Inhalable nicotine formulations and methods of making and using the same

Abstract

To provide dry powder formulations comprising nicotine, methods of using the same, and methods for making the same.SOLUTION: The dry powder formulations may further comprise excipients, therapeutic agents, and flavor components. The dry powder formulations may be manufactured by dry processes and wet processes.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. patent application Ser. No. 14 / 856,102, filed Sep. 16, 2015, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Smoking is an addictive habit that has been found to contribute to or be a causative factor in a number of diseases, including respiratory diseases such as emphysema, chronic bronchitis, lung infections, and lung cancer, as well as various cardiac conditions. With the rise in public awareness of the harmful effects of smoking on human health, an increasing number of smokers are trying to quit the habit. Today, it is widely accepted in the scientific and medical communities that nicotine in cigarette smoke creates addiction through the effects it has on nicotine receptors in the brain. Most daily smokers become addicted or dependent on the pharmacological effects of nicotine in tobacco smoke. A common strategy to overcome nicotine addiction in general, and nicotine craving in particular, is to mimic the effects of cigarette smoking, followed by a gradual reduction and eventual complete elimination. Smoking has several effects that potential therapeutic formulations or treatments seek to mimic. The most important effects of smoking are the chemical and mechanical effects of cigarette smoke on the smoker's airways and the absorption of nicotine into the smoker's blood. The chemical and mechanical effects of cigarette smoke on the smoker's airways result in the smoker experiencing a certain level of satisfaction. The absorption of nicotine into the smoker's blood results in nicotine reaching various receptors in the smoker's nervous system, which then influences the perception of nicotine craving experienced by the smoker. Both effects may be mimicked by administering a dose of a nicotine formulation to a subject seeking smoking cessation therapy. Nicotine addiction can be treated by gradually reducing the dose until complete elimination.

[0003] Leucine is an amino acid with an aliphatic isobutyl side chain. As a result, leucine is typically classified as a hydrophobic amino acid. Leucine is an essential amino acid because the human body cannot synthesize leucine and must obtain it from exogenous sources. Leucine has a variety of metabolic roles, particularly in the formation of sterols and in stimulating muscle protein synthesis. Lactose is a disaccharide found in milk and has two residues, galactose and glucose. Lactose is used in pharmaceutical applications, for example as a bulking agent, due to its physical properties (e.g., compressibility). Tartaric acid is a dibasic acid that occurs naturally in many plants, such as grapes and bananas. Tartrates are salts of tartaric acid with basic compounds, such as nicotine.

[0004] Menthol is a well-known and widely used topical analgesic, decongestant and antitussive. Nearly all cigarettes contain menthol to modify flavor and reduce coughing. If the concentration of menthol in a cigarette is greater than 3%, it is labeled as a menthol cigarette. The use of menthol in cigarettes includes its addition to tobacco leaves. Menthol-filled plastic balls can be provided in cigarette filters and then crushed before the cigarette is smoked. When the cigarette is lit, the heated smoke acts to volatilize and transport the menthol to the smoker's airways. There is a need in the art for improved formulations of nicotine, particularly dry powder formulations suitable for inhalation. The present invention fulfills this need. Summary of the Invention [Means for solving the problem]

[0005] A dry powder nicotine formulation suitable for inhalation is described. The formulation comprises nicotine, at least one sugar and at least one amino acid. In one embodiment, the nicotine comprises at least one nicotine salt. In another embodiment, the at least one nicotine salt is nicotine tartrate. In another embodiment, the concentration of nicotine is between about 0.5% and about 10%. In another embodiment, the concentration of nicotine is between about 0.7% and about 5%. In another embodiment, the concentration of nicotine is about 0.5%. In another embodiment, the concentration of nicotine is about 0.7%. In another embodiment, the concentration of nicotine is about 1%. In another embodiment, the concentration of nicotine is about 1.5%. In another embodiment, the concentration of nicotine is about 2%. In another embodiment, the concentration of nicotine is about 2.5%. In another embodiment, the concentration of nicotine is about 3%. In another embodiment, the concentration of nicotine is about 3.5%. In another embodiment, the concentration of nicotine is about 4%. In another embodiment, the concentration of nicotine is about 4.5%. In another embodiment, the concentration of nicotine is about 5%. In another embodiment, the concentration of nicotine is about 10%. In one embodiment, the at least one sugar is lactose. In one embodiment, the concentration of lactose is between about 50% and about 80%. In another embodiment, the concentration of lactose is between about 50% and about 99%. In another embodiment, the concentration of lactose is at least about 50%. In another embodiment, the concentration of lactose is about 85%. In another embodiment, the concentration of lactose is about 90%. In one embodiment, the at least one amino acid is leucine. In one embodiment, the concentration of leucine is between about 0.5% and about 10%. In one embodiment, the concentration of leucine is about 10%. In one embodiment, the formulation further comprises at least one flavor ingredient. In one embodiment, the formulation further comprises at least one therapeutic agent. In one embodiment, the at least one therapeutic agent is an antitussive. In one embodiment, the formulation further comprises menthol. In one embodiment, the concentration of menthol is between about 0.5% and about 20%. In one embodiment, the formulation further comprises mint. In one embodiment, the concentration of mint is between about 0.5% and about 20%. In one embodiment, the concentration of mint is about 0.5%.

[0006] Also described is a method for controlling the amount of nicotine and the amount of menthol in a formulation to be inhaled by a subject. The method includes the steps of specifying a desired concentration of nicotine in the formulation, specifying a desired total dose of nicotine in the formulation, specifying a desired concentration of menthol in the formulation, specifying a desired total dose of menthol in the formulation, and providing a quantity of the formulation to the subject, the formulation comprising nicotine particles and menthol particles, such that the total amount of nicotine particles in the quantity of the formulation is equal to the specified total dose of nicotine, and the total amount of menthol particles in the quantity of the formulation is equal to the specified total dose of menthol, and the formulation has a specified desired concentration of nicotine and a specified desired concentration of menthol. In one embodiment, the nicotine comprises at least one nicotine salt. In another embodiment, the at least one nicotine salt is nicotine tartrate. In one embodiment, the formulation further comprises at least one sugar. In one embodiment, the at least one sugar is lactose. In one embodiment, the formulation further comprises at least one amino acid. In one embodiment, the at least one amino acid is leucine. In one embodiment, the formulation further comprises at least one therapeutic agent. In one embodiment, the formulation further comprises at least one flavoring ingredient. In one embodiment, the formulation is delivered to a subject by a dry powder inhaler.

[0007] A method is also described for delivering various dosages of nicotine to a subject over multiple doses while maintaining a constant amount of menthol per inhalation for each dose. The method includes the steps of identifying a desired concentration of nicotine in a nicotine formulation having a base menthol concentration, preparing a first dose comprising an amount of the formulation comprising nicotine particles having the identified concentration of nicotine and menthol particles having a base menthol concentration, and preparing at least one further dose comprising an amount of the formulation comprising nicotine particles, wherein the at least one further dose comprises more nicotine particles than the formulation in the first dose or less nicotine particles than the formulation in the first dose and comprises the same base menthol concentration as in the first dose. In one embodiment, the nicotine comprises at least one nicotine salt. In one embodiment, the at least one nicotine salt is nicotine tartrate. In one embodiment, the formulation further comprises at least one sugar. In another embodiment, the at least one sugar is lactose. In one embodiment, the formulation further comprises at least one amino acid. In one embodiment, the at least one amino acid is leucine. In one embodiment, the formulation further comprises at least one therapeutic agent. In one embodiment, the formulation further comprises at least one flavoring ingredient. In one embodiment, the formulation is delivered to a subject by a dry powder inhaler.

[0008] Kits for delivering dry powder nicotine formulations are also described. The kits include at least a quantity of a nicotine formulation, which includes nicotine particles, and instructional materials. The following detailed description of the preferred embodiments of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. [Brief description of the drawings]

[0009] [Figure 1]1 is a flow chart illustrating an exemplary method for delivering a desired amount of nicotine and a desired amount of menthol to a subject. [Diagram 2] 1 is a flow chart illustrating an exemplary method for delivering reduced or increased dosages of nicotine to a subject over multiple doses while maintaining a constant level of menthol per dose. [Diagram 3] 1 is a table illustrating exemplary formulations of the present invention that deliver a constant amount of nicotine with increasing amounts of menthol. [Figure 4] 1 is a table illustrating exemplary formulations of the present invention that deliver decreasing amounts of nicotine while maintaining a constant amount of menthol. [Diagram 5] 1 is a flow chart illustrating an exemplary method of making a formulation of the present invention, including a dry blending step. [Figure 6] 1 is a flow chart illustrating an exemplary method of making a formulation of the present invention, which includes a wet-mixing step. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention provides dry powder formulations containing nicotine, methods for using the same, and methods for making the same. The dry powder formulations may further include excipients, therapeutic agents, and flavoring ingredients. The dry powder formulations may be manufactured by dry and wet processes.

[0011] definition Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. As used herein, each of the following terms has the meaning associated with it in this section. The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0012] As used herein, "about" when referring to a measurable value, e.g., an amount, a period of time, etc., is intended to encompass variations of ±20%, ±10%, ±5%, ±1%, and ±0.1% from the specified value, where such variations are appropriate. As used herein, the term "composition" refers to a mixture of at least one compound or molecule useful in the present invention with one or more different compounds, molecules or materials.

[0013] As used herein, the term "formulation amount" refers to the total or partial amount of a dry powder nicotine formulation packaged in a disposable container, such as a capsule or blister pack, for use with a dry powder inhaler, or the total or partial amount of an unpackaged dry powder nicotine formulation that may be loaded into a delivery chamber or compartment of a dry powder inhaler. As used herein, "inhalation" typically refers to the act of inhaling a quantity of a nicotine dry powder formulation from a dry powder inhaler and can mean, for example, a single inhalation or multiple inhalations. As used herein, "instruction material" includes physical or electronic publications, records, diagrams, or any other medium of expression that can be used to communicate the utility of the compositions and methods of the invention for their designated use. The instruction material of the kits of the invention may, for example, be affixed to a container containing the composition or shipped together with a container containing the composition. Alternatively, the instruction material may be delivered separately from the container, with the intention that the instruction material and the composition are used cooperatively by the recipient.

[0014] The term "pharmaceutical acceptable" refers to those properties and / or substances that are acceptable to patients from a pharmacological / toxicological standpoint and acceptable to the manufacturing pharmacist from a physical / chemical standpoint with respect to composition, formulation, stability, patient acceptance and bioavailability. "Pharmaceutically acceptable" may refer to a carrier and mean a medium that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the host to which it is administered. Other additional ingredients that may be included in the pharmaceutical composition used to carry out the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. Unless otherwise stated, a stated size or size range of a particle should be taken as the mass median aerodynamic diameter (MMAD) of a particle or set of particles. Such a value is the mass median aerodynamic diameter (MMAD) of a particle or set of particles that has the same aerodynamic behavior as the particle being characterized, within 1 gm / cm. 3 The particle sizes are based on the distribution of aerodynamic particle sizes, which is defined as the diameter of a sphere having a density of 100 nm to 100 nm. Because the particles described herein can vary in density and shape, the sizes of the particles are expressed as MMAD, which is not the actual diameter of the particle. Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have all possible subranges specifically disclosed, as well as individual numerical values ​​within that range. For example, the description of a range of 1 to 6 should be considered to have the specifically disclosed subranges of 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any whole and partial increments therebetween. This applies regardless of the breadth of the range.

[0015] Compositions and Compounds In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation. In one embodiment, nicotine is present in the formulation as a free base. In another embodiment, the formulation comprises a nicotine salt. In one such embodiment, the nicotine salt is nicotine tartrate. In another embodiment, the nicotine salt is nicotine hydrogen tartrate. In other embodiments, the nicotine salt may be prepared from any suitable non-toxic acid, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, hexafluorophosphoric acid, citric acid, gluconic acid, benzoic acid, propionic acid, butanoic acid, salicylic acid sulfuric acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, tartaric acid, arsonic acid, pamoic acid, p-toluenesulfonic acid, and mesylic acid. Suitable organic acids may be selected, for example, from the aliphatic, aromatic, carboxylic, and sulfonic classes of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, lactic acid, malic acid, mucic acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylate), stearic acid, sulfanilic acid, alginic acid, galacturonic acid, and the like.

[0016] In another aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation further comprising a sugar. In one embodiment, the sugar is a disaccharide. In one embodiment, the disaccharide is selected from the group consisting of sucrose, lactose, maltose, trehalose and cellobiose. In one embodiment, the sugar is lactose.

[0017] In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation further comprising an amino acid. In one embodiment, the amino acid is selected from the group consisting of histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, pyrrolysine, proline, selenocysteine, serine and tyrosine. In one embodiment, the amino acid is leucine.

[0018] In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation further comprising a flavor component. In one embodiment, the flavor component is derived from a natural flavor, a natural identical flavor, or an artificial flavor. Non-limiting examples of flavor components or flavors include banana, cherry, cinnamon, fruit, grape, orange, pear, pineapple, vanilla, quince, strawberry, and mint. In one embodiment, the flavor component is menthol. In another embodiment, the flavor component is mint.

[0019] As will be appreciated by those skilled in the art, mint generally refers to any and all flavors associated with the Lamiaceae plant genus, but is not limited to these. In one embodiment, the mint is a natural extract. In another embodiment, the mint is a commercial preparation, such as Coolmint Trusil Flavoring Powder supplied by International Flavors & Fragrances. In one embodiment, the mint is a substance. In another embodiment, the mint is a mixture of substances. In one embodiment, the mint includes menthol. In another embodiment, the mint includes trans-menthone. In another embodiment, the mint includes pinene. In another embodiment, the mint includes isomenthone. In another embodiment, the mint includes limonene. In another embodiment, the mint includes eucalyptol. In another embodiment, the mint includes pin-2(3)-ene. In another embodiment, the mint includes menthyl acetate. In another embodiment, the mint includes cineole. In another embodiment, the mint includes 4,5,6,7-tetrahydro-3,6-dimethylbenzofuran. In another embodiment the mint comprises pin-2(10)-ene. In another embodiment the mint comprises dipentene. In another embodiment the mint comprises d-limonene. In another embodiment the mint comprises (R)-p-mentha-1,8-diene.

[0020] In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation further comprising an antitussive. In one embodiment, the antitussive is menthol. In another embodiment, the antitussive is mint. As will be appreciated by those skilled in the art, menthol and / or mint may serve multiple roles in a formulation. In one embodiment, menthol is a flavoring ingredient. In another embodiment, menthol is a therapeutic agent, such as a cough suppressant. In one embodiment, mint is a flavoring ingredient. In another embodiment, mint is a therapeutic agent, such as a cough suppressant.

[0021] formulation The present invention relates to a dry powder formulation of nicotine suitable for inhalation. In one embodiment, the formulation comprises nicotine particles. In another embodiment, the formulation further comprises an excipient. In another embodiment, the formulation further comprises a therapeutic agent. In another embodiment, the formulation further comprises a flavor component.

[0022] As contemplated herein, any form of nicotine may be used as a nicotine-based ingredient. Preferably, the form of nicotine used is one that achieves rapid uptake into the patient's lungs. A form of nicotine that can be formed into particles is preferred. A form of nicotine that can be milled or co-milled with sugar or other ingredients may also be used. In another embodiment, nicotine is blended with sugar or other ingredients. In one embodiment, nicotine is a salt, which is a solid at room temperature. Nicotine may also be a pharmacologically active analog or derivative of nicotine, or a substance that mimics the effects of nicotine, either alone or in combination with other active substances. When nicotine is a base, it may be added to a liquid carrier, such as water, and mixed to produce a generally homogenous liquid mixture, which may then be dried by various methods to form a dry particulate formulation. In other embodiments, a form of nicotine that is soluble or miscible in a liquid carrier may also be used. For example, nicotine may be nicotine base, which is a liquid that is miscible in water at room temperature. Alternatively, nicotine base may be an oil formulation.

[0023] In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation, the nicotine concentration is between about 0.5% and about 10%. In another aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation, the nicotine concentration is between about 0.7% and about 5%. In one embodiment, the nicotine concentration is about 0.5%. In one embodiment, the nicotine concentration is about 0.7%. In another embodiment, the nicotine concentration is about 1%. In another embodiment, the nicotine concentration is about 1.5%. In another embodiment, the nicotine concentration is about 2%. In another embodiment, the nicotine concentration is about 2.5%. In another embodiment, the nicotine concentration is about 3%. In another embodiment, the nicotine concentration is about 3.5%. In another embodiment, the nicotine concentration is about 4%. In another embodiment, the nicotine concentration is about 4.5%. In another embodiment, the nicotine concentration is about 5%. In another embodiment, the nicotine concentration is about 5.5%. In another embodiment, the nicotine concentration is about 6%. In another embodiment, the nicotine concentration is about 6.5%. In another embodiment, the nicotine concentration is about 7%. In another embodiment, the nicotine concentration is about 7.5%. In another embodiment, the nicotine concentration is about 8%. In another embodiment, the nicotine concentration is about 8.5%. In another embodiment, the nicotine concentration is about 9%. In another embodiment, the nicotine concentration is about 9.5%. In another embodiment, the nicotine concentration is about 10%.

[0024] In one embodiment, the formulation comprises nicotine particles (also referred to herein as nicotine-based components) sized substantially between about 1-10 μm based on the MMD of the particles. In yet another embodiment, the formulation comprises nicotine particles sized substantially between about 1-7 μm. In another embodiment, the formulation comprises nicotine particles sized substantially between about 2-5 μm. In yet another embodiment, the formulation comprises nicotine particles sized substantially between about 2-3 μm. By selectively limiting or excluding nicotine particles less than about 1 μm in size or less than about 2 μm in size, the formulations of the present invention eliminate or at least reduce the ability of the subject to exhale nicotine back into the environment, thereby effectively reducing or eliminating the production of nicotine contained in sidestream smoke. Additionally, by selectively limiting or excluding nicotine particles that are not respirable, the formulations of the present invention reduce the undesirable irritation caused by nicotine particles taken up into the larger airways, oropharynx, glottal vocal cords, and other anatomical regions more proximal or more adjacent to the oral cavity. Thus, in some embodiments, the smallest particle in the nicotine particle size range is at least about 1 μm, at least about 1.1 μm, at least about 1.2 μm, at least about 1.3 μm, at least about 1.4 μm, at least about 1.5 μm, at least about 1.6 μm, at least about 1.7 μm, at least about 1.8 μm, at least about 1.9 μm, or at least about 2 μm. In some embodiments, the largest particle in the nicotine particle size range is about 10 μm or less, about 7 μm or less, about 6 μm or less, about 5 μm or less, about 4.5 μm or less, about 4 μm or less, about 3.5 μm or less, or about 3 μm or less. In certain embodiments, about 10% or less of the nicotine particles are less than about 1 μm. In certain embodiments, about 10% or less of the nicotine particles are less than about 2 μm. In other embodiments, at least 90% of the nicotine particles are less than about 10 μm. In other embodiments, at least 90% of the nicotine particles are less than about 7 μm. In other embodiments, at least 90% of the nicotine particles are less than about 5 μm. In one embodiment, no more than about 10% of the nicotine particles are less than about 1 μm, and at least 90% of the nicotine particles are less than about 10 μm.In one embodiment, about 10% or less of the nicotine particles are less than about 1 μm, and at least 90% of the nicotine particles are less than about 7 μm. In one embodiment, about 10% or less of the nicotine particles are less than about 2 μm, and at least 90% of the nicotine particles are less than about 5 μm. In one embodiment, about 10% or less of the nicotine particles are less than about 2 μm, and at least 90% of the nicotine particles are less than about 3 μm.

[0025] As will be understood by those skilled in the art, the particle size ranges described herein are not absolute ranges. For example, a nicotine particle mixture of the present invention in the size range of about 2-5 μm may contain some particles smaller or larger than the range of about 2-5 μm. In one embodiment, the particle size value presented for any particular component of the formulation of the present invention represents a D90 value, where 90% of the particles of the mixture are below the D90 value. In another embodiment, the particle size range represents a particle size distribution (PSD), where the percentage of the particles of the mixture falls within the recited range. For example, a nicotine particle size range of about 2-5 μm may represent a mixture of nicotine particles in which at least 50% of the particles are in the range of about 2-5 μm, although a higher percentage, such as but not limited to 60%, 70%, 80%, 90%, 95%, 97%, 98% or even 99%, is more preferred.

[0026] It should be appreciated that the particles of the nicotine-based component may be spherical or any other shape desired. In one embodiment, the particles have a rough or "dimpled" surface. In such an embodiment, the rough surface may increase the ability of the additional component to stick to the nicotine particles and produce a uniform coating. For example, the additional component may be a therapeutic agent, such as menthol, which ensures that all nicotine particles that hit the cough receptors are coated with menthol, thereby suppressing the cough reflex. The rough surface may also create relative turbulence as the particles move through the air, thus providing lift to the particles. In such an embodiment, particles with such a shape may more easily attach and remain attached to the air inhaled by the subject, thereby improving the ability of the nicotine-based component particles to move to and be retained in the alveoli and airways of the subject.

[0027] In one embodiment, the formulation comprises an amino acid. In one embodiment, the amino acid is leucine. In one embodiment, leucine acts as a stabilizer by reducing any degree of degradation of the compositions of the invention. In another embodiment, leucine prevents degradation of the compositions of the invention by acting as a buffer due to its buffering capacity. In another embodiment, leucine acts as a powder flow enhancer. In another embodiment, leucine in the compositions of the invention improves powder flow. In another embodiment, leucine in the compositions of the invention allows the particles of the powder formulation to more easily entrain and remain entrained in the air inhaled by the subject, thereby improving the ability of the composition particles to travel to and be retained in the alveoli and airways. In one embodiment, the percentage of leucine in the formulation is between 0.5% and 10%. In some embodiments, the percentage of leucine in the formulation is between 1.5% and 2.5%. In other embodiments, the percentage of leucine in the formulation is between 0.5% and 2.5%. In yet other embodiments, the percentage of leucine in the formulation is between 1.5% and 5%. In one embodiment, the percentage of leucine in the formulation is about 2.5%. In another embodiment, the percentage of leucine in the formulation is about 5%. In another embodiment, the percentage of leucine in the formulation is about 7.5%. In another embodiment, the percentage of leucine in the formulation is about 10%.

[0028] In one embodiment, the formulation further comprises an excipient. As contemplated herein, one embodiment of the excipient is a bulking agent. The bulking agent may comprise an inhalable sugar that is generally solid at room temperature. The sugar may be milled alone or co-milled with the nicotine component into the microparticle formulation. The sugar may also be soluble in a liquid carrier, such as water. Without limitation, examples of suitable sugars are lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, lecithin, mannitol, or combinations thereof. In one embodiment, the sugar is lactose. In another embodiment, the lactose is crude lactose. In another embodiment, the sugar is alpha monohydrate lactose. The sugar may be a natural or synthetic sugar, and may include any analog or derivative of sugar. It should be appreciated that any form of sugar approved as an excipient may be used as a carrier in the production of nicotine-based components. Although not required, the sugar is preferably of pharmaceutical grade, as will be understood by those skilled in the art. Preferably, the pharmaceutical grade sugar used to be ground alone, co-ground with the nicotine component, or to create a flowable mixture is a non-spheronized sugar. The pharmaceutical grade sugar may be prepared in a non-spheronized form prior to dry or wet mixing with the nicotine. For example, the pharmaceutical grade sugar may be first prepared in a non-spheronized form by lyophilization, grinding, micronization, etc. In certain embodiments, the pharmaceutical grade sugar may be subjected to grinding, bussing, grinding, squeezing, cutting, sieving, or other physical degradation processes as understood by those skilled in the art, which ultimately reduce the particle size of the sugar and result in a non-spheronized sugar.

[0029] It should be appreciated that there is no limit to the ratio of nicotine to sugar used, and the actual ratio used will be based on the concentration of nicotine desired in the nicotine-based ingredient particles. Thus, in one embodiment, the sugar concentration is at least about 50%. In another embodiment, the sugar concentration is between about 50% and about 99%. In another embodiment, the sugar concentration is about 85%. In another embodiment, the sugar concentration is about 90%.

[0030] In another embodiment, the formulation may further comprise an excipient, which is any pharma- ceutically acceptable material, composition or carrier involved in carrying or transporting the compound useful in the present invention in or to the subject, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, thickener, solvent or encapsulating material, so that the compound useful in the present invention can perform its intended function. In one embodiment, the formulation further comprises a stabilizer. Each material must be "acceptable" in the sense of being compatible with the other components of the formulation, including nicotine, and not harmful to the subject. Some materials that may be useful in the formulations of the present invention include pharma- ceutically acceptable carriers, such as sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and acetylcellulose; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and Include polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; amino acids, such as leucine, L-leucine, D-leucine, DL-leucine, isoleucine, lysine, valine, arginine, aspartic acid, threonine, methionine, phenylalanine; alginic acid; amino acid derivatives, such as aspartame or acesulfame K; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical preparations.Other pharmaceutically acceptable materials that can be used in the preparation include any and all coating agents, antibacterial and antifungal agents, and absorption retardants, etc., that are compatible with the activity of nicotine or any other compound useful in the present invention and are physiologically acceptable to subjects.Supplementary active compounds, including pharma- ceutically acceptable salts of those compounds, can also be incorporated into the composition.Other additional components that can be included in the composition used in the practice of the present invention are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0031] In one embodiment, the formulation of the present invention may further comprise a therapeutic agent. In one embodiment, the additional antitussive component is menthol. In one embodiment, the concentration of menthol in the formulation is between about 0.5% and about 20%. As contemplated herein, any form of menthol, such as a solid form of menthol, may be used for processing into menthol particles, powders, solutions, or suspensions useful in the present invention. Non-limiting examples of solid forms of menthol include powders, crystals, solidified distillates, flakes, and compacts. In one embodiment, the menthol is in the form of crystals. The menthol may be processed into particles ranging in size from about 5 μm to about 10 μm using any method known in the art. In some embodiments, the menthol is mixed with additional liquid or solid additives for processing. Particulate additives may also be further used. In one embodiment, the menthol is mixed with silicon dioxide. In another embodiment, the menthol is mixed with a sugar, such as lactose. In some embodiments of the wet process, the menthol is processed in a liquid carrier. In another embodiment, the additional antitussive component is mint. In one embodiment, the concentration of mint in the formulation is between about 0.5% and about 20%. In another embodiment, the concentration of mint in the formulation is about 0.5%. As contemplated herein, any form of mint, for example a solid form of mint, can be used to process into mint particles, powders, solutions or suspensions useful in the present invention.

[0032] In one embodiment, the therapeutic agent may include an antitussive component having particles sized substantially between 5-10 μm. In another embodiment, the additional antitussive component may include benzocaine. It should be appreciated that the additional antitussive component may include any compound approved for suppressing cough. By selectively including menthol particles between 5-10 μm, these non-respirable menthol particles may reduce coughing in the upper respiratory tract of a subject. Thus, in some embodiments, the smallest particles in the particle size range of the additional antitussive component are at least about 5 μm, at least about 6 μm, at least about 7 μm, or at least about 8 μm. In some embodiments, the largest particles in the particle size range of the additional antitussive component are about 10 μm or less, about 9 μm or less, about 8 μm or less, or about 7 μm or less. In certain embodiments, about 10% or less of the additional antitussive particles are less than about 5 μm. In other embodiments, at least 90% of the additional antitussive particles are less than about 10 μm. In other embodiments, at least 90% of the additional cough suppressant particles are less than about 8 μm. In one embodiment, no more than about 10% of the additional cough suppressant particles are less than 4 μm and at least 90% of the additional cough suppressant particles are less than about 10 μm. In one embodiment, no more than about 10% of the additional cough suppressant particles are less than about 5 μm and at least about 90% of the additional cough suppressant particles are less than about 8 μm. In a preferred embodiment, the additional cough suppressant component is substantially comprised of particles in the 5-10 μm range, although the additional cough suppressant component may comprise a broader range of particles. In one embodiment, the additional cough suppressant component may comprise particles in the 5-25 μm range. In another embodiment, the additional cough suppressant component comprises particles substantially in the 5-50 μm range. In yet another embodiment, the additional cough suppressant component comprises particles substantially in the 5-100 μm range.

[0033] In another embodiment, the formulation of the present invention may further comprise an additional antitussive component having particles sized substantially between 10-200 μm. This additional antitussive component may be added to the formulation in place of or in addition to the additional antitussive components in the range of 5-10 already discussed. Thus, the formulation of the present invention may comprise two additional antitussive components, where each additional antitussive component has a substantially different particle size distribution. The 10-200 μm additional antitussive component may reduce coughing caused by irritation of the oropharynx, glottal vocal cords, and other anatomical areas proximal or more proximal to the oral cavity that contain receptors that may cause coughing or other undesirable sensations. As contemplated herein, these larger particles are substantially unable to enter the subglottic airway. Thus, in some embodiments, the smallest particles within the particle size range of the additional antitussive component are at least about 10 μm, at least about 12 μm, at least about 20 μm, at least about 30 μm, or at least about 50 μm. In some embodiments, the largest particle in the particle size range of the additional cough suppressant component is about 200 μm or less, about 150 μm or less, about 120 μm or less, about 100 μm or less, about 90 μm or less, or about 80 μm or less. In certain embodiments, about 10% or less of the particles of the additional cough suppressant component are less than about 10 μm. In certain embodiments, about 10% or less of the particles of the additional cough suppressant component are less than about 20 μm. In other embodiments, at least 90% of the particles of the additional cough suppressant component are less than about 200 μm. In other embodiments, at least 90% of the particles of the additional cough suppressant component are less than about 150 μm. In other embodiments, at least 90% of the particles of the additional cough suppressant component are less than about 100 μm. In one embodiment, about 10% or less of the particles of the additional cough suppressant component are less than 10 μm and at least 90% of the particles of the additional cough suppressant component are less than about 200 μm. In one embodiment, no more than about 10% of the particles of the further antitussive component are less than about 12 μm, and at least 90% of the particles of the further antitussive component are less than about 100 μm, hi one embodiment, the further antitussive component comprises menthol particles with a size between about 10-200 μm.In another embodiment, the additional antitussive component having particles between about 10-200 μm in size may include benzocaine. It should be appreciated that the additional antitussive component having particles between about 10-200 μm in size may include any compound approved for suppressing cough. In another example, the addition of at least one component in the formulation of the present invention other than the nicotine component may act to dilute the nicotine-containing particles and reduce coughing caused by nicotine irritation of the oropharynx, vocal cords, and other anatomical areas proximal to the trachea.

[0034] In one embodiment, the formulation of the present invention may include a flavoring ingredient having particles sized substantially between about 10-1000 μm. In one embodiment, the flavoring ingredient is substantially comprised of particles in the range of about 10-200 μm. In a preferred embodiment, the flavoring ingredient is substantially comprised of particles in the range of about 10-100 μm. The flavoring ingredient utilizes larger particles embedded therein that may impact in the oral cavity of a subject to provide the desired flavor. Furthermore, by limiting the particles of such flavoring ingredients to a size greater than about 10 μm, the ability of these particles to enter the lungs of a subject is limited. Thus, in some embodiments, the smallest particles within the particle size range of the flavoring ingredient are at least about 10 μm, at least about 12 μm, at least about 20 μm, at least about 30 μm, or at least about 50 μm. In some embodiments, the largest particle in the particle size range of the flavoring ingredient is about 1000 μm or less, about 500 μm or less, about 200 μm or less, about 150 μm or less, about 120 μm or less, about 100 μm or less, about 90 μm or less, or about 80 μm or less. In certain embodiments, about 10% or less of the particles of the flavoring ingredient are less than about 10 μm. In certain embodiments, about 10% or less of the particles of the flavoring ingredient are less than about 20 μm. In other embodiments, at least 90% of the particles of the flavoring ingredient are less than about 1000 μm. In other embodiments, at least 90% of the particles of the flavoring ingredient are less than about 500 μm. In other embodiments, at least 90% of the particles of the flavoring ingredient are less than about 200 μm. In other embodiments, at least 90% of the particles of the flavoring ingredient are less than about 150 μm. In other embodiments, at least 90% of the particles of the flavoring ingredient are less than about 100 μm. In one embodiment, about 10% or less of the particles of the flavoring ingredient are less than 10 μm and at least 90% of the particles of the flavoring ingredient are less than about 1000 μm. In one embodiment, about 10% or less of the particles of the flavoring ingredient are less than 10 μm and at least 90% of the particles of the flavoring ingredient are less than about 200 μm. In one embodiment, about 10% or less of the particles of the flavoring ingredient are less than about 10 μm and at least about 90% of the particles of the flavoring ingredient are less than about 100 μm. In one embodiment, the flavoring ingredient is mint. In another embodiment, the flavoring ingredient is menthol.In other embodiments, the flavoring ingredients may include tobacco, fruit flavors, or food grade flavors used in confectionery or baking. It should be recognized that the flavoring ingredients may be any flavoring agent known in the art, preferably an agency approved flavoring agent.

[0035] In various embodiments, the relative mass percentages of each component in the formulation of the present invention may be varied to achieve different characteristics. Thus, as will be appreciated by those skilled in the art, the relative mass percentages of the components may be altered for various reasons, including, but not limited to, achieving a certain level of blood nicotine concentration while adjusting the level of tightness in the subject's airways, achieving a certain level of tightness while adjusting the level of satisfaction perceived by the subject of treatment, achieving better uptake of nicotine in the patient's lungs, achieving faster blood nicotine kinetics, optimizing the antitussive performance of the formulation, altering or improving the taste of the formulation, and adjusting the relative dose of nicotine. In certain embodiments, the formulation may be about 1-20% by weight of flavor component, with 1-5% by weight of flavor component being preferred. In certain embodiments, the formulation may be about 1% by weight to about 10% by weight of antitussive, with 0.5% by weight to about 5% by weight of antitussive being preferred. In various embodiments, the remainder of the formulation, excluding any flavor component, antitussive component, carrier or other component, is the nicotine component. In one embodiment, the formulation may be approximately 10% nicotine content. In another embodiment, the formulation may be approximately 0.7% nicotine content. In another embodiment, the formulation may be approximately 0.75% nicotine content. In another embodiment, the formulation may be approximately 1.5% nicotine content. In another embodiment, the formulation may be approximately 5% nicotine content. In one embodiment, the percentage of lactose in the formulation is between 50% and 99%. In one embodiment, the percentage of lactose in the formulation is between 50% and 80%. In some embodiments, the percentage of lactose in the formulation is between 75% and 90%. In other embodiments, the percentage of lactose in the formulation is between 75% and 85%. In still other embodiments, the percentage of lactose in the formulation is between 80% and 90%. In still other embodiments, the percentage of lactose in the formulation is between 80% and 99%. In one embodiment, the percentage of lactose in the formulation is about 50%. In one embodiment, the percentage of lactose in the formulation is about 60%. In one embodiment, the percentage of lactose in the formulation is about 70%. In one embodiment, the percentage of lactose in the formulation is about 80%. In one embodiment, the percentage of lactose in the formulation is about 85%. In another embodiment, the percentage of lactose in the formulation is about 90%. In another embodiment, the percentage of lactose in the formulation is about 95%.In another embodiment, the percentage of lactose in the formulation is about 99%.

[0036] In one embodiment, the percentage of menthol in the formulation is between 0% and 20%. In some embodiments, the percentage of menthol in the formulation is between 5% and 20%. In other embodiments, the percentage of menthol in the formulation is between 5% and 15%. In yet other embodiments, the percentage of menthol in the formulation is between 10% and 20%. In one embodiment, the percentage of menthol in the formulation is about 0.5%. In one embodiment, the percentage of menthol in the formulation is about 5%. In another embodiment, the percentage of menthol in the formulation is about 20%.

[0037] In one embodiment, the percentage of mint in the formulation is between 0% and 20%. In some embodiments, the percentage of mint in the formulation is between 5% and 20%. In other embodiments, the percentage of mint in the formulation is between 5% and 15%. In yet other embodiments, the percentage of mint in the formulation is between 10% and 20%. In one embodiment, the percentage of mint in the formulation is about 0.5%. In another embodiment, the percentage of mint in the formulation is about 5%. In another embodiment, the percentage of mint in the formulation is about 20%.

[0038] Usage In one aspect, the present invention relates to a method for controlling the amount of nicotine and the amount of menthol inhaled by a subject, comprising increasing, decreasing or maintaining the amount of nicotine and the amount of menthol in a powder formulation inhaled by a subject. For example, as shown in FIG. 1, the method 100 includes steps 110 of specifying a concentration of nicotine for the subject to inhale, 120 of specifying a total dose of nicotine for the subject to inhale, 130 of specifying a concentration of menthol for the subject to inhale, and 140 of specifying a total dose of menthol for the subject to inhale. Finally, step 150 provides a quantity of the formulation to the subject, comprising nicotine particles having a specified concentration of nicotine and comprising menthol particles having a specified concentration of menthol, such that the total amount of nicotine particles and menthol particles in the formulation is equal to the total dose of nicotine and the total dose of menthol.

[0039] In another embodiment, as shown in Figure 2, a method 200 includes steps for decreasing the amount of nicotine while maintaining the amount of menthol inhaled by a subject. The method 200 includes steps of identifying 210 a concentration of nicotine in a nicotine formulation for inhalation by the subject having a base menthol concentration, providing 220 a first dose including a quantity of the formulation including nicotine particles having the identified concentration of nicotine and menthol particles having a base menthol concentration, and providing 230 at least one further dose including a quantity of the formulation including nicotine particles, the at least one further dose including fewer nicotine particles than the formulation in the first dose and including the same base menthol concentration as in the first dose.

[0040] Now referring to FIG. 3, three different formulations are outlined, where each formulation is designed to deliver the same dose of nicotine (1 mg). To achieve a basic level of nicotine delivery (formulation 1), the total dose of nicotine is formed as a part of a total formulation amount of 20 mg of powder containing 5% leucine and 90% lactose, resulting in a nicotine concentration in the formulation of 5%. Assuming that approximately 1 mg of powder can be inhaled per single inhalation, approximately 0.05 mg of nicotine is inhaled per single inhalation, and the total dose of nicotine is administered after the completion of approximately 20 inhalations to incorporate 20 mg of the formulation powder. To achieve an increased level of menthol delivery when delivering 1 mg of nicotine, the total dose of nicotine is a part of a total formulation amount of 20 mg of powder containing 5% leucine, 85% lactose and 5% menthol, resulting in a nicotine concentration of 5% (formulation 2). Assuming that approximately 1 mg of powder can be inhaled per inhalation, approximately 0.05 mg of nicotine is inhaled per inhalation, and the total dose of nicotine is administered after approximately 20 inhalations to incorporate 20 mg of formulation powder. By incorporating a certain amount of menthol per inhalation, the user experiences an increased level of cough suppression compared to formulation 1. In order to achieve an even increased level of cough suppression when delivering 1 mg of nicotine, the total dose of nicotine forms part of a total formulation amount of 20 mg of powder containing 5% leucine, 70% lactose and 20% menthol, resulting in a nicotine concentration of 5% (formulation 3). Assuming that approximately 1 mg of powder can be inhaled per inhalation, approximately 0.05 mg of nicotine is inhaled per inhalation, and the total dose of nicotine is administered after approximately 20 inhalations to incorporate 20 mg of formulation powder. By taking in an increased amount of menthol per inhalation, the user experiences an increased level of cough suppression compared to formulations 1 and 2.

[0041] In another embodiment, the total dose of nicotine can be reduced stepwise. For example, as shown in FIG. 4, three different formulations are outlined, where each formulation is designed to deliver a different (smaller) total dose of nicotine while maintaining the same amount of antitussiveness. Starting with formulation 4, a total dose of 1 mg of nicotine forms part of a total formulation amount of 20 mg of powder containing 5% leucine, 80% lactose and 10% menthol, resulting in a nicotine concentration of 5%. Assuming that approximately 1 mg of powder can be inhaled per single inhalation, this means that approximately 0.05 mg of nicotine is inhaled per single inhalation, and the total dose of nicotine is administered after the completion of approximately 20 inhalations of the first nicotine dose. Formulation 5 is designed to deliver a total dose of 0.5 mg of nicotine with the same level of antitussiveness. Thus, a total dose of 0.5 mg of nicotine may form part of a total formulation of 20 mg of powder containing 5% leucine, 82.5% lactose and 10% menthol, resulting in a nicotine concentration of about 2.5%. Assuming that approximately 1 mg of powder may be inhaled per single inhalation, this means that approximately 0.025 mg of nicotine is inhaled per single inhalation, and the total dose of nicotine is administered after approximately 20 inhalations with the same level of antitussiveness. Formulation 6 is designed to deliver a total dose of 0.3 mg of nicotine, again with the same level of antitussiveness. Thus, a total dose of 0.3 mg of nicotine may form part of a total formulation of 20 mg of powder containing 5% leucine, 83.5% lactose and 10% menthol, resulting in a nicotine concentration of about 1.5%. Assuming that approximately 1 mg of powder can be inhaled per single inhalation, this means that approximately 0.015 mg of nicotine is inhaled per single inhalation, and the total dose of nicotine is administered after approximately 20 completed inhalations at the same level of antitussiveness. Thus, the subject can gradually reduce the total dose of nicotine administered by subsequently administering formulations 4-6, while experiencing a constant level of antitussiveness throughout the reduction in the delivered nicotine. In one embodiment, formulations that reduce nicotine concentration can be used in smoking cessation regimens.Similarly, a subject can gradually increase the total dose of nicotine administered by subsequently administering formulations of increasing nicotine concentrations, while experiencing a constant level of cough suppression throughout the increases in nicotine delivered.

[0042] It should be appreciated that any manner in which the total dose of nicotine in a nicotine formulation is increased, decreased or maintained may be combined with any manner in which the amount of menthol in the formulation is increased, decreased or maintained. As contemplated herein, there is no limit to the concentration of nicotine in a particular formulation or total formulation of powder; rather, the present invention relates to the ability to vary one or both of these parameters when delivering a total dose of nicotine to a subject via a dry powder inhaler. Furthermore, there is no limit to the actual amount of powder inhaled per inhalation. Such amount may depend on the functionality of the dry powder inhaler used, or such amount may depend on the user's actions, where the user chooses to inhale shallower or deeper through the dry powder inhaler used. Furthermore, by administering the total dose of nicotine via multiple inhalations, the subject can ensure a more consistent uptake of the total dose of nicotine, and any user error that occurs during one inhalation is ultimately corrected by one or more subsequent inhalations.

[0043] Manufacturing method The present invention also relates to a method of making the formulation of the present invention. In one embodiment, the method comprises a dry blending step. In one embodiment, the method comprises a wet blending step. Referring now to FIG. 5, an exemplary dry process or method 300 for producing any one of the formulations described herein is illustrated. For example, in step 310, nicotine tartrate is dry milled. In step 312, nicotine is mixed with lactose and leucine. In step 313, a therapeutic agent, such as menthol, may be added. In some embodiments, nicotine or nicotine salt is not bound to any other component of the formulation. That is, the formulation contains discrete particles of nicotine or nicotine salt and discrete particles of other components of the formulation, such as sugar. In one embodiment, nicotine is not bound to lactose and leucine particles. In another embodiment, nicotine is not bound to menthol particles. In another embodiment, nicotine is at least partially bound to menthol particles. Alternatively, nicotine tartrate, lactose and leucine may be first dry mixed, for example, in step 314, and co-milled in step 316. In another embodiment, nicotine tartrate, lactose, leucine and a therapeutic agent, such as menthol, are first dry mixed, for example, at step 318, and co-milled at step 320. At step 330, the particles of the resulting formulation are filtered, for example, by a sieve, to remove any particles larger than a size threshold. At step 340, the particles of the resulting formulation are filtered again to remove any particles smaller than a size threshold to obtain the final dry powder formulation 350. In some embodiments, only one filtration step is required. In other embodiments, two or more filtration steps are required. At step 360, a flavor ingredient may be added to the final formulation 350. Step 360 may contain any number of processing steps necessary to obtain the desired particle size (e.g., 10-1000 μm) for the flavor ingredient to be added.

[0044] In the method of the present invention and for the formulation of the present invention, any method of blending particles is contemplated here.The blending step can be carried out in one or more steps of continuous, batch or semi-batch process.For example, when two or more excipients are used, they can be blended together before or at the same time as blending with pharmaceutical microparticles.

[0045] The blending step can be carried out using essentially any suitable technique or device for combining microparticles with one or more other materials (e.g., excipients) that are effective in achieving blend uniformity. The blending process can be carried out using a variety of blenders. Representative examples of suitable blenders include V-blenders, tilted cone blenders, cube blenders, bin blenders, static continuous blenders, dynamic continuous blenders, annular screw blenders, planetary blenders, Forberg blenders, horizontal double arm blenders, horizontal high intensity mixers, vertical high intensity mixers, impeller mixers, twin cone mixers, drum mixers and tumble blenders. The blenders are preferably designed to meet the strict hygienic requirements of pharmaceutical products. Tumble blenders are often preferred for batch operations. In one embodiment, the blending step is accomplished by aseptically combining two or more ingredients (which may include both dry ingredients and small amounts of liquid ingredients) in a suitable container. One example of a tumble blender is the TURBULA™ distributed by Glen Mills Inc., Clifton, NJ, USA, and made by Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzerland.

[0046] For continuous or semi-continuous operation, the blender may be equipped with a rotary feeder, screw conveyor, or other feeding mechanism to control the introduction of dry powder ingredients into the blender(s). The milling step is used to break up and / or deagglomerate the blended particles to achieve the desired particle size and size distribution, and to improve the distribution of the particles within the blend. As will be appreciated by those skilled in the art, any milling method can be used to form the particles of the present invention. Various milling processes and equipment known in the art may be used. Examples include hammer mills, ball mills, roller mills, disc grinders, jet mills, etc. Preferably, a dry milling process is used.

[0047] Referring now to FIG. 6, an exemplary wet process or method 400 for producing any one of the formulations described herein is illustrated. For example, in step 410, nicotine tartrate is mixed with excipients, such as lactose and leucine, to form a flowable mixture. In step 412, the mixture is atomized. Alternatively, in step 414, nicotine tartrate can be mixed with excipients, such as lactose and leucine, and a therapeutic agent, such as menthol, to form a flowable mixture. As contemplated herein, any liquid carrier can be used in the process for producing a solution or suspension. In one embodiment, the liquid carrier is water. Preferably, the liquid carrier is one in which the components of the formulation are either soluble or suspendable. Thus, the liquid carrier can be any liquid or liquids by which the components of the formulation, either alone or in combination, form a flowable mixture or suspension that is preferably a generally homogenous composition.

[0048] In step 416, the mixture is atomized. In step 420, the mixture is dried, for example, by a spray dryer. Alternatively, the process may be performed by fluidized bed drying, where nicotine tartrate may be spray dried onto the excipient mixture instead. In step 430, the resulting nicotine particles are filtered, for example, by a sieve, to remove any particles larger than a size threshold. In step 440, the resulting nicotine particles are filtered again to remove any particles smaller than a size threshold to obtain the final dry powder formulation 450. In some embodiments, only one filtration step is required. In other embodiments, two or more filtration steps are required. In step 460, a flavoring ingredient may be added to the final formulation 450. Step 460 may contain any number of processing steps necessary to obtain the desired particle size (e.g., 10-1000 μm) for the flavoring ingredient to be added.

[0049] The flowable mixture is dried, for example by a spray dryer, to produce composite particles of the flowable mixture suitable for delivery to the alveoli and lower airways of a subject. It should be recognized that there is no limit to the method of drying the flowable mixture. Although a preferred method utilizes a spray dryer, other drying techniques, such as fluidized bed drying, may be used that can produce appropriately sized particles. In one embodiment, the mixture is subdivided via passage through an orifice upon entry into the spray dryer. In another embodiment, the flowable mixture may be passed through an atomizer, such as a rotary atomizer, to feed the flowable liquid to the spray dryer. Still further, any rate of drying (e.g., drying at a low or high speed) may be used, provided that such rate of drying results in the formation of dried particles in the desired size range. Prior to the desired particle size division of the nicotine-based component, the resulting particles formed by the spray dryer may have a particle size of about 0.1 to about 5 μm.

[0050] Further fractionation / filtration of selected particle sizes can be performed in both dry and wet processes. In wet processes, the operating conditions of the spray dryer can be adjusted to generate particles sized to be able to travel to the alveoli and smaller airways of the lungs. For example, the rotary atomizer can be operated at a liquid feed rate of about 2 to about 20 ml / min, or about 2 to about 10 ml / min, or about 2 to about 5 ml / min. Furthermore, the rotary atomizer can be operated at about 10,000 to about 30,000 rpm, about 15,000 to about 25,000 rpm, or about 20,000 to about 25,000 rpm. It should be appreciated that particles of various sizes can be obtained by spray drying, and particles having a desired particle size can be more specifically selected when filtered, for example, by one or more sieving steps, as described elsewhere herein. The spray dryer may be operated at a temperature high enough to rapidly develop the liquid carrier without raising the temperature of the sugar and nicotine in the mixture to the point where these compounds begin to decompose. Thus, the spray dryer may be operated at an internal temperature of about 120°C to about 170°C, and an external temperature of about 70°C to about 100°C.

[0051] It should be recognized that there is no limit to the method of drying the flowable mixture.Examples of the method for drying the flowable mixture include, but are not limited to, spray drying, vacuum drying and freeze drying.Furthermore, any speed of drying (e.g., drying at low speed or high speed) can be used, provided that such speed of drying results in the formation of dry particles of desired size range. As already mentioned, in the wet process, the liquid carrier is dried, for example by a fluidized bed dryer, to produce composite particles of menthol-coated nicotine suitable for delivery to the alveoli and lower airways of a subject.It should be recognized that there is no limit to the method of drying the fluid mixture.Although the preferred method utilizes a fluidized bed dryer, other drying techniques may be used that can remove the liquid carrier and provide a uniform menthol coating on the nicotine particles.

[0052] As contemplated herein, the particles of the present invention may be produced in a relatively narrow size range by the use of at least one sieving step. In such an embodiment, the sieving step includes using a sieve corresponding to the minimum or maximum of the desired particle size range to remove particles smaller or larger than the desired range from the mixture. For example, a mixture of nicotine particles produced using the milling process described herein may be provided to obtain nicotine particles in the range of about 1-5 μm. The mixture of nicotine particles will have a size distribution that depends on the milling conditions used and / or the characteristics of the input mixture to the mill. The mixture of nicotine particles may first be passed through a 5 μm sieve, where substantially all of the particles smaller than 5 μm pass through the sieve and are collected. The particles that pass through the sieve may then be transferred to a 1 μm sieve, where substantially all of the particles larger than 1 μm do not pass through the sieve. The particles larger than 1 μm may be collected from the sieve, where the collected particles are substantially sized to the range of 1-5 μm. Thus, such processes can be used to narrow the range of any particle mixture into any of the desired particle size ranges described throughout this specification.

[0053] In another embodiment, a mixture of particles can be provided that substantially meets either the minimum or maximum criteria of the desired particle size range. For example, if a nicotine particle size range of about 2-5 μm is desired, a mixture of nicotine particles can be provided in which substantially all of the particles are less than 5 μm. Such a mixture can be produced by modifying the grinding conditions, or, if the particles are spray dried, by grinding the spray dried material to result in a mixture of particles that are generally less than 5 μm. The mixture is then transferred to a 2 μm sieve, where the particles that do not pass through the sieve are collected, and the collected particles are substantially within the desired 2-3 μm range. It is contemplated that for any of the components of the formulation of the present invention, the percentage of particles that fall within the desired particle size range may depend on the technology used to produce that component.For example, if the target size of a nicotine component is within the range of 2-5 μm, it is understood that when using spray-drying manufacturing technology on a relatively small scale, more than 90% of the component will fall within the desired range.However, when using milling manufacturing technology on a relatively large scale, only more than 70% of the nicotine component within such target range may be obtained.

[0054] Kits of the Invention The present invention also relates to nicotine kits, including but not limited to nicotine therapy kits and smoking cessation kits.In one embodiment, the kit can include a plurality of nicotine-based powder formulation doses contained in a sealed storage chamber, such as a capsule or blister pack.As contemplated herein, at least two formulation doses have equal total nicotine amounts but different nicotine concentrations.In another embodiment, the kit includes at least two sets of unpackaged nicotine-based powders with different nicotine concentrations, and a means for measuring the set amount of powder, such as a measuring spoon or graduated measuring container, that can be loaded into the storage chamber of dry powder inhaler.

[0055] In another embodiment, the kit includes pre-filled powder capsules for a set course of nicotine therapy or treatment, such as a 30-day course of treatment. The capsules can be loaded with various amounts of powder with various nicotine concentrations to suit the treatment regimen. In other embodiments, the kit includes instructional materials describing steps for a method for nicotine therapy, including but not limited to smoking cessation therapy. The method steps can include a starting dose, followed by a standard dose, e.g., multiple daily doses, and a final dose, to be administered by loading the dry powder formulation dose into a dry powder inhaler.

[0056] In another embodiment, the instructional material may instruct the user on a set course of days of nicotine therapy during which the daily nicotine dose may be adjusted. In one embodiment, the course of nicotine therapy lasts for between about 7 days and about 30 days. In another embodiment, the course of nicotine therapy lasts for between about 10 days and about 45 days. In another embodiment, the course of nicotine therapy lasts for between about 15 days and about 60 days. In another embodiment, the course of nicotine therapy lasts for between about 30 days and about 90 days. In a preferred embodiment, the course of nicotine therapy lasts for about 30 days. In another preferred embodiment, the course of nicotine therapy lasts for about 45 days. In another preferred embodiment, the course of nicotine therapy lasts for about 60 days. In another preferred embodiment, the course of nicotine therapy lasts for about 90 days.

[0057] The disclosures of all patents, patent applications and publications referenced herein are incorporated herein by reference in their entirety. Although the present invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the present invention may be devised by those skilled in the art without departing from the true spirit and scope of the present invention. It is intended that the appended claims be construed to include all such embodiments and equivalent variations.

Claims

1. A dry powder nicotine formulation suitable for inhalation, said formulation comprising nicotine complex particles comprising 0.5% to 10% of a nicotine salt, 60% to 85% of at least one sugar and at least one amino acid; at least 90% of said nicotine composite particles have a mass median aerodynamic diameter of less than 5μ; The nicotine concentration is between 0.7% and 5%. formulation.

2. 2. The formulation of claim 1, wherein the nicotine salt is a salt of nicotine with a carboxylic acid, including formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, lactic acid, malic acid, mucic acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylate), stearic acid, sulfanilic acid, alginic acid, or galacturonic acid.

3. 2. The formulation of claim 1, wherein the nicotine composite particles comprise between 50% and 85% of the at least one sugar.

4. 2. The formulation of claim 1, wherein the nicotine composite particles comprise between 60% and 80% of the at least one sugar.

5. 2. The formulation of claim 1, wherein the nicotine composite particles comprise between 70% and 80% of the at least one sugar.

6. 2. The formulation of claim 1, wherein the at least one sugar comprises lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, mannitol, or a combination thereof.

7. 2. The formulation of claim 1, wherein the at least one amino acid is leucine.

8. 10. The formulation of claim 1, further comprising at least one flavor ingredient or a cough suppressant or both.

9. 9. The formulation of claim 8, wherein the at least one flavor ingredient and / or antitussive comprises menthol.

10. 2. The formulation of claim 1, comprising said nicotine composite particles and optional flavor particles and further optional cough suppressant particles.

11. The formulation of claim 1 comprising a polyol.

12. 1. A method for producing a dry powder formulation comprising: mixing the nicotine salt, sugar and amino acid with a liquid carrier to form a flowable mixture; and spraying and drying said flowable mixture to form nicotine composite particles having a mass median aerodynamic diameter of less than 5 microns. The method includes:

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