JP7680823B2 - Inhalable nicotine formulations and methods of making and using same - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 15/452,133, filed March 7, 2017, which is a continuation-in-part of U.S. Patent Application No. 14/856,102, filed September 16, 2015, now U.S. Patent No. 9,585,835, both of which are incorporated by reference in their entireties herein.

Smoking is an addictive practice that has been shown to be a contributing or causal factor in many diseases, including respiratory diseases such as emphysema, chronic bronchitis, lung infections and lung cancer, and in various cardiac conditions. Growing concern over the harmful effects of smoking on human health has led to an increase in the number of smokers attempting to quit the habit. It is widely accepted in the scientific and medical communities that nicotine in tobacco smoke creates addiction through its effects on nicotine receptors in the brain. Many 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 and gradually reduce and eventually completely eliminate the effects of cigarette smoking.

There are several smoking effects that potential therapeutic formulations or methods attempt 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 a certain level of satisfaction experienced by the smoker. The absorption of nicotine into the smoker's blood allows nicotine to reach various receptors in the smoker's nervous system, which influences the perceived nicotine craving experienced by the smoker. Both effects can potentially be mimicked by the administration of a nicotine formulation dose to a subject seeking smoking cessation therapy. Nicotine addiction can be treated by gradually decreasing the dose until complete elimination is achieved.

Leucine is an amino acid with an aliphatic isobutyl side chain. As a result, leucine is generally classified as a hydrophobic amino acid. Leucine is an essential amino acid because the human body cannot synthesize it and must be provided from external sources. Leucine has a variety of metabolic roles, notably participating in the formation of sterols and stimulating muscle protein synthesis. Lysine is a basic amino acid with an amine side chain. Lysine is also an essential amino acid important for calcium absorption. The terminal amine of lysine can be chemically modified. Glycine, which has no side chain, is the smallest amino acid. Glycine is important in the biosynthesis of the structural protein collagen and has been used as a sweetener.

Lactose is a disaccharide found in milk, with 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, e.g. grapes and bananas. Tartrates are salts of tartaric acid with basic compounds, e.g. nicotine. Phospholipids are major components of cell membranes due to their amphipathic nature. Phospholipids are natural components of lung surfactant and are found in high concentrations in egg yolks and milk.

Menthol is a well-known and widely used topical analgesic, decongestant and antitussive. Nearly all cigarettes contain menthol to modify flavor and reduce coughing. Cigarettes with a menthol concentration greater than 3% are labeled as menthol cigarettes. Use of menthol in cigarettes includes addition to tobacco leaves. Menthol-filled plastic balls may be stored in the cigarette filter and then crushed before the cigarette is smoked. When the cigarette is lit, the heated smoke acts to volatilize the menthol and transport it 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.

In one aspect of the invention, a dry powder nicotine formulation suitable for inhalation is described. The formulation comprises nicotine, at least one sugar, and at least one amino acid selected from the group consisting of glycine and lysine or a combination thereof. In one embodiment, the formulation further comprises at least one phospholipid. In one embodiment, the formulation further comprises menthol. In another embodiment, the formulation further comprises mint. In one embodiment, the nicotine comprises nicotine tartrate. In one embodiment, the concentration of nicotine is between 0.5% and 10%. In one embodiment, the concentration of sugar is between 50% and 99%. In one embodiment, the concentration of amino acid is between 0.5% and 50%.

In another aspect of the invention, a dry powder nicotine formulation suitable for inhalation is described. The formulation comprises nicotine, at least one sugar, a mint, and at least one amino acid selected from the group consisting of glycine, lysine, and leucine. In one embodiment, at least 40% of the nicotine particles and amino acid particles are 3-4 microns. In another embodiment, at least about 80% of the nicotine particles and amino acid particles are 1-7 microns. In one embodiment, the sugar particle size is at least about 50 microns. In one embodiment, the mint particle size is at least about 20 microns.

In another aspect of the invention, a dry powder nicotine formulation suitable for inhalation is described. The formulation comprises nicotine particles, particles of at least one sugar, and particles of at least one amino acid selected from the group consisting of glycine, lysine, and leucine. In the formulation, the amino acid particles are not substantially bound to the nicotine particles. In one embodiment, the formulation further comprises at least one phospholipid. In one embodiment, the formulation further comprises a mint.

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 will be understood, however, that the invention is not limited to the precise arrangements and equipment of the embodiments shown in the drawings.
FIG. 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. FIG. 2 is a flow chart illustrating an exemplary method of delivering reduced or increased nicotine doses to a subject over multiple doses while maintaining a constant level of menthol per dose. FIG. 3 is a chart illustrating exemplary formulations of the present invention that deliver a constant amount of nicotine with increasing amounts of menthol. FIG. 4 is a chart illustrating an exemplary formulation of the present invention that provides a reduced amount of nicotine while maintaining a constant amount of menthol. FIG. 5 is a flow chart illustrating an exemplary method for making a formulation of the present invention, including dry blending. FIG. 6 is a flow chart illustrating an exemplary method for making a formulation of the present invention that involves wet blending.

The present invention provides dry powder formulations containing nicotine, methods of use thereof, and methods of manufacture thereof. 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.

Definitions Unless defined elsewhere, 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.

As used herein, the term "a" or "an" is used to refer to one or more than one (e.g., at least one) of the modified term. By way of example, "an element" means one element or more than one element.

As used herein, "about" when referring to measurable values such as amounts, lengths of time, and the like, is intended to include variations of ±20%, ±10%, ±5%, ±1%, and ±0.1% of the particular 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 using one or more different compounds, molecules, or materials.

As used herein, the term "formulation amount" refers to the total or partial amount of a powdered nicotine formulation packaged in a disposable container, such as a capule or blister pack, for use in a dry powder inhaler, or the total or partial amount of a bulk dry powder nicotine formulation that can be loaded into a delivery chamber or compartment of a powder inhaler.

As used herein, the term "inhalation" generally refers to the act of inhaling a quantity of a nicotine dry powder formulation from a dry powder inhaler and may refer, for example, to a single inhalation or multiple inhalations.

As used herein, "instruction material" includes physical or electronic publications, records, drawings, 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 be used cooperatively by the recipient.

The term "pharmacologically acceptable" refers to those properties and/or substances that are acceptable to the patient 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 also 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 pharmaceutical compositions used in the practice of the present invention are well 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, the stated size or size range of a particle should be considered as the mass median aerodynamic diameter (MMAD) of the particle or set of particles. Such value is based on the distribution of aerodynamic particle sizes, defined as the diameter of a sphere with a density of 1 gm/cm3 that has the same aerodynamic behavior as the particle being characterized. Because the particles described herein can vary in density and shape, the size of the particle is expressed as an 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 will be appreciated 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 include all the possible subranges specifically disclosed as well as individual numerical values within that range. For example, a description of a range such as 1 to 6 should be considered to include the specifically disclosed subranges such as 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, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any integers and decimals therebetween. This applies regardless of the breadth of the range.

Compositions and Compounds In one aspect, the 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 embodiment, the nicotine salt is nicotine tartrate. In another embodiment, the nicotine salt is nicotine hydrogen tartrate. In another embodiment, 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 include 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.

In another aspect, the present 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.

In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation further comprising at least one 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. In one embodiment, the amino acid is lysine. In one embodiment, the amino acid is glycine.

In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation further comprising at least one phospholipid. Phospholipids that may be used in the present invention include, but are not limited to, phosphatidic acid, phosphatidylcholine having both saturated and unsaturated lipids, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, lysophosphatidyl derivatives, cardiolipin, and β-acyl-y-alkyl phospholipids. Examples of phosphatidylcholines include dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphorylphosphatidylcholine, dipalmitrylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DSPPC), diarachidosanoylphosphatidylcholine (DTPC), detricosanoylphosphatylcholine (DTPC), dioleoylphatidylcholine (DLPC); and phosphatidylethanolamines such as dioleoylphosphatidylethanolamine or 1-hexadecyl-2-palmitoylglycerophosphocetanolamine. Examples of phosphatidylethanolamines include dicaprylphosphatidylethanolamine, dioctanoylphosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoleoylphosphatidylethanolamine, distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine, and dilineoylphosphatidylethanolamine. Examples of phosphatidylglycerol include dicaprylphosphatidylglycerol, dioctanoylphosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol (DSPG), dipalmitriphosphotidylglycerol (DSPG), dioleoylphosphatidylglycerol, and dioleoylphosphatidylglycerol.Synthetic phospholipids with asymmetric acyl chains (e.g., 6-carbon acrylic chain and another 12-carbon acrylic chain) may also be used. Additional examples of phospholipids include modified phospholipids, e.g., phospholipids whose head groups have been modified, e.g., alkylated phospholipids or polyethylene glycol (PEG) modified hydrogenated phospholipids, phospholipids with a variety of head groups (phosphatidylmethanol, phosphatidylethanol, phosphatidylpropanol, phosphatidylbutanol, etc.), dibromophosphatidylcholine, monophytanoyl phosphatide, diphytanoyl phosphatide, monoacetylene phosphatide, diacetylene phosphatide, PEG phosphatide.

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 material, a nature-identical flavor material, or an artificial flavor material. Non-limiting examples of flavor components or flavorings include banana, cherry, cinnamon, fruit, grape, orange, pear, pineapple, vanilla, wintergreen, strawberry, and mint. In one embodiment, the flavor component is menthol. In another embodiment, the flavor component is mint.

As will be appreciated by those skilled in the art, mint generally refers to any and all flavors associated with the Lamiaceae plant genus, including, but not limited to, mint. In one embodiment, the mint is a natural extract. In another embodiment, the mint is a commercially available preparation, such as Coolmint Trusil Flavoring Powder, available from 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 comprises menthol. In another embodiment, the mint comprises trans-menthone. In another embodiment, the mint comprises pinene. In another embodiment, the mint comprises isomenthone. In another embodiment, the mint comprises limonene. In another embodiment, the mint comprises eucalyptol. In another embodiment, the mint comprises pin-2(3)ene. In another embodiment, the mint comprises menthyl acetate. In another embodiment, the mint comprises cineole. In another embodiment, the mint comprises 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-1,8-mentha-diene.

In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation further comprising a cough suppressant. In one embodiment, the cough suppressant is menthol. In another embodiment, the cough suppressant is mint.

Those skilled in the art will appreciate that menthol and/or mint can serve multiple roles in a formulation. In one embodiment, menthol is a flavor component. In another embodiment, menthol is a therapeutic agent, such as, for example, a cough suppressant. In one embodiment, mint is a flavor component. In another embodiment, mint is a therapeutic agent, such as, for example, a cough suppressant.

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.

As contemplated herein, any form of nicotine may be used as a nicotine-based ingredient. The form of nicotine used is preferably 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, the nicotine is mixed with sugar or other ingredients. In one embodiment, the nicotine is a salt and is a solid at room temperature. The 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. If the nicotine is a base, it is 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 produce a dry particulate formulation. In other embodiments, a form of nicotine that is soluble or miscible in the liquid carrier may also be used. For example, the nicotine may be nicotine base, which is a liquid that is miscible in water at room temperature. Alternatively, the nicotine base may be an oil formulation.

In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation, the formulation having a nicotine concentration of about 0.5% to about 10%. In one embodiment, the nicotine concentration is about 0.5%. 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 concentration of nicotine is about 8.5%. In another embodiment, the concentration of nicotine is about 9%. In another embodiment, the concentration of nicotine is about 9.5%. In another embodiment, the concentration of nicotine is about 10%.

In one embodiment, the formulation comprises nicotine particles (also referred to herein as nicotine-based components) sized substantially to about 1-10 microns based on the MMAD of the particles. In yet another embodiment, the formulation comprises nicotine particles sized substantially to about 1-7 microns. In another embodiment, the formulation comprises nicotine particles sized substantially to about 2-5 microns. In yet another embodiment, the formulation comprises nicotine particles sized substantially to about 2-3 microns. By selectively limiting or excluding nicotine particles less than about 1 micron in size or less than about 2 microns 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. Furthermore, 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 particles within the nicotine particle size range may be at least about 1 micron, at least about 1.1 microns, at least about 1.2 microns, at least about 1.3 microns, at least about 1.4 microns, at least about 1.5 microns, at least about 1.6 microns, at least about 1.7 microns, at least about 1.8 microns, at least about 1.9 microns, at least about 2 microns, at least about 2.1 microns, at least about 2.2 microns, at least about 2.3 microns, at least about 2.4 microns, at least about 2.5 microns, at least about 2.6 microns, at least about 2.7 microns, at least about 2.8 microns, at least about 2.9 microns, or at least about 3 microns. In some embodiments, the largest particles within the nicotine particle size range are about 10 microns or less, about 7 microns or less, about 6 microns or less, about 5 microns or less, about 4.5 microns or less, about 4 microns or less, 3.5 microns or less, or about 3 microns or less. In certain embodiments, about 10% or less of the nicotine particles are less than about 1 micron. In certain embodiments, about 10% or less of the nicotine particles are less than about 2 microns. In another embodiment, at least 90% of the nicotine particles are less than about 10 microns. In another embodiment, at least 90% of the nicotine particles are less than about 7 microns. In another embodiment, at least 90% of the nicotine particles are less than about 5 microns. In one embodiment, about 10% or less of the nicotine particles are less than about 1 micron and at least 90% of the nicotine particles are less than about 10 microns. In one embodiment, about 10% or less of the nicotine particles are less than about 1 micron and at least 90% of the nicotine particles are less than about 7 microns. In one embodiment, about 10% or less of the nicotine particles are less than about 2 microns and at least 90% of the nicotine particles are less than about 5 microns. In one embodiment, about 10% or less of the nicotine particles are less than about 2 microns and at least 90% of the nicotine particles are less than about 3 microns.

In one embodiment, the particles have a mass median aerodynamic diameter (MMAD) of about 2.0 microns. In one embodiment, the particles have a MMAD of about 2.1 microns. In one embodiment, the particles have a MMAD of about 2.2 microns. In one embodiment, the particles have a MMAD of about 2.3 microns. In one embodiment, the particles have a MMAD of about 2.4 microns. In one embodiment, the particles have a MMAD of about 2.5 microns. In one embodiment, the particles have a MMAD of about 2.6 microns. In one embodiment, the particles have a MMAD of about 2.7 microns. In one embodiment, the particles have a MMAD of about 2.8 microns. In one embodiment, the particles have a MMAD of about 2.9 microns. In one embodiment, the particles have a MMAD of about 3.0 microns. In one embodiment, the particles have a MMAD of about 3.1 microns. In one embodiment, the particles have a MMAD of about 3.2 microns. In one embodiment, the particles have a MMAD of about 3.3 microns. In one embodiment, the particles have a MMAD of about 3.4 microns. In one embodiment, the MMAD of the particle is about 3.5 microns. In one embodiment, the MMAD of the particle is about 3.6 microns. In one embodiment, the MMAD of the particle is about 3.7 microns. In one embodiment, the MMAD of the particle is about 3.8 microns. In one embodiment, the MMAD of the particle is about 3.9 microns. In one embodiment, the MMAD of the particle is about 4.0 microns. In one embodiment, the MMAD of the particle is about 4.1 microns. In one embodiment, the MMAD of the particle is about 4.2 microns. In one embodiment, the MMAD of the particle is about 4.3 microns. In one embodiment, the MMAD of the particle is about 4.4 microns. In one embodiment, the MMAD of the particle is about 4.5 microns. In one embodiment, the MMAD of the particle is about 4.6 microns. In one embodiment, the MMAD of the particle is about 4.7 microns. In one embodiment, the MMAD of the particle is about 4.8 microns. In one embodiment, the MMAD of the particle is about 4.9 microns. In one embodiment, the MMAD of the particle is about 5.0 microns.

As will be appreciated 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 microns may contain some particles smaller or larger than the range of about 2-5 microns. 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 particle sizes of the mixture are less than the D90 value. In another embodiment, the particle size range represents a particle size distribution (PSD), where the percentage of particles of the mixture falls within the recited range. For example, a nicotine particle size range of about 2-5 microns may represent a mixture of nicotine particles in which at least 50% of the particles are in the range of about 2-5 microns, although a higher percentage, such as but not limited to 60%, 70%, 80%, 90%, 95%, 97%, 98% or even 99%, is more preferred.

Of course, the particles of the nicotine-based component can be spherical or any other shape desired. In one embodiment, the particles can have an uneven or "dimpled" surface. In such an embodiment, the uneven surface can increase the ability of the additional component to stick to the nicotine particles and create a uniform coating. For example, the additional component can be a therapeutic agent, such as menthol, that ensures that all nicotine particles that strike the cough receptors are coated with menthol, thereby suppressing the cough reflex. The uneven surface can 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 can be more easily entrained and remain entrained in air inhaled by the subject, which can improve the ability of the nicotine-based component particles to move to and be retained in the subject's airways.

In one embodiment, the formulation includes at least one amino acid. In one embodiment, leucine acts as a stabilizer by reducing any degree of degradation of the compositions of the invention. In one embodiment, the amino acid acts as a carrier. In another embodiment, the amino acid prevents degradation of the compositions of the invention by acting as a buffer due to its buffering capacity. In another embodiment, the amino acid acts as a powder flow enhancer. In another embodiment, the amino acid in the composition of the invention improves the flowability of the powder. In another embodiment, the amino acid in the composition of the invention allows the particles of the powder formulation to be more easily entrained 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 airways. In one embodiment, the percentage of the amino acid in the formulation is 0.5% to 10%. In some embodiments, the percentage of the amino acid in the formulation is 1.5% to 2.5%. In another embodiment, the percentage of the amino acid in the formulation is 0.5% to 2.5%. In yet another embodiment, the percentage of the amino acid in the formulation is 1.5% to 5%. In one embodiment, the percentage of the amino acid in the formulation is about 2.5%. In another embodiment, the percentage of the amino acid in the formulation is about 5%. In another embodiment, the percentage of amino acids in the formulation is about 7.5%. In another embodiment, the percentage of amino acids in the formulation is about 10%. In another embodiment, the percentage of amino acids is about 20%. In another embodiment, the percentage of amino acids is about 30%. In another embodiment, the percentage of amino acids is about 40%. In another embodiment, the percentage of amino acids is about 50%. In another embodiment, the percentage of amino acids is about 60%. In another embodiment, the percentage of amino acids is about 70%. In another embodiment, the percentage of amino acids is about 80%. In another embodiment, the percentage of amino acids is about 90%. In another embodiment, the percentage of amino acids is about 95%. In another embodiment, the percentage of amino acids is about 97.5%. In another embodiment, the percentage of amino acids is about 99%. In one embodiment, the amino acid is leucine. In another embodiment, the amino acid is lysine. In another embodiment, the amino acid is glycine.

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 by itself or co-milled with the nicotine component into the particulate formulation. The sugar may also be soluble in a liquid carrier, such as water. Non-limiting 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. Of course, any form of sugar approved as an excipient may be used as a carrier in the production of the nicotine-based component. Although not required, the sugar is preferably of pharmaceutical grade, as will be appreciated by those skilled in the art. The pharmaceutical grade sugar that is ground by itself, co-ground with the nicotine component, or used to create the 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 will be understood by those skilled in the art that ultimately reduce the particle size of the sugar and result in a non-spheronized sugar. In one embodiment, the sugar particle size is at least about 60 microns. In one embodiment, the sugar particle size is 60-90 microns. In one embodiment, the average particle size is greater than about 90 microns. In one embodiment, the sugar particle size is about 60 microns.

Of course, there is no limit to the ratio of nicotine to sugar that may be used, and the actual ratio used may be based on the desired concentration of nicotine in the particles of the nicotine-based component. Thus, in one embodiment, the concentration of sugar is at least about 50%. In another embodiment, the concentration of sugar is from about 50% to about 99%.

In another embodiment, the formulation may further include an excipient, which is any pharma- ceutically acceptable material, composition, or carrier, e.g., a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, thickener, solvent, or encapsulating material, involved in carrying or transporting the compound useful in the invention in or to the subject so that the compound useful in the invention may perform its intended function. In one embodiment, the formulation further includes 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 of the materials that may be useful in the formulations of the present invention include pharma- ceutically acceptable carriers, e.g., sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and acetylcellulose, excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax, oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, magnesium hydroxide, and and aluminum hydroxide, surfactants, amino acids such as leucine, L-leucine, D-leucine, DL-leucine, isoleucine, lysine, valine, arginine, aspartic acid, threonine, methionine, phenylalanine, glycine, alginic acid, derivatives of amino acids, e.g., aspartame or acesulfame K, phospholipids such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine or diphosphatidylglycerol, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, and other non-toxic compatible substances used in pharmaceutical formulations. Other pharma- ceutically acceptable materials that may be useful in the formulation include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of nicotine or any other compound useful in the invention and are physiologically acceptable to the subject. Supplementary active compounds, including pharma- ceutically acceptable salts of these compounds, may also be incorporated into the compositions. Other additional components that may be included in the compositions used in the practice of the 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. In one embodiment, the carrier is an amino acid.

In one embodiment, the formulation of the present invention may further include a therapeutic agent. In one embodiment, the therapeutic agent is an antitussive. In one embodiment, the antitussive component is menthol. In one embodiment, the menthol concentration in the formulation is from about 0.5% to 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 compressed articles. In one embodiment, the menthol is in the form of crystals. The menthol may be processed into particles ranging in size from about 5 microns (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. Particle 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 wet process embodiments, menthol is processed in the liquid carrier. In another embodiment, the additional antitussive component is mint. In one embodiment, the mint concentration in the formulation is from about 0.5% to about 20%. As contemplated herein, any form of mint, for example a solid form of mint, may be used for processing into mint particles, powders, solutions or suspensions useful in the present invention. In one embodiment, the formulation of the present invention does not include a therapeutic agent. In one embodiment, the therapeutic agent is an anti-cancer agent.

In one embodiment, the therapeutic agent may include an antitussive component having particles substantially sized between 5 and 10 microns. In another embodiment, the additional antitussive component may include benzocaine. Of course, the additional antitussive component may include any compound approved for suppressing coughs. By selectively including menthol particles between 5 and 10 microns, 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 microns, at least about 6 microns, at least about 7 microns, or at least about 8 microns. In some embodiments, the largest particles in the particle size range of the additional antitussive component are about 10 microns or less, about 9 microns or less, about 8 microns or less, or about 7 microns or less. In certain embodiments, about 10% or less of the additional antitussive particles are less than about 5 microns. In another embodiment, at least 90% of the additional antitussive particles are less than about 10 microns. In another embodiment, at least 90% of the additional cough suppressant particles are less than about 8 microns. In one embodiment, no more than about 10% of the additional cough suppressant particles are less than 4 microns and at least 90% of the additional cough suppressant particles are less than about 10 microns. In one embodiment, no more than about 10% of the additional cough suppressant particles are less than about 5 microns and at least about 90% of the additional cough suppressant particles are less than about 8 microns. In a preferred embodiment, the additional cough suppressant component is comprised of particles in the 5-10 micron range, although the additional cough suppressant component can include a broader range of particles. In one embodiment, the additional cough suppressant component can include particles in the 5-25 micron range. In another embodiment, the additional cough suppressant component includes particles substantially in the 5-50 micron range. In yet another embodiment, the additional cough suppressant component includes particles substantially in the 5-100 micron range.

In another embodiment, the formulation of the present invention may further include an additional antitussive component having particles sized substantially between 10 and 200 microns. This additional antitussive component may be added to the formulation in place of or in addition to the 5 to 10 additional antitussive components already discussed. Thus, the formulation of the present invention may include two additional antitussive components, where each additional antitussive component has a substantially different particle size distribution. The 10 to 200 micron additional antitussive component may reduce coughing caused by irritation of the oropharynx, glottal vocal cords, and other anatomical areas more proximal or closer 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 microns, at least about 12 microns, at least about 20 microns, at least about 30 microns, or at least about 50 microns. In some embodiments, the largest particle in the particle size range of the additional antitussive component is about 200 microns or less, about 150 microns or less, about 120 microns or less, about 100 microns or less, about 90 microns or less, or about 80 microns or less. In certain embodiments, about 10% or less of the particles of the additional antitussive component are less than about 10 microns. In certain embodiments, about 10% or less of the particles of the additional antitussive component are less than about 20 microns. In another embodiment, at least 90% of the particles of the additional antitussive component are less than about 200 microns. In another embodiment, at least 90% of the particles of the additional antitussive component are less than about 150 microns. In another embodiment, at least 90% of the particles of the additional antitussive component are less than about 100 microns. In one embodiment, about 10% or less of the particles of the additional antitussive component are less than 10 microns and at least 90% of the particles of the additional antitussive component are less than about 200 microns. In one embodiment, about 10% or less of the particles of the additional antitussive component are less than about 12 microns, and at least 90% of the particles of the additional antitussive component are less than about 100 microns. In one embodiment, the additional antitussive component comprises menthol particles having a size between about 10-200 microns. In another embodiment, the additional antitussive component having particles having a size between about 10-200 microns may comprise benzocaine. Of course, the additional antitussive component having particles having a size between about 10-200 microns may comprise any compound approved for suppressing coughs. 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 to the oropharynx, vocal cords, and other anatomical areas proximal to the trachea.

In one embodiment, the formulations of the present invention may optionally include a flavoring component having particles sized substantially between about 10 and 1000 microns. In one embodiment, the flavoring component is substantially comprised of particles in the range of about 10 to 200 microns. In a preferred embodiment, the flavoring component is substantially comprised of particles in the range of about 10 to 100 microns. The flavoring component utilizes larger embedded particles that may impact in the oral cavity of a subject to provide the desired flavor. Furthermore, by limiting such flavoring component particles to a size greater than about 10 microns, 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 component are at least about 10 microns, at least about 12 microns, at least about 20 microns, at least about 30 microns, or at least about 50 microns. In some embodiments, the largest particle in the flavoring particle size range is about 1000 microns or less, about 500 microns or less, about 200 microns or less, about 150 microns or less, about 120 microns or less, about 100 microns or less, about 90 microns or less, or about 80 microns or less. In certain embodiments, about 10% or less of the flavoring particles are less than about 10 microns. In certain embodiments, about 10% or less of the flavoring particles are less than about 20 microns. In another embodiment, at least 90% of the flavoring particles are less than about 1000 microns. In another embodiment, at least 90% of the flavoring particles are less than about 500 microns. In another embodiment, at least 90% of the flavoring particles are less than about 200 microns. In another embodiment, at least 90% of the flavoring particles are less than about 150 microns. In another embodiment, at least 90% of the flavoring particles are less than about 100 microns. In one embodiment, about 10% or less of the flavor particles are less than 10 microns and at least 90% of the flavor particles are less than about 1000 microns. In one embodiment, about 10% or less of the flavor particles are less than 10 microns and at least 90% of the flavor particles are less than about 200 microns. In one embodiment, about 10% or less of the flavor particles are less than about 10 microns and at least 90% of the flavor particles are less than about 100 microns. In one embodiment, the flavor is mint. In another embodiment, the flavor is menthol. In another embodiment, the flavor may include tobacco, fruit flavors, or food grade flavors used in confectionery or baking. Of course, the flavor may be any flavor known in the art, preferably an agency approved flavor.

The present invention includes formulations of nicotine, sugar, and amino acids. The present invention also includes formulations of nicotine, sugar, a flavoring component, and an amino acid. The present invention also includes formulations of nicotine, sugar, an amino acid, and an excipient. The present invention also includes formulations of nicotine, sugar, an amino acid, and a cough suppressant. The present invention also includes formulations of nicotine, sugar, a flavoring component, an amino acid, and an excipient ... In one embodiment, the sugar is lactose. In one embodiment, the amino acid is selected from the group consisting of glycine and lysine. In one embodiment, the excipient is a phospholipid. In one embodiment, the flavoring component is menthol. In one embodiment, the cough suppressant is selected from the group consisting of menthol and mint.

In various embodiments, the relative weight percentages of each component in the formulations of the present invention may be varied to achieve different characteristics. Thus, as one of ordinary skill in the art will appreciate, the relative weight percentages of the components may be altered for a variety of reasons, including, but not limited to, achieving a certain level of nicotine blood 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 nicotine blood 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 flavor component, with 1-5% by weight flavor component being preferred. In certain embodiments, the formulation may be about 1% to about 10% by weight antitussive, with 0.5% to about 5% by weight 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 have approximately 10% 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 another embodiment, the percentage of lactose in the formulation is between 75% and 85%. In yet another embodiment, the percentage of lactose in the formulation is between 80% and 90%. In yet another embodiment, 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 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%. In some embodiments, any concentration of carrier may be substituted for lactose.

In one embodiment, the percentage of menthol in the formulation is 0%-20%. In some embodiments, the percentage of menthol in the formulation is 5%-20%. In another embodiment, the percentage of menthol in the formulation is 5%-15%. In yet another embodiment, the percentage of menthol in the formulation is 10%-20%. 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%.

In one embodiment, the percentage of mint in the formulation is 0%-20%. In some embodiments, the percentage of mint in the formulation is 5%-20%. In another embodiment, the percentage of mint in the formulation is 5%-15%. In yet another embodiment, the percentage of mint in the formulation is 10%-20%. In one embodiment, the percentage of mint in the formulation is about 5%. In another embodiment, the percentage of mint in the formulation is about 20%.

Method of Use 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 the subject. For example, as shown in FIG. 1, the method 100 includes steps 110, 120, 130, 140, of determining the concentration of nicotine inhaled by the subject, determining the total dose of nicotine inhaled by the subject, determining the concentration of menthol inhaled by the subject, and determining the total dose of menthol inhaled by the subject. Finally, in step 150, a quantity of the formulation is provided 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.

In other embodiments, as shown in FIG. 2, method 200 includes steps for reducing the amount of nicotine while maintaining the amount of menthol inhaled by the subject. Method 200 includes steps 210 of identifying a concentration of nicotine in a nicotine formulation to be inhaled by the subject, the formulation having a base menthol concentration, 220 of providing 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 230 of providing at least one additional dose including a quantity of the formulation including nicotine particles, the at least one additional dose including fewer nicotine particles than the formulation in the first dose and including the same base menthol concentration as in the first dose.

Now referring to FIG. 3, three different formulations are outlined, each designed to deliver the same dose of nicotine (1 mg). To achieve a base level of nicotine delivery (Formulation 1), the total dose of nicotine is formed as a fraction of a 20 mg total formulation 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 fraction of a 20 mg total formulation 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 antitussive relief compared to formulations 1 and 2. The formulations provided in Figures 3 and 4 are exemplary, and any component may be substituted with an equivalent substitute or excipient as described herein.

In another embodiment, the total dose of nicotine can be reduced in stages. For example, as shown in FIG. 4, three different formulations are outlined, each designed to deliver a different (smaller) total dose of nicotine while maintaining the same amount of cough suppression. Starting with formulation 4, a total dose of 1 mg of nicotine forms part of a total formulation 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 cough suppression. 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, with the total dose of nicotine administered after approximately 20 completed inhalations at the same level of antitussiveness. Thus, a 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 nicotine delivered. In one embodiment, formulations that decrease the 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 that increase the nicotine concentration, while experiencing a constant level of antitussiveness throughout the increase in nicotine delivered. The formulations described in the figures are exemplary, and any component may be substituted with an equivalent substitute or excipient as described herein.

Of course, 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 more shallowly or more deeply through the dry powder inhaler used. Furthermore, by administering the total dose of nicotine via multiple inhalations, the subject may ensure a more consistent uptake of the total dose of nicotine, with any user error occurring during a single inhalation ultimately being corrected by one or more subsequent inhalations.

Methods of Manufacture The present invention also relates to methods of making the formulations of the present invention. In one embodiment, the method comprises dry blending. In one embodiment, the method comprises wet blending.

5, an exemplary dry process or method 300 for making any one of the formulations described herein is illustrated. For example, at step 310, nicotine tartrate is dry milled. At step 312, nicotine is mixed with lactose and leucine. Optionally, at step 313, a therapeutic agent such as menthol is added. In some embodiments, nicotine or nicotine salt is not bound to any other component of the formulation. That is, the formulation includes separate particles of nicotine or nicotine salt and separate particles of other components of the formulation, such as sugar. In one embodiment, nicotine is not bound to sugar. In one embodiment, nicotine is not bound to amino acid particles. In one embodiment, nicotine is not bound to leucine particles. In one embodiment, nicotine is not bound to glycine particles. In one embodiment, nicotine is not bound to lysine particles. In one embodiment, nicotine is not bound to a carrier. 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 may be dry mixed first, such as at step 314, and co-milled at step 316. In another embodiment, nicotine tartrate, lactose, leucine, and a therapeutic agent, such as menthol, are dry mixed first, such as at step 318, and co-milled at step 320. At step 330, the particles of the resulting formulation are filtered, such as by sieving, to remove particles larger than a threshold size value. At step 340, the particles of the resulting formulation are filtered again to remove particles smaller than a threshold size value, resulting in a final dry powder formulation at 350. In some embodiments, only one filtering step is required. In other embodiments, two or more filtering steps are required. Optionally, at step 360, a flavoring ingredient may be added to the final formulation at 350. Step 360 may include any number of processing steps necessary to obtain the desired particle size (e.g., 10-1000 microns) of the flavoring ingredient to be added.

Particle mixing methods in and for the methods and formulations of the invention are contemplated herein. Mixing can be done in one or more steps, in a continuous, batch, or semi-batch process. For example, if two or more excipients are used, they can be mixed together prior to or simultaneously with mixing with the pharmaceutical agent microparticles.

The blending step can be carried out using essentially any technique or device suitable for combining the microparticles with one or more other materials (e.g., excipients) effective to achieve blend uniformity. The blending step 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 blender is 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, N.J., USA, and manufactured by Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzerland.

For continuous or semi-continuous operation, the blender may be provided with a rotary feeder, screw conveyor, or other feeding mechanism to control the introduction of one or more dry powdered ingredients into the blender.

A milling process is used to break up and/or deagglomerate the mixed 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 may 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, and the like. It is preferred that a dry milling process is used.

Now referring to FIG. 6, an exemplary wet process or method 400 for making 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 may be mixed with excipients such as lactose and leucine and with a therapeutic agent such as menthol to form a flowable mixture. As contemplated herein, any liquid carrier may be used in the process for making a solution or suspension. In one embodiment, the liquid carrier is water. The liquid carrier is preferably one in which the components of the formulation are either soluble or suspendable. Thus, the liquid carrier may be any liquid or liquids whereby the components of the formulation, either alone or in combination, form a flowable mixture or suspension that is preferably a generally homogenous composition.

At step 416, the mixture is atomized. At step 420, the mixture is dried, such as via a spray dryer. Alternatively, this step may be performed by fluid bed drying, where nicotine tartrate may instead be spray dried onto the excipient mixture. At step 430, the resulting nicotine particles are filtered, for example by a sieve, to remove particles larger than a threshold size value. At step 440, the resulting nicotine particles are filtered again to remove particles smaller than a threshold size value, resulting in a final dry powder formulation at 450. In some embodiments, only one filtering step is required. In other embodiments, two or more filtering steps are required. Optionally, at step 460, a flavoring ingredient may be added to the final formulation at 450. Step 460 may include any number of processing steps necessary to obtain the desired particle size (e.g., 10-1000 microns) of the added flavoring ingredient.

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. Of course, there is no limit to the method by which the flowable mixture is dried. Although a preferred method utilizes a spray dryer, other drying techniques, such as fluidized bed drying, that can produce appropriately sized particles may be used. 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 slow or fast rate) 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 microns.

Further fractionation/filtration of selected particle sizes can be performed in both the dry and wet processes. In the wet process, the operating conditions of the spray dryer can be adjusted to produce 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 2 to about 10 ml/min, or about 2 to about 5 ml/min. Additionally, 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. Of course, particles of various sizes can be obtained by spray drying, and particles having the 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 can 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 can 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.

Of course, there is no limit to the method by which the flowable mixture may be dried. Examples of methods for drying the flowable mixture include, but are not limited to, spray drying, vacuum drying, and freeze drying. Still further, any rate of drying (e.g., drying at a slow or fast rate) may be used, provided that such rate of drying results in the formation of dry particles in the desired size range.

As previously discussed, in a wet process, the liquid carrier is dried, for example, by a fluid bed dryer, to produce composite particles of menthol-coated nicotine suitable for delivery to the alveoli and lower airways of a subject. Of course, there is no limit to the method by which the fluid mixture is dried. A preferred method utilizes a fluid bed dryer, but other drying techniques capable of removing the liquid carrier and providing a uniform menthol coating on the nicotine particles may also be used.

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 steps described herein to obtain nicotine particles in the range of about 1 to 5 microns may be provided. 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 micron sieve, with substantially all of the particles smaller than 5 microns passing through the sieve. The particles that pass through the sieve may then be transferred to a 1 micron sieve, with substantially all of the particles larger than 1 micron not passing through the sieve. The particles larger than 1 micron may be collected from the sieve, with the collected particles being substantially sized in the 1 to 5 micron range. Thus, such processes can be used to narrow the range of any particle mixture to any desired particle size range described throughout this specification.

In other embodiments, a mixture of particles may be provided that substantially meets either the minimum or maximum criteria for the desired particle size range. For example, if a nicotine particle size range of about 2-5 microns is desired, a mixture of nicotine particles may be provided in which substantially all of the particles are less than 5 microns. Such a mixture may be produced by modifying the milling conditions, or, if the particles are spray dried, by milling the spray dried material, resulting in a mixture of particles that are generally less than 5 microns. The mixture may then be transferred to a 2 micron sieve, with any particles that do not pass through the sieve being collected, such that the collected particles are substantially within the desired 2-3 micron range.

It is believed that the percentage of particles that fall within a desired particle size range for any of the components of the formulations of the present invention 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 microns, it will be appreciated that when using spray drying manufacturing techniques on a relatively small scale, greater than 90% of that component will fall within the desired range. However, using milling manufacturing techniques on a relatively large scale, only greater than 70% of the nicotine component within such target range may be obtained.

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 may 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 amounts of total nicotine 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 amounts of powder, such as a measuring spoon or graduated measuring container, that can be loaded into the storage chamber of the dry powder inhaler.

In another embodiment, the kit includes pre-filled powder capsules for a nicotine therapy or set course of treatment, such as, for example, a 30-day course of treatment. The capsules can be filled with various amounts of powder at various nicotine concentrations to suit the treatment regimen. In another embodiment, 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.

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 between about 7 days and about 30 days. In another embodiment, the course of nicotine therapy lasts between about 10 days and about 45 days. In another embodiment, the course of nicotine therapy lasts between about 15 days and about 60 days. In another embodiment, the course of nicotine therapy lasts 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.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety. Although the invention has been disclosed with reference to specific embodiments, it will be apparent to those skilled in the art that other embodiments and variations of the invention may be devised without departing from the true spirit and scope of the invention. It is intended that the appended claims be interpreted to include all such embodiments and equivalent variations.

Claims (13)

1. A dry powder nicotine formulation comprising:
particles comprising nicotine, at least one sugar, and an amino acid;
the concentration of said nicotine in said formulation is between 0.5% and 7% and the concentration of said at least one sugar in said formulation is between 50% and 99%;
the amino acid is lysine or a combination of glycine and lysine;
the formulation is suitable for inhalation;
At least 80% of the particles have a particle size of 1 to 7 micrometers;
Dry powder nicotine formulations. The formulation of claim 1, further comprising at least one phospholipid. The formulation of claim 1, wherein the nicotine comprises nicotine tartrate. 2. The formulation of claim 1, wherein the concentration of the amino acid in the formulation is from 0.5% to 50%. The formulation of claim 1 further comprising menthol. The formulation of claim 1 further comprising mint. 1. A dry powder nicotine formulation comprising:
a nicotine particle comprising nicotine, at least one sugar, and an amino acid;
and mint particles containing mint ,
the amino acid is lysine or a combination of glycine and lysine;
The formulation is suitable for inhalation.
Dry powder nicotine formulations. The formulation of claim 7, wherein at least about 40% of the nicotine particles are 3-4 microns. The formulation of claim 7, wherein the mint particle size is at least about 20 microns. 1. A dry powder nicotine formulation comprising:
The present invention includes a nicotine particle comprising nicotine and at least one sugar, and a particle consisting of only amino acids ,
the concentration of said nicotine in said formulation is between 0.5% and 10% and the concentration of said at least one sugar in said formulation is between 50% and 99%;
the amino acid is lysine or a combination of glycine and lysine;
the particles consisting essentially of amino acids are not substantially bound to the nicotine particles, and the formulation is suitable for inhalation.
Dry powder nicotine formulations. The formulation of claim 10, further comprising at least one phospholipid. The formulation of claim 10 further comprising menthol. The formulation of claim 10 further comprising mint.

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