.

[0070] Typical melt formulations generally include a nicotine compound and a lipid. The lipid can be various and can be, for example, a fat, an oil, or a wax substance (or a combination thereof) that forms part of the formulation. The lipid component can be derived from animal or plant sources and usually contains mainly triglycerides along with smaller amounts of free fatty acids and monoglycerides or diglycerides. In certain embodiments, the lipid is a plant-derived fatty substance 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 can be various and can be, in certain embodiments, 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 mainly composed of saturated or unsaturated fatty acid chains 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 (most of which are bonded within the triglyceride structure). Examples of 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 substance may be hydrogenated, partially hydrogenated, or not hydrogenated. In some examples, the lipid substance may contain a mixture of lipid components. For example, the lipid substance may contain a mixture of palm oil and palm kernel oil.

[0072] In certain embodiments, a melt-type formulation is provided that contains 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 filler, flavoring 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 containing lipids can be found in U.S. Patent Application Publication No. 13 / 330,929 to Cantrell et al., filed December 20, 2011, which is incorporated herein by reference.

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

[0074] Typical hard-coated formulations usually contain a nicotine compound, a binder, and a sugar alcohol syrup. In one particular embodiment, the hard-coated formulation contains a nicotine compound, a binder, a sugar alcohol, isomalt, sodium hydroxide, sucralose, and a flavoring. The hard-coated formulations according to the present invention usually contain such constituents, but in certain embodiments other various coating materials can be applied, and it is noted that in some embodiments other various coating materials can be applied in addition to the hard-coated formulations. For example, in certain embodiments, the entire multilayer pharmaceutical composition of the present invention and / or any of the component formulations described herein can include an outer coating material, and the outer coating can include components such as carnauba wax and / or shellac in a pharmaceutically acceptable form, which are a polishing composition and a surface polishing agent. The application of the coating material can be achieved using techniques such as airless spray coating, fluidized bed coating, the use of a coating pan, etc. Other materials used as coating materials can be polymeric substances such as cellulose materials (e.g., cellulose butyrate phthalate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethylcellulose), and polymers and copolymers of acrylic acid, methacrylic acid, and their esters. For example, such coating materials can include a film-forming polymer such as a cellulose-based polymer and any plasticizer. Other optional coating components include flavorings, sweeteners, colorants, and salts.

[0075] Typical injection-molded formulations (i.e., pastilles) can include, for example, a nicotine compound and a polysaccharide filler component of from about 10 weight percent to about 25 weight percent on a dry weight basis. The polysaccharide filler can be various, but in certain embodiments, includes polydextrose. Certain embodiments include a sugar alcohol filler (e.g., sorbitol), a binder including a water-soluble gum (e.g., gum arabic), and / or one or more of flavoring agents, binders, emulsifiers, disintegrating aids, humectants, and mixtures thereof. In one particular embodiment, the formulation includes a nicotine 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, by Cantrell et al., which is incorporated herein by reference.

[0076] Typical starch-molded formulations (i.e., pastilles) can include, for example, a nicotine 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 includes a nicotine 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 includes at least about 10 percent sugar alcohol filler, at least about 10 percent binder, from about 0.1 to about 2 percent artificial sweetener, from about 1 to about 5 percent humectant, from about 1 to about 5 percent natural sweetener, up to about 5 percent flavoring agent, and up to about 3 percent salt, based on the total dry weight of the pharmaceutical composition.

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

[0078] The formulations that make up the pharmaceutical composition of the present invention can have various functional properties. For example, starch-molded formulations can, in certain embodiments, be characterized as being soluble and lightly crushable, and are generally in the shape of a hardened solid gel (e.g., a "paste"). In certain embodiments, the starch-molded formulations are characterized by sufficient binding properties to resist mild chewing behavior in the oral cavity without rapid disintegration. Such formulations of the present disclosure typically do not exhibit the very deformable chewability seen in conventional chewing gums. Melting formulations can, in certain embodiments, be described as providing a smooth, creamy feel when placed in the user's mouth (more like a smooth, waxy or gooey feel rather than a sticky feel). Lozenge formulations generally have a firm texture and exhibit solubility. Chewable formulations generally exhibit a chew response between that of the pastes and gums described herein. Like pastes, chewable formulations typically exhibit binding properties that resist mild chewing behavior in the oral cavity, but generally disintegrate at a slower rate than pastes, allowing for more chewing behavior before complete disintegration of the composition. Hard-coated formulations generally provide some degree of crunchiness or crispness.

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

[0080] Table 1 describes various combinations of formulations that can include multi-layered pharmaceutical compositions. 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 the specific composition 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 variously intermixed sensory properties. In certain embodiments, such pharmaceutical compositions are multilayered and can thus provide the user with various sensations of sensory irritation during use of the product. For example, the pharmaceutical composition can be adjusted to exhibit a certain range of sensory properties in a desired order of experience (e.g., a chewy sensation following an initial hard and dissolving sensation).

[0089] Due to the multi-layered structure of the pharmaceutical composition of the present invention, in certain embodiments, the flavor and / or nicotine release profile of the product can be adjusted as a whole. In other words, the manner and / or rate at which nicotine is released can vary. Certain types of formulations typically exhibit faster or slower nicotine release. Such formulations advantageously are located within the multi-layered structure of the pharmaceutical composition such that the product exhibits a desired release profile. For example, in one particular embodiment, the outer formulation comprises a formulation that exhibits 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 rapid release of nicotine and a sustained release of nicotine. In certain embodiments, various flavorants and / or other components (e.g., perceptible substances) can be incorporated into a particular layer. By varying the flavor and / or the sensory irritation sensation of different layers, a unique range of taste and / or sensory experiences can be provided to the user during use of the product.

[0090] The compositions of the present invention incorporate a pharmaceutically effective amount of nicotine. The dosage of the active ingredient (i.e., all of the various forms of nicotine) is preferably an amount effective to treat some of the symptoms of the medical condition, disease, or disorder that the subject or patient is suffering from, or effective to prevent the occurrence of such symptoms. "Effective amount", "therapeutic amount" or "effective dosage" means an amount sufficient to induce the desired pharmacological or therapeutic effect and thus result in effective prevention or treatment of a medical condition, disease, or disorder. Accordingly, the effective amount of the active ingredient is an amount sufficient to enter the appropriate region of the body (e.g., to cross the blood-brain barrier of the subject), an amount sufficient to bind to the appropriate receptor sites of the CNS and PNS of the subject, and / or an amount sufficient to induce a neuropharmacological effect (e.g., to induce the secretion of neurotransmitters and thus result in effective prevention or treatment of a medical condition, disease, or disorder). Prevention of a disorder is manifested, for example, by delaying the onset of the symptoms of the medical condition, disease, or disorder. Treatment of a disorder is manifested, for example, by a reduction in the symptoms of the medical condition, disease, or disorder, or an improvement in the recurrence of such symptoms.

[0091] For the compositions of the present invention, the intended daily dose of the active ingredient can vary. The total dose of the active ingredient can depend on factors such as the body weight of the subject ingesting the composition, the medical condition being treated, the state or severity of the disease or disorder being treated, the desired pharmacological effect, or other such factors. The amount of nicotine active ingredient administered to a subject in a day is usually at least about 2 mg, often at least about 4 mg, and frequently at least about 10 mg, calculated on a nicotine basis. The amount of nicotine active ingredient administered to a subject in a day usually does not exceed about 60 mg, often does not exceed about 50 mg, and frequently does not exceed about 40 mg. See also, for example, the various types of dosing regimens and administration techniques shown in U.S. Patent No. 5,593,684 to Baker et al.; U.S. Patent 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 various types of forms and configurations, and as a result, the characteristics, properties, behavior, hardness, shape, morphology, size, and weight of the compositions can vary. The shape of representative compositions can generally be spherical, cylindrical (ranging from the general shape of a flat disc to the general shape of a relatively long and slender rod), helical, elliptical, square, rectangular, etc. Or the composition can have the form of beads, granules, crystalline powder, capsules, films, strips, gels, etc. The shape of the composition can be similar to the various pills, tablets, lozenges, capsules, capsule-shaped tablets, pouches, and gum-type products that have traditionally been used for the administration of pharmaceutical-type products. The general properties of representative compositions can be soft to the touch, hard, or of intermediate softness or hardness, and thus the composition can be seen as malleable, flexible, chewy, elastic, brittle, etc. When administered orally, the various components of the product can be readily dispersed, or the dispersion can be seen as slow, or the various components can dissolve at various rates (e.g., from a relatively fast rate to a relatively slow rate). As a result, for the composition ingested by placing it in the mouth of a human subject, the release rate of the active ingredient during use of the product can vary from a relatively fast to a relatively slow rate depending on factors such as the design of the product and the method of using the product by the subject using the product.The various products proposed in U.S. Patent No. 4,655,231 to Ray et al.; U.S. Patent No. 5,147,654 to Place et al.; U.S. Patent No. 5,543,424 to Carlsson et al.; U.S. Patent No. 6,268,386 to Thompson; U.S. Patent No. 6,319,510 to Yates; U.S. Patent No. 6,488,953 to Halliday et al.; U.S. Patent No. 6,709,671 to Zerbe et al.; U.S. Patent No. 7,025,983 to Leung et al.; U.S. Patent No. 7,105,173 to Rolling; U.S. Patent No. 7,115,297 to Stillman; U.S. Patent No. 7,435,749 to Knight; and U.S. Patent No. 7,491,406 to Leung et al.; and U.S. Patent Application Publication No. 2006 / 0198873 to Chan et al.; U.S. Patent Application Publication No. 2006 / 0240087 to Houze et al.; U.S. Patent Application Publication No. 2006 / 0204559 to Bess et al.; U.S. Patent Application Publication No. 2007 / 0269492 to Steen et al.; U.S. Patent Application Publication No. 2008 / 0020050 to Chau et al.; U.S. Patent Application Publication No. 2008 / 0286340 to Andersson et al.; U.S. Patent Application Publication No. 2008 / 0292683 to Sanghvi et al.; and U.S. Patent Application Publication No. 2009 / 0004248 to Bunick et al., which are incorporated herein by reference, are also referred to as examples.

[0093] There can be various ways to make a multi-layered nicotine-containing pharmaceutical composition. Generally, the core formulation can be provided by any method for providing such a formulation. Examples of methods for providing certain types of formulations are provided herein, but it should be noted that other methods can be used without departing from the present invention. Usually, the core formulation is made and one or more additional layers are applied thereto. The core can be shaped into the desired form (e.g., roll-shaped or press-shaped) by, for example, injecting the formulation mixture directly into a mold, or extruded into the desired form. In some embodiments, the mixture can 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 facilitate the application of the formulation to the core of the pharmaceutical composition or to a previous layer. For example, the second and subsequent layers of a pharmaceutical composition are often applied by coating means (e.g., by dip coating, spray coating, or by preparing separate sheets of formulation that can be used to encapsulate the core formulation or adhere to one or more surfaces of the core formulation, as in a side-by-side configuration).

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

[0096] In certain embodiments, melt-type formulations can be prepared by mixing the components (e.g., a nicotinic compound and one or more additional components) with a melted lipid to form a molten pharmaceutical formulation paste, which can then be placed in a mold or coated onto another formulation.

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

[0098] In certain embodiments, the injection-molded formulation is prepared by mixing 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 then cooling the pharmaceutical formulation mixture (e.g., to a temperature of about 20°C to about 25°C) to form a solidified pharmaceutical formulation.

[0099] The methods for preparing formulations can vary, and a particular method for making a particular type of formulation may need to be adapted according to the composition of a given pharmaceutical composition. For example, if the formulation includes an outer layer formed by traditional techniques, the method may need to be modified so that the formulation can be coated with another formulation. For example, such a formulation may be capable of being wet sprayed or dry sprayed onto another surface, or applied to the surface by dipping another surface into the formulation. The method of application may require modification of traditional spray coating techniques depending on the nature of the formulation. For example, it may be necessary to raise and maintain the temperature of the formulation and the spray coating equipment during the process to spray coat a lozenge-shaped formulation onto another formulation. In certain embodiments, temperature control is important to avoid changes in the properties of other formulations. For example, care must be taken to avoid melting of the melt-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 can be determined by any technique commonly used in the art. However, it is generally measured by the light transmittance of spectrophotometry over a range of wavelengths (e.g., up to about 400 - 700 nm). The 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 the light diffuses through the product.

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

Examples

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

[0103] The heating of the isomalt mixture is stopped and it is allowed to cool to 132°C. The remaining components (i.e., the nicotine-containing solution and optionally the sodium hydroxide solution) are combined and optionally added to a solution containing one or more flavorings. The combined solution is poured into the hot isomalt mixture and mixed.

[0104] Pour the resulting mixture into a mold. If the mixture becomes too viscous to pour, the mixture may be heated (e.g., for about 7 seconds) in a microwave oven using high heat. Representative pharmaceutical formulations are described below. Mixture 1 below contains no base, while mixtures 2 and 3 contain different amounts of sodium hydroxide.

[0105] [Table 2]

[0106] [Table 3]

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

[0108] Example 2: Preparation of a melt formulation a) Melt formulation 1 A nicotine compound-containing formulation suitable for use as a melt component of a pharmaceutical composition for oral use is provided by the following method. Prepare various dried components, which include a filler (isomalt), a salt (sodium chloride), a sweetener (sucralose), and flavors (vanillin, spray-dried peppermint, spray-dried menthol). Add all of the dried components, which are in powder form, together with a nicotine compound (e.g., nicotine), and mix thoroughly in a paddle-hover mixer at about 120 rpm for about 3 minutes.

[0109] Prepare a lipid substance having a melting point of about 38°C to about 42°C (available as 108 - 24 - B from Aarhus Karlshamn USA Inc.). The lipid substance is a non - hydrogenated lauric - coated fat containing a mixture of palm kernel oil and palm oil. Melt the lipid substance in a mixing vessel. While maintaining heat to the mixing vessel having the melted lipid substance, add the mixed dry formulation while mixing, thereby creating a fluid slurry of a nicotine - containing composition having a water content of less than about 10 percent. Place the slurry in a mold to obtain a pharmaceutical composition weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure it in ambient air, and then remove each piece of the meltable nicotine - containing formulation from the mold. The mixture of the nicotine - containing composition is about 53.0 parts lipid substance, 39.8 parts filler, 0.2 part nicotine, 0.8 part salt, 0.7 part sweetener, and 5.5 parts flavoring.

[0110] b) Meltable formulation 2 Provide a nicotine - containing formulation suitable for use as a meltable component of a pharmaceutical composition for oral use by the following method. Prepare various dry ingredients, which include a filler (isomalt), a salt (sodium chloride), a sweetener (sucralose), and flavorings (vanillin, spray - dried peppermint, spray - dried menthol). Add all of the dry ingredients, which are in powder form, together with a nicotine - containing compound (e.g., nicotine) and mix thoroughly in a paddle - equipped Hobart mixer at about 120 rpm for about 3 minutes.

[0111] Prepare a lipid substance having a melting point of about 38°C to about 42°C (available as 108-24-B from Arcos Organics USA). The lipid substance is a non-hydrogenated lauric coating fat containing a mixture of palm kernel oil and palm oil. Melt the lipid substance in a mixing container. While maintaining heat to the mixing container having the melted lipid substance, add the mixed dry formulation while mixing, thereby creating a fluid slurry of a nicotine-containing compound composition having a water content of less than about 10 percent. Place the slurry in a mold to obtain a pharmaceutical composition weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure in ambient air, then remove each piece of the meltable nicotine-containing compound formulation from the mold. The mixture of the nicotine-containing compound composition is about 53.0 parts lipid substance, 38.2 parts filler, 0.2 part nicotine, 0.8 part salt, 0.7 part sweetener and 7.1 parts flavorant.

[0112] c) Meltable formulation 3 Provide a nicotine-containing compound formulation suitable for use as a meltable component of a pharmaceutical composition for oral use by the following method. Prepare various dry ingredients, including a filler (isomalt), a salt (sodium chloride), a sweetener (sucralose) and a flavorant (vanillin, spray-dried peppermint, spray-dried menthol). Add all of the dry ingredients, which are in powder form, together with a nicotine-containing compound (e.g., nicotine) and mix thoroughly for about 3 minutes at about 120 rpm in a paddle-equipped Hobart mixer.

[0113] Prepare a lipid substance having a melting point of about 38°C to about 42°C (available as 108-24-B from Arscal Sham USA). The lipid substance is a non-hydrogenated lauric coating fat containing a mixture of palm kernel oil and palm oil. Melt the lipid substance in a mixing container. While maintaining heat to the mixing container having the melted lipid substance, add the mixed dry formulation while mixing, thereby creating a fluid slurry of a nicotine compound-containing composition having a water content of less than about 10 percent. Place the slurry in a mold to obtain a nicotine compound-containing formulation weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure in ambient air, then remove each piece of the meltable nicotine compound-containing formulation from the mold. The mixture of the nicotine compound-containing composition is about 53.0 parts lipid substance, 36.6 parts filler, 0.2 part nicotine, 0.8 part salt, 0.7 part sweetener and 8.7 parts flavorant.

[0114] d) Meltable formulation 4 Provide a nicotine compound-containing formulation suitable for use as a meltable component of a pharmaceutical composition for oral use by the following method. Prepare various dry materials, which include a filler (isomalt), a sweetener (sucralose) and a flavorant (vanillin). Add all of the dry components, which are in powder form, together with a nicotine compound (e.g., nicotine) and mix thoroughly in a paddle-hover mixer at about 120 rpm for about 3 minutes.

[0115] Prepare a lipid substance having a melting point of about 38°C to about 42°C (available as 108-24-B from Arscal Sham USA). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. Melt the lipid substance in a mixing container. While maintaining heat to the mixing container having the melted lipid substance, add the mixed dry formulation while mixing, thereby creating a fluid slurry of a nicotine compound-containing composition having a water content of less than about 10 percent. Place the slurry in a mold to obtain a nicotine compound-containing formulation weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure in ambient air, then remove each piece of the nicotine compound-containing formulation from the mold. The mixture of the nicotine compound-containing composition is about 52.9 parts lipid substance, 46.1 parts filler, 0.2 parts nicotine, 0.7 parts sweetener and 0.1 parts flavoring.

[0116] e) Melting formulation 5 Provide a nicotine compound-containing formulation suitable for use as a melting component of a pharmaceutical composition for oral use by the following method. Prepare various dry ingredients, which include a filler (isomalt), additives (sodium chloride, wheat flour), a sweetener (sucralose) and a flavoring (vanillin). Add all of the dry ingredients, which are in powder form, together with a nicotine compound (e.g., nicotine) and mix thoroughly at about 120 rpm for about 3 minutes in a paddle-hover mixer.

[0117] Prepare a lipid substance having a melting point of about 38°C to about 42°C (available as 108-24-B from Arskal Shamu USA). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. Melt the lipid substance in a mixing container. While maintaining heat to the mixing container having the melted lipid substance, add the mixed dry formulation while mixing, thereby creating a fluid slurry of a nicotine-containing composition having a water content of less than about 10 percent. Place the slurry in a mold to obtain a nicotine-containing formulation weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure in ambient air, then remove each piece of the nicotine-containing formulation from the mold. The mixture of the nicotine-containing composition is about 53.0 parts lipid substance, 45.2 parts filler, 0.2 part nicotine, 0.8 part additive, 0.7 part sweetener and 0.1 part flavoring.

[0118] f) Melting formulation 6 Provide a nicotine-containing formulation suitable for use as a melting component of a pharmaceutical composition for oral use by the following method. Prepare various dry components, which include a filler (isomalt), an additive (sodium chloride, wheat flour), a sweetener (sucralose) and a flavoring (vanillin). Add all of the dry components, which are in powder form, together with a nicotine compound (e.g., nicotine) and mix thoroughly in a paddle-hover mixer at about 120 rpm for about 3 minutes.

[0119] Prepare a lipid substance having a melting point of about 39°C to about 41°C (available as 108-48-B from Arscal Sham USA). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. Melt the lipid substance in a mixing container. While maintaining heat to the mixing container having the melted lipid substance, add the mixed dry formulation while mixing, thereby creating a fluid slurry of a nicotine-containing compound composition having a water content of less than about 10 percent. Place the slurry in a mold to obtain a pharmaceutical composition weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure it in ambient air, then remove each piece of the nicotine-containing compound composition from the mold. The mixture of the nicotine-containing compound composition is about 53.0 parts lipid substance, 45.2 parts filler, 0.2 part nicotine, 0.8 part additive, 0.7 part sweetener and 0.1 part flavoring.

[0120] g) Melting formulation 7 Provide a nicotine-containing compound formulation suitable for use as a melting component of a pharmaceutical composition for oral use by the following method. Prepare various dry ingredients, which include a filler (isomalt), a salt (sodium chloride), a sweetener (sucralose) and two flavorings (vanillin and mint). Add all of the dry ingredients in powder form, together with a nicotine-containing compound (e.g., nicotine), and mix thoroughly in a paddle-hover mixer at about 120 rpm for about 3 minutes.

[0121] Prepare a lipid substance having a melting point of about 38°C to about 42°C (available as 108-24-B from Arscal Sham USA). The lipid substance is a non-hydrogenated lauric coating fat containing palm kernel oil and palm oil. Melt the lipid substance in a mixing container using a microwave oven. Slowly add the melted lipid to the dry mixture while stirring. While maintaining the heat to the mixing container having the melted lipid substance, add the entire melted lipid component to make a fluid slurry of the nicotine-containing composition. Place the slurry in a mold to obtain a nicotine-containing composition weighing about 1 gram per piece. Dry the slurry for about 45 minutes to cure it in ambient air, and then remove each piece of the nicotine-containing formulation from the mold. The mixture of the nicotine-containing composition is about 53.0 parts lipid substance, 45.2 parts filler, 0.2 part nicotine, 0.8 part additive, 0.7 part sweetener and 0.1 part flavoring.

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

[0123] Example 3: Preparation of a starch molding formulation (pastille) a) Starch molding formulation 1 Provide a nicotine-containing formulation suitable for use as a starch forming component of a pharmaceutical composition for oral use by the following method. Prepare an aqueous mixture. Hydrate the binder material (gum arabic) with water, and then mix the hydrated gum with a filler (isomalt), an additional filler (maltitol; available as LYCASIN from Roquette Freres S.A.) and a salt in a high-shear mixer to form an aqueous mixture. The aqueous mixture is about 33 parts binder material, 29 parts isomalt, 4.1 parts maltitol, 2 parts salt and 33 parts water.

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

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

[0126] b) Starch Formed Preparation 2 A nicotine-containing preparation suitable for use as a starch forming component of a pharmaceutical composition for oral use is provided by the following method. A binder material (gum arabic) is hydrated with water and then sodium hydroxide is added to adjust the mixture to a pH of 8.0 to prepare an aqueous mixture. The mixture is heated to about 82 °C. Separately, isomalt and maltitol syrup are combined, heated to about 166 °C, cooled to about 132 °C and added to the aqueous mixture. Flavoring, salt, sucralose, glycerin and nicotine are added and mixed. The mixture of the nicotine-containing compound composition 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 nicotine-containing compound composition is placed in a starch mold at a temperature of about 71 °C (the placement temperature should be above about 66 °C). The nicotine-containing compound composition is left in the starch mold at about 60 °C for about 72 hours. The nicotine-containing compound composition is allowed to cool and then removed from the starch mold. The nicotine-containing compound composition is then cured at ambient room temperature for about 24 hours.

[0128] Other acceptable excipients for starch molding 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 an injection molding formulation (pastille) a) Injection molding formulation 1 A nicotine compound-containing formulation suitable for use as an injection molding component of a pharmaceutical composition for oral use is provided by the following method. A wetting agent (available as Hystar 3375 from Corn Products International), an emulsifier (available as Dur-Em117 from Loders Croklaan), corn syrup, glycerin, and a flavoring are mixed and heated to form a liquid mixture.

[0130] Nicotine is mixed with a 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 components are mixed in a Hobart mixer (model N-50) at about 120 rpm for about 4 - 5 minutes to form a nicotine compound-containing composition. The nicotine compound-containing composition is passed through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. The nicotine compound-containing composition is extruded from the grinder. After extrusion, the nicotine compound-containing composition is placed in the Hobart mixer to form powder granules. The mixture of the nicotine compound-containing composition consists of about 21.4 parts of binder material, 0.2 part of nicotine, 42.7 parts of wetting agent, 1.5 parts of emulsifier, 21.4 parts of polydextrose, 5.3 parts of corn syrup, 3.2 parts of glycerin, 2.8 parts of salt, 0.3 part of sucralose, and 1.2 parts of flavoring.

[0131] Transfer the granulated nicotine-containing composition to an injection molding mold and compress it at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel, filled with the nicotine-containing composition, and then compressed in engagement with a hydraulic press unit (Wabach Hydraulic Press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, remove the nicotine-containing composition from the injection molding mold.

[0132] b) Injection molding formulation 2 Provide a nicotine-containing composition suitable for use as a pharmaceutical composition for oral use by the following method. Mix a filler (maltitol; available as Recatin from Rocket Frail S.A.), an emulsifier (available as DUR-EM117 from Rhoders Croclean), corn syrup, glycerin and a flavoring, and heat to form a liquid mixture.

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

[0134] Transfer the granulated nicotine-containing composition to an injection molding mold and compress it at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel, filled with the nicotine-containing composition, and then compressed in engagement with a hydraulic press unit (Waback hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, remove the nicotine-containing composition from the injection molding mold.

[0135] c) Injection molding formulation 3 Provide a nicotine-containing composition suitable for use as a pharmaceutical composition for oral use by the following method. Mix a filler (maltitol; available as Recatin from Rocket Frail S.A.), an emulsifier (available as DUR-EM117 from Rodas Croclan), corn syrup, glycerin and a flavoring, and heat to form a liquid mixture.

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

[0137] Transfer the granulated nicotine-containing composition to an injection molding mold and compress it at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel, filled with the nicotine-containing composition, and then compressed in engagement with a hydraulic press unit (Waback hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, remove the nicotine-containing composition from the injection molding mold.

[0138] d) Injection molding formulation 4 Provide a nicotine-containing composition suitable for use as a pharmaceutical composition for oral use by the following method. Mix a wetting agent (available as Hystar 3375 from Cargill Products International), an emulsifier (available as Dur-Em 117 from Rhodia Clariant), corn syrup, glycerin and a flavoring, and heat to form a liquid mixture.

[0139] Mix nicotine with a salt, sucralose, a binder material (gum arabic) and polydextrose powder (available as Litesse from Danisco A / S) in a Hobart mixing bowl. Add the liquid mixture to the Hobart mixing bowl containing the nicotine mixture, binder material and polydextrose powder, where the components are mixed in a Hobart mixer (model N-50) at about 120 rpm for about 4 - 5 minutes to form a nicotine-containing composition. Pass the nicotine-containing composition through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. Extrude the nicotine-containing composition from the grinder. After extrusion, place the nicotine-containing composition in the Hobart mixer to form powder granules. The mixture of the nicotine-containing composition consists of about 22.4 parts of binder material, 0.2 part of nicotine, 40 parts of wetting agent, 1.6 parts of emulsifier, 22.4 parts of polydextrose, 5.6 parts of corn syrup, 3.4 parts of glycerin, 2.8 parts of salt, 0.3 part of sucralose and 1.3 parts of flavoring.

[0140] Transfer the granulated nicotine-containing composition to an injection molding mold and compress it at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel, filled with the nicotine-containing composition, and then compressed in engagement with a hydraulic press unit (Waback hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, remove the nicotine-containing composition from the injection molding mold. e) Injection molding formulation 5 Provide a nicotine-containing composition suitable for use as a pharmaceutical composition for oral use by the following method. Mix a wetting agent (available as Hystar 3375 from Corn Products International), an emulsifier (available as Dur-Em 117 from Rhodia's Croclan), corn syrup, glycerin, and a flavoring, and heat to form a liquid mixture.

[0141] Mix nicotine with a salt, sucralose, a binder material (gum arabic), and polydextrose powder (available as Litesse from Danisco A / S) in a Hobart mixing bowl. Add the liquid mixture to the Hobart mixing bowl containing the nicotine mixture, binder material, and polydextrose powder, where the components are mixed in a Hobart mixer (model N-50) at about 120 rpm for about 4 - 5 minutes to form a nicotine-containing composition. Pass the nicotine-containing composition through a meat grinder on the Hobart mixer to incorporate the liquid components into the dry components. Extrude the nicotine-containing composition from the grinder. After extrusion, place the nicotine-containing composition in the Hobart mixer to form powder granules. The mixture of the nicotine-containing composition consists of about 26 parts of binder material, 0.2 parts of nicotine, 31.5 parts of wetting agent, 1.2 parts of emulsifier, 26 parts of polydextrose, 6.2 parts of corn syrup, 4.1 parts of glycerin, 2 parts of salt, 0.2 parts of sucralose, and 0.9 parts of flavoring.

[0142] Transfer the nicotine-containing composition to an injection molding mold and compress it at about 103,500 kPa for 1 minute. The mold is a two-piece block of stainless steel, filled with the nicotine-containing composition, and then compressed in engagement with a hydraulic press unit (Waback hydraulic press, model 12-102T, serial 2201). After cooling at ambient temperature for about 60 minutes, remove the nicotine-containing composition from the injection molding mold.

[0143] Other acceptable excipients for injection molding 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 mold formulation A nicotine-containing formulation suitable for use as a chewable component of a pharmaceutical composition for oral use is provided by the following method. Prepare an aqueous mixture. Add nicotine and hydrate the binder material (gum arabic) with water to form an aqueous mixture. The aqueous mixture consists of about 49.7 parts of binder, about 0.6 part of nicotine and about 49.7 parts of water. Mix the aqueous mixture with salt (NaCl), buffer (sodium hydroxide), sweetener (sucralose), glycerin and emulsifier (sunflower lecithin) and dissolve the added components therein. Heat the mixture to about 49 °C. Combine the heated mixture with a lipid material (available as 108-24-B from Arisco Sham, USA) heated to form a melt and flavorant having a melting point of about 38 °C to about 42 °C. The mixture of the nicotine-containing composition consists of about 36 parts of aqueous mixture, 24 parts of lipid material, 6 parts of glycerin, 0.2 part of emulsifier component, 0.2 part of sucralose, 0.6 part of salt, 0.3 part of buffer, 0.6 part of flavorant and 32 parts of water.

[0145] Nicotine-containing compositions are formed in various ways. In one example, it is placed in a mold and left in the mold under ambient conditions until dry, and then removed from the mold. In another example, it is poured onto the top plate of a table, air-dried to a semi-moist state, and formed into the desired shape using a drop roller.

[0146] Example 6: Preparation of a 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 consists of 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. Flavorings and dyes (to provide an appearance with a pearlescent sheen) are added to obtain a nicotine-containing composition consisting of about 10 parts aqueous mixture (about 0.2 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 onto a sheet (for example, by casting onto a sheet on a stainless steel plate), or can be dip-coated or spray-coated onto the composition described above in this example. When casting the formulation onto a sheet, it is cut (for example, using a casting knife) and can be applied as a sandwich coating onto the composition described above in this example. When dip-coating or spray-coating the formulation, it is maintained at a temperature above about 66 °C, applied as a liquid, and then cooled until cured.

[0148] Example 7: Preparation of a Two-Layer Product a) Lozenge / Meltability Prepare the lozenge-shaped preparation as described in Example 1, pour it into a mold, and cool it. Prepare the melt-type preparation described in Example 2. However, instead of pouring the fluid slurry into the mold, apply it directly to the surface of the cooled lozenge-shaped preparation. For example, immerse the shaped lozenge-shaped preparation in the fluid slurry, dry and cure it at room temperature to provide a two-layer product comprising a lozenge-shaped core and a melt-type coating material.

[0149] b) Lozenge / Tubular Prepare the lozenge-shaped preparation as described in Example 1, pour it into a mold, and cool it. Prepare the tubular preparation described in Example 5. Pour the preparation onto the top plate of a table and air-dry it to a semi-moist state, form it around the surface of the lozenge-shaped preparation, and provide a two-layer product comprising a lozenge-shaped core and a tubular-type coating material.

[0150] c) Lozenge / Hard Coating Material Prepare the lozenge-shaped preparation as described in Example 1, pour it into a mold, and cool it. Prepare the hard-coated type preparation described in Example 6. Cast the coated preparation onto a sheet, cut it, and apply it directly as a sandwich coating material to the surface of the lozenge-shaped product to provide a two-layer product comprising a lozenge-shaped core and a hard-coated type coating material.

[0151] d) Melting / Lozenge Prepare the melt-type preparation as described in Example 2. Prepare the lozenge-shaped preparation as described in Example 1, but instead of pouring the high-temperature mixture into the mold, apply it directly to the surface of the melt-type preparation. For example, the high-temperature mixture can be introduced into a spray coating apparatus adapted to maintain a temperature of about 132 °C and sprayed onto the surface of the cooled melt-type preparation. As described in Example 1, the mixture must be kept at a high temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape. Since the melt-type preparation can exhibit some melting at such high temperatures, steps must be taken to avoid or limit the melting of the melt-type preparation during the application of the lozenge-shaped preparation. For example, the melt-type preparation can be frozen before applying the lozenge-shaped preparation to limit the degree of melting.

[0152] e) Melting / hard coating material Prepare the melt-type preparation as described in Example 2. Prepare the hard-coated preparation described in Example 6. Cast the coated preparation onto a sheet, cut it, and directly apply it as a sandwich coating material onto the surface of the melt-type product to provide a two-layer product comprising a melt-type core and a hard-coated coating material.

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

[0154] g) Starch molding / lozenge Prepare the starch molding preparation as described in Example 3, pour it into a mold, and cool it. Prepare the lozenge-type preparation described in Example 1, but instead of pouring the high-temperature mixture into the mold, directly apply it onto the surface of the starch molding preparation. For example, the high-temperature mixture can be introduced into a spray coating apparatus adapted to maintain a temperature of about 132°C and sprayed onto the surface of the cooled starch molding preparation. As described in Example 1, the mixture must be kept at a high temperature to maintain sufficient elasticity and flexibility to be manipulated into the desired shape.

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

[0156] i) Injection molding / Lozenges Prepare the injection molding formulation as described in Example 4, injection mold it into the desired size and shape, and cool it. Prepare the lozenge formulation as described in Example 1, except that instead of pouring the hot mixture into a mold, apply it directly to the surface of the injection molding formulation. For example, the hot mixture can be introduced into a spray coating apparatus adapted to maintain a temperature of about 132 °C and sprayed onto the surface of the cooled injection molding formulation. As described in Example 1, the mixture must be kept hot to maintain sufficient elasticity and flexibility to be manipulated into the desired shape.

[0157] Example 8: Preparation of a three-layered product a) Lozenge / melt / hard coating Prepare a two-layered product comprising a lozenge core and a melt coating as described above in Example 7a. Prepare the hard coating formulation described in Example 6. Cast the coated formulation onto a sheet, cut it, and apply it directly as a sandwich coating onto the surface of the two-layered lozenge / melt composition to provide a three-layered product comprising a lozenge core, a melt first coating, and a hard coating second coating.

[0158] b) Starch molding / Lozenge / melt Prepare a two-layered product comprising a starch molding core and a lozenge coating as described above in Example 7g. Prepare the melt formulation described in Example 2. However, instead of pouring the fluid slurry into a mold, apply it directly to the surface of the cooled two-layered starch molding / lozenge composition. For example, immerse the two-layered composition in the fluid slurry, dry and cure it at room temperature to provide a three-layered product comprising a starch molding core, a lozenge first coating, and a melt second coating.

[0159] Using the teachings set forth in the foregoing specification, many modifications and other embodiments related to the present invention will come to mind to those skilled in the art to which the present invention pertains. Accordingly, it is understood that the present invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Specific terms are used in this specification, but they are used only in a generic and descriptive sense and not for purposes of limitation.

Claims

A pharmaceutical suitable for oral administration to a human subject, comprising two different formulations, wherein the two different formulations are a) a first formulation comprising a powder as the core of the pharmaceutical and nicotine adsorbed on a porous microparticle carrier; and b) a second formulation comprising, as a soluble outer coating material surrounding the first formulation, at least 10% by weight, based on the weight of the second formulation, of one or more film formers or binders, and optionally a plasticizer, flavor, sweetener, colorant, salt, or combinations thereof. comprising wherein the first and second formulations have different functional properties; a pharmaceutical. **Claim 2** The pharmaceutical according to claim 1, wherein the one or more film formers or binders comprise one or more components selected from the group consisting of film-forming polymers, starch-based binders, and modified cellulose-based binders. **Claim 3** The pharmaceutical according to claim 1, wherein the one or more film formers or binders are selected from the group consisting of povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium alginate, acacia gum, xanthan gum, gum arabic, gellan gum, lecithin, pullulan, potato starch, corn starch, and combinations thereof. **Claim 4** The pharmaceutical according to claim 1, wherein the second formulation further comprises a filler component selected from the group consisting of grains, polysaccharides, maltodextrin, glucose, calcium carbonate, calcium phosphate, polycarbophil calcium, corn starch, lactose, sugar alcohol, cellulose, and combinations thereof. **Claim 5** The pharmaceutical according to any one of claims 1 to 4, wherein the second formulation comprises at least 20% by weight, based on the weight of the second formulation, of the one or more film formers or binders. **Claim 6** The pharmaceutical according to claim 1, wherein the second formulation is in the form of a single continuous layer surrounding the core. **Claim 7** The pharmaceutical according to claim 1, wherein the second formulation further comprises one or more flavors. **Claim 8** The pharmaceutical according to claim 1, wherein the second formulation further comprises nicotine. **Claim 9** The pharmaceutical according to claim 1, wherein the second formulation further comprises one or more sweeteners. **Claim 10** The pharmaceutical according to claim 1, wherein the porous microparticle carrier of the first formulation comprises microcrystalline cellulose (MCC).

11. A method for preparing the pharmaceutical composition according to claim 1, comprising: combining nicotine adsorbed on the porous microparticle carrier with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorings, sweeteners, emulsifiers, disintegrating aids, wetting agents, buffering agents, and mixtures thereof to form a mixture of a first formulation and preparing the mixture of the first formulation, and forming the mixture of the first formulation on the core of the pharmaceutical composition; combining the one or more film formers or binders with one or more components selected from the group consisting of binders, lipid components, polysaccharide fillers, sugar substitutes, sugar alcohol syrups, flavorings, sweeteners, emulsifiers, disintegrating aids, wetting agents, buffering agents, and mixtures thereof to form a mixture containing a second nicotine compound and preparing a mixture of a second formulation; and applying the mixture of the second formulation to the core to provide the pharmaceutical composition wherein the method includes the above steps.

12. The method according to claim 11, wherein the applying includes spray coating the mixture of the second formulation onto the core, dip coating the core in the mixture of the second formulation, or forming the mixture of the second formulation on a sheet applied to the core as a sandwich coating material on the core.

13. The pharmaceutical composition according to claim 4, wherein the sugar alcohol is selected from the group consisting of erythritol, arabinitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof.

14. The pharmaceutical composition according to claim 9, wherein the one or more sweeteners include natural sweeteners selected from the group consisting of fructose, sucrose, glucose, maltose, vanillin, ethyl vanillin glucoside, mannose, galactose, lactose, and combinations thereof.

15. The pharmaceutical composition according to claim 9, wherein the one or more sweeteners include artificial sweeteners selected from the group consisting of sucralose, saccharin, aspartame, acesulfame K, neotame, and combinations thereof.