RU2847044C1 - Active compositions in powder form with low hygroscopicity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: inhalable powder contains crystalline particles of a dry powder. Crystalline particles of the dry powder include a solid alkaloid salt and a sugar alcohol. Salt is solid at 25 °C. Sugar alcohol can contain erythrite, myo-inositol, adonitol, xylitol or a combination thereof. Inhalable powder can be part of a powder system which additionally contains a number of flavouring agent particles having a particle size exceeding that of the dry powder crystalline particles.

EFFECT: disclosed are active compositions in powder form with low hygroscopicity.

14 cl, 2 tbl, 9 dwg

Description

The present invention relates to active compositions in powder form that exhibit low hygroscopicity. Sugar or sugar alcohol and the active agent form crystalline dry particles.

Active compositions in powder form have been described that have an amorphous structure. An amorphous structure lacks the long-range order characteristics characteristic of a crystalline form. Such amorphous powder compositions typically exhibit greater water solubility than their crystalline counterparts and may have a shorter shelf life or delivery time due to absorption of moisture from the environment.

Amorphous powder compositions are prone to hygroscopicity and agglomeration, becoming sticky or even liquefied when exposed to humid conditions, such as relative humidity of approximately 40% or greater and temperatures of approximately 25°C or greater. Tropical conditions, such as relative humidity of approximately 60% or greater and temperatures of approximately 30°C or greater, can exacerbate these problems. Transport and storage of such amorphous powder compositions may require hermetically sealed packaging to maintain stability. If the hermetically sealed packaging is broken (e.g., if the packaging is opened by the consumer), the contents can rapidly absorb moisture. Furthermore, delivery of amorphous powder compositions to the user's lungs may require separation of moisture from the inhalation airstream, which increases the complexity and cost of the associated inhalation device or product.

It would be desirable to provide an active composition in powder form that exhibits reduced hygroscopicity. It would be desirable to provide an active composition in powder form that is resistant to water or moisture absorption when exposed to humid or tropical conditions. It would be desirable to provide an active composition in powder form that exhibits reduced agglomeration when exposed to humid or tropical conditions. It would be desirable to provide an active composition in powder form that is stable and has a long shelf life.

According to an aspect of the present invention, an inhalable composition in powder form is provided, comprising crystalline dry powder particles. The crystalline dry powder particles comprise a sugar or sugar alcohol and an active agent. Preferably, the crystalline dry powder particles comprise a sugar alcohol and a solid alkaloid salt.

Inhalable powder exhibits low or reduced hygroscopicity. Inhalable powder does not readily absorb water or moisture when exposed to humid or tropical conditions. Inhalable powder does not readily agglomerate when exposed to humid or tropical conditions. Furthermore, inhalable powder is stable and has a long shelf life.

The phrase "spray-drying temperature" refers to the temperature of the liquid mixture exiting the nozzle of the spray dryer. The spray-drying temperature may preferably be less than approximately 80 degrees Celsius, or less than 70 degrees Celsius, or less than 65 degrees Celsius, or less than 60 degrees Celsius, or less than 55 degrees Celsius.

The term "crystalline" refers to a solid form of a compound exhibiting long-range order in its microscopic lattice. One skilled in the art can identify a crystalline material by examining its X-ray diffraction (XRD) pattern, such as a powder X-ray diffraction (pXRD) trace. For example, XRD patterns of a crystalline substance are shown in Fig. 1 and Figs. 4-8 herein. A crystalline material may exhibit some amorphous structure.

The expression "crystalline dry powder particles" refers to a free-flowing composition of particles that contains crystalline material.

The term "active agent" refers to an alkaloid or other pharmaceutically active ingredient. "Active agent" always refers only to the active agent component of a compound. Preferably, the active agent may be a salt of the active agent.

The term "low hygroscopicity" refers to a measured hygroscopicity value of 5% by weight or less, 4% or less, 3% or less, 2.5% or less, or 2% or less water absorption. Hygroscopicity can be determined by measuring the water absorption or adsorption (increase in wt%) of a sample when exposed to tropical conditions (in an atmosphere at 75% relative humidity and 30 degrees Celsius) for 20 minutes. Before exposure to tropical conditions, the sample is equilibrated at 0% relative humidity and a temperature of 25 degrees Celsius for 24 hours to reduce or remove unbound water from the sample. The hygroscopicity value can be measured using the "SPSx-1u high-load vapor sorption analyzer" manufactured by ProUmid GmbH & Co. KG, as described in the examples below.

A method for forming crystalline dry powder particles may involve mixing an active agent with a sugar or sugar alcohol and a liquid carrier, wherein the active agent is added in solid form. In some embodiments, the active agent is a base and is mixed with an acid to form a salt. For example, the active agent may comprise an alkaloid, such as nicotine, anatabine, or anabasine, in the form of a free base, which is combined with an acid to form a pharmaceutically acceptable salt.

Any pharmaceutically acceptable salt can be used to prepare a salt of the active agent. In a preferred embodiment, the salt of the alkaloid can be solid at room temperature (e.g., solid at 25°C). Suitable salts include, for example, a salt of aspartic acid ("aspartate"), gentisic acid ("gentisate"), benzoic acid ("benzoate"), lactic acid ("lactate"), malic acid ("malate"), fumaric acid ("fumarate"), maleic acid ("maleate"), muconic acid ("muconate"), hydrochloric acid ("hydrochlorate"), alpha-resorcylic acid ("alpha-resorcylate"), beta-resorcylic acid ("beta-resorcylate"), oxalic acid ("oxalate"), para-anisic acid ("anisate"), tartaric acid ("bitartrate") or glutaric acid ("glutarate"). Preferably, the salt includes aspartate, bitartrate, malate, or glutarate.

A preferred alkaloid is nicotine. Nicotine may preferably be a nicotine salt. Nicotine salts include, for example, nicotine aspartate, nicotine bitartrate, nicotine glutarate, nicotine lactate, nicotine gentisate, nicotine benzoate, nicotine fumarate, nicotine hydrochlorate, nicotine alpha-resorcylate, nicotine beta-resorcylate, nicotine oxalate, nicotine malate, and nicotine anisate. A preferred nicotine salt is selected from one or more of nicotine bitartrate, nicotine aspartate, nicotine malate, and nicotine glutarate.

Another preferred alkaloid is anatabine. Anatabine may preferably be an anatabine salt. A preferred anatabine salt is anatabine glutarate. Anatabine glutarate is described, for example, in WO2020/127225A1.

Anatabine is an alkaloid present in tobacco and, in lower concentrations, in various foods, including green tomatoes, green potatoes, ripe red peppers, Mexican tomatoes, and sun-dried tomatoes. It is the main active component of the commercially available dietary supplement anatablok, which provides anti-inflammatory support, as disclosed in U.S. Patent No. 9,387,201 and WO 2013/032558. The preparation of isolated forms of anatabine is described, for example, in WO 2011/119722.

Anatabine is also known as 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine. Enantioselective syntheses of the S- and R-enantiomers of anatabine are described, for example, in Ayers, J. T.; Xu, R.; Dwoskin, L. P.; Crooks, P. A. A general procedure for the enantioselective synthesis of the minor Tobacco alkaloids nornicotine, anabasine, and anatabine. The AAPS Journal 2005; 7(3) Article 75.

As used herein, the term "anatabine" may refer to (1) a racemic mixture of anatabine (R,S); (2) a purified form of S-(-)-anatabine; or (3) a purified form of R-(+)-anatabine. A preferred anatabine compound is a salt of anatabine, such as anatabine glutarate or 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate. Preferably, 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate is characterized by a 1:1 molar ratio of 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine to glutarate.

Pharmaceutically acceptable salts of anatabine are described in U.S. Patent No. 8,207,346 and U.S. Patent No. 8,557,999. In particular, Example 6 of U.S. Patent No. 8,207,346 and Example 6 of U.S. Patent No. 8,557,999 describe the preparation of anatabine tartrate and anatabine citrate by adding tartaric or citric acid to a solution of anatabine in acetone.

It should be understood that any reference to "3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate" or "anatabine glutarate" in this document shall be understood as a reference to any pharmaceutically acceptable solvate thereof.

3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate is characterized by the chemical structure represented by the following formula (I):

.

Thus, in a preferred embodiment, 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine glutarate may be characterized by the following formula (Ia):

.

Preferably, anatabine glutarate is a specific polymorph (also referred to herein as a polymorphic form) of 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate and, in particular, a crystal of 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate. The polymorph is preferably characterized by a powder X-ray diffraction pattern (CuKα) substantially as shown in Fig. 1. The polymorph is preferably characterized by a powder X-ray diffraction pattern (CuKα) containing one or more peaks selected from 8.0 ± 0.2 °2θ, 11.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 16.5 ± 0.2 °2θ, 18.0 ± 0.2 ⋅ °2θ, 20.7 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.4 ± 0.2 °2θ, 22.0 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 23.3 ± 0.2 °2θ and 24.5 ± 0.2 °2θ. More preferably, the polymorph is preferably characterized by a powder X-ray diffraction pattern (CuKα) comprising one or more peaks selected from 8.0 ± 0.2 °2θ, 13.3 ± 0.2 °2θ, 16.5 ± 0.2 °2θ, 21.4 ± 0.2 °2θ, 22.0 ± 0.2 °2θ and 24.5 ± 0.2 °2θ.

Even more preferably, the polymorph is preferably characterized by a powder X-ray diffraction pattern (CuKα) comprising one or more peaks selected from 8.0 ± 0.1 °2θ, 11.0 ± 0.1 °2θ, 13.3 ± 0.1 °2θ, 16.5 ± 0.1 °2θ, 18.0 ± 0.1 °2θ, 20.7 ± 0.1 °2θ, 21.0 ± 0.1 °2θ, 21.4 ± 0.1 °2θ, 22.0 ± 0.1 °2θ, 22.3 ± 0.1 °2θ, 23.3 ± 0.1 °2θ and 24.5 ± 0.1 °2θ. Even more preferably, the polymorph is preferably characterized by an X-ray powder diffraction pattern (CuKα) comprising one or more peaks selected from 8.0 ± 0.1 °2θ, 13.3 ± 0.1 °2θ, 16.5 ± 0.1 °2θ, 21.4 ± 0.1 °2θ, 22.0 ± 0.1 °2θ and 24.5 ± 0.1 °2θ.

Even more particularly, the polymorph is preferably characterized by an X-ray powder diffraction pattern (CuKα) comprising one or more peaks selected from 7.960 ± 0.2 °2θ, 10.907 ± 0.2 °2θ, 13.291 ± 0.2 °2θ, 14.413 ± 0.2 °2θ, 15.239 ± 0.2 °2θ, 16.479 ± 0.2 °2θ, 17.933 ± 0.2 °2θ, 20.610 ± 0.2 °2θ, 20.977 ± 0.2 °2θ, 21.318 ± 0.2 °2θ, 21.927 ± 0.2 °2θ, 22.203 ± 0.2 °2θ, 22.792 ± 0.2 °2θ, 23.246 ± 0.2 °2θ, 24.426 ± 0.2 °2θ and 24.769 ± 0.2 °2θ. Even more particularly, the polymorph is preferably characterized by an X-ray powder diffraction pattern (CuKα) comprising one or more peaks selected from 7.960 ± 0.1 °2θ, 10.907 ± 0.1 °2θ, 13.291 ± 0.1 °2θ, 14.413 ± 0.1 °2θ, 15.239 ± 0.1 °2θ, 16.479 ± 0.1 °2θ, 17.933 ± 0.1 °2θ, 20.610 ± 0.1 °2θ, 20.977 ± 0.1 °2θ, 21.318 ± 0.1 °2θ, 21.927 ± 0.1 °2θ, 22.203 ± 0.1 °2θ, 22.792 ± 0.1 °2θ, 23.246 ± 0.1 °2θ, 24.426 ± 0.1 °2θ and 24.769 ± 0.1 °2θ. The above form of anatabine glutarate can be obtained using a method comprising the steps of:

a) obtaining a solution containing 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine, glutaric acid and a solvent,

b) ensuring the formation of a salt of 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine with glutaric acid and

c) reduction of 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridinelutaric acid salt.

The solvent used in preparing the solution of 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine, glutaric acid and a solvent preferably includes 2-methyltetrahydrofuran, acetonitrile and/or ethyl acetate. More preferably, the solvent includes 2-methyltetrahydrofuran.

The method may further comprise step d) of recrystallizing the 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridinelutaric acid salt. Suitable solvents for such recrystallization include acetonitrile.

In step a), anatabine glutarate can be prepared by combining anatabine free base, a solvent, and glutaric acid to form a reaction mixture. Anatabine glutarate is typically formed in such a reaction mixture by contact of anatabine free base with glutaric acid. Preferably, anatabine free base in the form of a 1-5 wt.% solution in acetonitrile is combined with glutaric acid.

Preferably, a solution or suspension of anatabine free base, solvent, and glutaric acid is combined to form a reaction mixture, followed by precipitation and recovery of the anatabine glutarate salt from the mixture. Glutaric acid can be added either as a solid or as a solution or suspension in a solvent.

The solvent is preferably selected from the group consisting of alkanols containing from 1 to 8 carbon atoms, aliphatic esters containing from 3 to 8 carbon atoms, aliphatic linear or cyclic ethers containing from 3 to 8 carbon atoms, aliphatic ketones containing from 3 to 8 carbon atoms, aromatic C _6-12 hydrocarbons (such as benzene and naphthalene), acetonitrile, water and any mixtures thereof. Preferably, the solvent is selected from aliphatic esters containing from 3 to 8 carbon atoms, aliphatic cyclic ethers containing from 3 to 8 carbon atoms, acetonitrile and mixtures thereof. More preferably, the solvent is selected from ethyl acetate, acetonitrile, 2-methyltetrahydrofuran and any mixtures thereof. Even more preferably, the solvent comprises acetonitrile. Even more preferably, the solvent is acetonitrile.

Anatabine free base, glutaric acid, and at least one solvent are preferably combined to form a reaction mixture at room temperature (i.e., preferably in the range of 15 to 25°C). The concentration of glutaric acid present in such a reaction mixture is preferably close to the saturation point (e.g., at least 80%, preferably 90%, more preferably 95% of the maximum achievable concentration). Anatabine glutarate typically precipitates from the mixture. Precipitation can occur spontaneously or be induced, for example, by the introduction of seed crystals. The reaction mixture can be stirred before, during, or after precipitation.

The reaction mixture can be heated and then cooled to facilitate precipitation of anatabine glutarate. Heating can be performed to any temperature (e.g., from about 50°C to about 80°C) in the range from room temperature to the boiling point of the solvent. Cooling is then typically performed to a temperature of less than 40°C, preferably from about 30°C to about 20°C, and more preferably to room temperature (i.e., preferably in the range from 15°C to 25°C), to facilitate precipitation.

The resulting precipitate can be recovered using various techniques, such as filtration. The precipitate can be dried at atmospheric or reduced pressure and/or elevated temperature.

Anatabine glutarate, and in particular the polymorphic form described above, possesses advantageous properties such as high crystallinity, morphology, thermal and mechanical stability against polymorphic transformation and/or dehydration, storage stability, low residual solvent content, low hygroscopicity, flowability, and advantageous processing and handling characteristics. Furthermore, anatabine glutarate recrystallizes as a crystalline salt even after exposure to moisture, provided the moisture is removed by suitable means, such as vacuum drying.

Anatabine (e.g., anatabine glutarate) can be administered to humans for the treatment of disorders involving an inflammatory component, including chronic low-grade inflammation. Anatabine can be administered to humans to reduce a symptom or disorder involving an NFκB-mediated inflammatory component and/or to reduce the risk of developing such a disorder. An NFκB-mediated inflammatory component can be associated with chronic inflammation, such as that seen in thyroiditis, cancer, arthritis, Alzheimer's disease, and multiple sclerosis. An inhalable powder containing anatabine may inhibit monoamine oxidase (MAO). Additionally or alternatively, an inhalable powder containing anatabine may inhibit STAT3 phosphorylation.

In some embodiments, anatabine is formulated as a salt. Any pharmaceutically acceptable salt can be used. Preferably, the anatabine salt is solid at room temperature (e.g., solid at 25°C). Suitable salts include, for example, a salt of aspartic acid ("aspartate"), gentisic acid ("gentisate"), benzoic acid ("benzoate"), fumaric acid ("fumarate"), hydrochloric acid ("hydrochlorate"), alpha-resorcylic acid ("alpha-resorcylate"), beta-resorcylic acid ("beta-resorcylate"), oxalic acid ("oxalate"), para-anisic acid ("anisate"), or glutaric acid ("glutarate"). Preferably, the salt comprises glutarate, such as anatabine glutarate. Preferably, the anatabine salt is anatabine glutarate. Preferably, the anatabine glutarate is the polymorphic form described above.

Another preferred alkaloid is anabasine. Anabasine is preferably anabasine salt. Anabasine is a pyridine and piperidine alkaloid found in the tobacco plant.

Additional pharmaceutically active ingredients include, for example, an antiviral compound such as acyclovir; an anti-inflammatory compound such as salicylic acid, aceclofenac, or ketoprofen; an antidiabetic compound such as metformin or glipizide; an antihypertensive compound such as oxprenolol; an antiemetic compound such as promethazine; a compound having an antidepressant effect such as seproxetine; an anticoagulant compound such as picotamide; a bronchodilator such as clenbuterol; or an anticancer compound such as beta-lapachone.

Favorable crystallinity and reduced hygroscopicity can be achieved by selecting one or more parameters of the composition and manufacturing method of the inhalable powder. For example, the active agent can be selected such that it is solid at room temperature (e.g., solid at 25°C). The active agent can be solid at 30°C or below, or at 25°C. The sugar or sugar alcohol can be selected such that it has a suitable glass transition temperature (Tg), so that the desired crystallinity can be achieved by spray drying.

The sugar or sugar alcohol may be selected to have a suitable glass transition temperature of 100°C or less, 75°C or less, 50°C or less, 25°C or less, or 0°C or less. The sugar or sugar alcohol may be selected to have a suitable solubility in water, such as 75 g or less, 60 g or less, 50 g or less, or 30 g or less in 100 g of water at 25°C.

The crystalline dry powder particles described herein may be formed by spray drying or freeze drying. In either method, a liquid mixture may be formed by combining an active agent (such as an alkaloid), a sugar or sugar alcohol, and, optionally, an amino acid. This liquid mixture is then dried or dehydrated and, optionally, milled to form the crystalline dry powder particles described herein. Each crystalline dry powder particle may comprise a crystalline sugar or a crystalline sugar alcohol matrix and an active agent (such as an alkaloid) dispersed within the crystalline sugar or crystalline sugar alcohol matrix.

The spray-drying temperature can be selected, at least in part, based on the choice of sugar or sugar alcohol, such that the spray-drying temperature is higher than the glass transition temperature of the sugar or sugar alcohol, but also as low as possible to prevent or mitigate the degradation or migration of the active agent during spray-drying. The glass transition temperature of the sugar or sugar alcohol is lower than the temperature encountered by the particle during spray-drying to ensure the necessary molecular mobility of the sugar or sugar alcohol molecule to enable crystallization. For example, the spray-drying temperature can be less than 80°C, or less than 70°C, or less than 65°C, or less than 60°C, or less than 55°C, or approximately 50°C or less.

Using spray drying or freeze-drying, composite particles are formed, each containing an active agent and a sugar or sugar alcohol. The active agent can be dispersed in a sugar or sugar alcohol matrix. Preferably, the active agent is a solid, stable salt at 25°C. Preferably, the active agent is a solid, stable salt at 25°C and is contained within a crystalline matrix of sugar or sugar alcohol to form a particle or composite particle.

Preferably, the sugar or sugar alcohol is a sugar alcohol. Sugar alcohols include, for example, the following compounds and their stereoisomers: erythritol, adonitol, xylitol, arabitol, mannitol, sorbitol, myo-inositol, etc. Preferably, the sugar alcohol is selected from erythritol (Tg=-44°C), mannitol (Tg=13°C), myo-inositol (Tg=50°C), their stereoisomers, and combinations thereof. Preferably, the sugar alcohol is erythritol, mannitol, or myo-inositol.

Crystalline dry powder particles formed by spray drying or freeze drying can be milled or micronized to achieve a desired final particle size (e.g., a reduced particle size from about 50 micrometers to about 2 micrometers). The respirable powder or crystalline dry powder particles can have a final particle size in the range of about 1 micrometer to about 5 micrometers, or from about 1 micrometer to about 3 micrometers, or from about 1.5 micrometers to about 2.5 micrometers.

The inhalable powder may further comprise an amino acid. The amino acid may be added to the active agent and sugar or sugar alcohol prior to the spray-drying or freeze-drying step. The amino acid may be added to the crystalline dry powder particles after the spray-drying or freeze-drying step. For example, the crystalline dry powder particles formed by spray-drying or freeze-drying may be co-milled (e.g., using a vortex mill) with the amino acid particles. Co-milling may result in the amino acid at least partially coating the crystalline dry powder particles. The crystalline dry powder particles may be coated with the amino acid. Co-milling may further achieve the desired final particle size (e.g., reduce the particle size from approximately 50 micrometers to approximately 2 micrometers).

The combining step may include combining a sugar or sugar alcohol with an active agent, an amino acid, and a liquid carrier to form a liquid mixture and spray-drying or freeze-drying the liquid mixture at a temperature to form crystalline dry powder particles. The spray-drying temperature is greater than the glass transition temperature of the sugar or sugar alcohol. At least each of the selected dry powder particles comprises an amino acid coating the crystalline dry powder particles containing a solid active agent dispersed in a crystalline sugar matrix or a crystalline sugar alcohol matrix.

The amino acid may include histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, pyrrolysine, proline, selenocysteine, serine, tyrosine, or a combination thereof. Preferably, the amino acid includes leucine, such as L-leucine.

The crystalline dry powder particles may contain 5 wt.% or more or 10 wt.% or more of the amino acid and 30 wt.% or less or 25 wt.% or less of the amino acid by weight of the crystalline dry powder particles. The crystalline dry powder particles may include from 5 wt.% to 30 wt.%, from 10 wt.% to 30 wt.%, from 15 wt.% to 25 wt.% of the amino acid by weight of the crystalline dry powder particles.

Preferably, the crystalline dry powder particles may contain 5 wt.% or more or 10 wt.% or more leucine and 30 wt.% or less or 25 wt.% or less leucine by weight of the crystalline dry powder particles. The crystalline dry powder particles may include from 5 wt.% to 30 wt.%, from 10 wt.% to 30 wt.%, from 15 wt.% to 25 wt.% leucine by weight of the crystalline dry powder particles.

By providing an amino acid such as L-leucine with the crystalline dry powder particles, the adhesive forces of the crystalline dry powder particles can be reduced and the attraction between the particles can be reduced, and thus the formation of particle agglomerates can be further reduced.

Crystalline dry powder particles or crystalline dry powder particles can preferably form a homogeneous plurality of particles, wherein each particle comprises an active agent, a sugar or sugar alcohol, and optionally an amino acid. Each of the crystalline dry powder particles can contain from about 1 to about 10% active agent, from 99 to about 50% sugar or sugar alcohol, and optionally from 1 to about 40% amino acid. Preferably, each of the crystalline dry powder particles can contain from about 1 to about 10% active agent, from 80 to about 70% sugar alcohol, and from 15 to about 25% amino acid.

The crystalline particles of the dry powder may contain approximately 60% by weight or more of a sugar alcohol and 10% or more of an amino acid and from approximately 1% to approximately 10% by weight of a solid alkaloid salt. At least each of the selected particles comprises a sugar alcohol matrix, and the solid alkaloid salt is dispersed in the sugar alcohol matrix.

Each of the crystalline particles of the dry powder may contain from about 1 to about 10% of the active agent, from 99 to about 60% of the sugar or sugar alcohol, and optionally from 10 to about 30% of the amino acid. Preferably, each of the crystalline particles of the dry powder may contain from about 1 to about 10% of the active agent, from 85 to about 65% of the sugar alcohol, and from 10 to about 30% of the amino acid.

Each of the crystalline particles of the dry powder may contain from about 1 to about 10% nicotine, from 99 to about 60% sugar or sugar alcohol, and optionally from 10 to about 30% amino acid. Each of the crystalline particles of the dry powder may contain from about 1 to about 10% nicotine, from 85 to about 65% sugar alcohol, and from 10 to about 30% amino acid.

According to an aspect of the present invention, the crystalline particles of the dry powder contain about 60% by weight or more of a sugar alcohol, and 10% or more of an amino acid, and from about 1% to about 10% by weight of a solid alkaloid salt.

According to an aspect of the present invention, the crystalline dry powder particles may comprise a solid alkaloid salt and a sugar alcohol comprising mannitol, erythritol, myo-inositol, adonitol, xylitol, or a combination thereof.

According to an aspect of the present invention, the crystalline dry powder particles may comprise a solid alkaloid salt and a sugar alcohol comprising mannitol, erythritol, myo-inositol, or a combination thereof.

According to an aspect of the present invention, the crystalline dry powder particles may comprise a solid alkaloid salt, a sugar alcohol containing mannitol, erythritol, myo-inositol, or a combination thereof, and leucine.

According to an aspect of the present invention, the crystalline dry powder particles may comprise nicotine aspartate, a sugar alcohol containing mannitol, erythritol, myo-inositol, or a combination thereof, and leucine.

According to an aspect of the present invention, the crystalline dry powder particles may comprise nicotine bitartrate, a sugar alcohol containing mannitol, erythritol, myo-inositol, or a combination thereof, and leucine.

According to an aspect of the present invention, the crystalline dry powder particles may comprise nicotine glutarate, a sugar alcohol containing mannitol, erythritol, myo-inositol, or a combination thereof, and leucine.

According to an aspect of the present invention, the crystalline dry powder particles may comprise nicotine malate, a sugar alcohol containing mannitol, erythritol, myo-inositol, or a combination thereof, and leucine.

According to an aspect of the present invention, the crystalline dry powder particles may comprise anatabine glutarate, a sugar alcohol containing mannitol, erythritol, myo-inositol, or a combination thereof, and leucine.

Spray-drying or freeze-drying produces crystalline dry powder particles that contain the active ingredient and are suitable for inhalation. Crystalline dry powder particles typically exhibit low or reduced hygroscopicity. Crystalline dry powder particles do not readily absorb water or moisture when exposed to humid or tropical conditions. Crystalline dry powder particles also do not readily agglomerate when exposed to humid or tropical conditions. Another advantage is that crystalline dry powder particles are stable and have a long shelf life.

The present invention describes inhalable powders containing various active agents. Preferably, the active agent comprises an alkaloid, such as nicotine, anatabine, or anabasine. Preferably, the active agent comprises a solid salt of the alkaloid.

The salt may be formed during the process (during the combining step) or may be formed before the combining step. For example, the active agent in free base form can be mixed with aspartic acid, gentisic acid, benzoic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, muconic acid, hydrochloric acid, alpha-resorcylic acid, beta-resorcylic acid, oxalic acid, p-anisic acid, glutaric acid, or a combination thereof, preferably aspartic acid, tartaric acid, or glutaric acid. The acid can be mixed with the active agent in free base form in any suitable ratio depending on the desired salt form and the reaction rate. For example, a monoprotic acid such as benzoic acid can be combined with nicotine in a molar ratio of approximately 1:1 to produce a monoprotonated nicotine salt.

The amount of active agent can be selected depending on the desired or intended use of the inhalable powder. For example, the amount of active agent can be from 0.5 wt. % to 10 wt. % of the total weight of the crystalline dry powder particles. In some embodiments, the crystalline dry powder particles contain 0.5 wt. % or more, 1 wt. % or more, 2 wt. % or more, or 3 wt. % or more of the active agent and 12 wt. % or less, 10 wt. % or less, 9 wt. % or less, 8 wt. % or less, or 7 wt. % or less of the active agent, or from 0.5 wt. % to 10 wt. %, from 1 wt. % to 8 wt. %, from 1.5 wt. % to 6 wt. %, or from 2 wt. % to 5 wt. of the active agent.

In some embodiments, the crystalline dry powder particles comprise 0.5 wt.% or more, 1 wt.% or more, 2 wt.% or more, or 3 wt.% or more nicotine and 12 wt.% or less, 10 wt.% or less, 9 wt.% or less, 8 wt.% or less, or 7 wt.% or less nicotine, or from 0.5 wt.% to 10 wt.%, from 1 wt.% to 8 wt.%, from 1.5 wt.% to 6 wt.%, or from 2 wt.% to 5 wt.% nicotine.

The amount of active agent may also be selected on a per dose basis. The inhalable powder may be packaged in single dose form or in multi-dose form. For example, the inhalable powder may contain 0.5 mg or more, 1 mg or more, 2 mg or more, or 5 mg or more of active agent per dose. The inhalable powder may contain 500 mg or less, 200 mg or less, 100 mg or less, 50 mg or less, 20 mg or less, or 10 mg or less of active agent per dose. In some embodiments, the inhalable powder contains from 0.01 to 10 mg of anatabine, or nicotine, or anabasine per dose, from 0.05 to 5 mg of anatabine, or nicotine, or anabasine per dose, or from 0.1 to 1 mg of anatabine, or nicotine, or anabasine per dose.

An inhalable powder composition can be prepared by a method comprising combining a sugar or sugar alcohol with an active agent and a liquid carrier to form a liquid mixture. The liquid mixture can be spray-dried or freeze-dried to form crystalline particles of a dry powder. Preferably, the liquid carrier is aqueous. Preferably, the liquid carrier is water. Preferably, the liquid carrier comprises at least about 95% water, or at least 99% water, or 100% water (based on the total weight of the liquid carrier).

The liquid carrier may also contain an organic solvent such as an alkanol containing from 1 to 8 carbon atoms, an aliphatic ester containing from 3 to 8 carbon atoms, an aliphatic linear or cyclic ether containing from 3 to 8 carbon atoms, an aliphatic ketone containing from 3 to 8 carbon atoms, methanol, ethanol, acetone or acetonitrile.

The liquid mixture can be spray-dried at a spray-drying temperature greater than the glass transition temperature of the sugar or sugar alcohol. The spray-drying temperature can be 80°C or less, 70°C or less, 60°C or less, or 50°C or less. In some embodiments, the spray-drying temperature is also selected based on the active agent. Such spray-drying temperatures can be used to produce nicotine powder and to minimize the loss or destruction of nicotine during drying. The spray-drying temperature is the temperature at the outlet of the spray nozzle of the spray dryer. The spray-drying temperature can be the maximum temperature any droplet is exposed to during the spray-drying process.

Spray-drying or freeze-drying from a liquid mixture of the active ingredient and sugar or sugar alcohol results in crystalline dry powder particles containing the active ingredient dispersed throughout the particles in a sugar or sugar alcohol matrix. The crystalline sugar or crystalline sugar alcohol matrix can help protect the active ingredient from environmental factors such as high temperature and humidity. The crystalline sugar or crystalline sugar alcohol matrix also helps minimize agglomeration and maintain good flowability and aerodynamic properties of the crystalline dry powder particles. However, once the crystalline dry powder particles reach the user's lungs, they quickly dissolve, facilitating rapid absorption of the active ingredient.

The crystalline particles of the dry powder may have a particle size of 20 μm or less, 10 μm or less, or 5 μm or less, or 0.1 μm or more, 0.2 μm or more, or 0.5 μm or more, or in the range of 0.5 μm to 10 μm, or 0.75 μm to 5 μm, or 1 μm to 5 μm, or 1 μm to 3 μm, or 1.5 μm to 2.5 μm. The desired particle size range can be achieved by spray drying, milling, sieving, or a combination thereof.

Crystalline dry powder particles may have a pH (in solution) in the range recommended for human consumption. In some embodiments, the crystalline dry powder particles have a pH of 6 or less, 7 or less, or 8 or less, or 3 to 8, or 3 to 6, or 6 to 8 when dissolved in water. The pH of the crystalline dry powder particles can be measured by reconstituting the powder in deionized water at a concentration of 1 mg/mL and measuring the pH of the resulting solution at standard temperature and pressure. The crystalline dry powder particles can be formulated without the use of an additional buffer. Additional buffering agents can be compounds capable of buffering (e.g., salts, acids, bases, and combinations thereof) other than the acid used to form a salt with the active agent or the amino acid included in the crystalline dry powder particles. The crystalline dry powder particles may not contain surfactants.

The crystalline dry powder particles can be further mixed with a second plurality of particles to form a powder system. Preferably, the second plurality of particles has a different particle size or a larger particle size than the crystalline dry powder particles. For example, the second plurality of particles can have a particle size of approximately 20 μm or greater, or approximately 50 μm or greater, 200 μm or less, 150 μm or less, or in the range of 50 μm to 200 μm, or 50 μm to 150 μm. The second plurality of particles can have any suitable size distribution for delivery by inhalation selectively to the oral or buccal cavity of the user. The larger second plurality of flavoring particles can facilitate the delivery of the crystalline dry powder particles into the inhaled air stream for the user.

The crystalline dry powder particles and the second plurality of particles may be combined in any suitable relative amount, such that the second plurality of particles is perceived by the user upon consumption of the crystalline dry powder particles. Preferably, the crystalline dry powder particles and the second plurality of particles constitute at least about 90 wt.%, or at least about 95 wt.%, or at least about 99 wt.%, or 100 wt.% of the total weight of the powder system.

The crystalline dry powder particles may be further mixed with a second plurality of flavor particles to form a powder system. Preferably, the second plurality of flavor particles has a different particle size or a larger particle size than the crystalline dry powder particles. For example, the flavor particles may have a particle size of approximately 20 μm or greater, or approximately 50 μm or greater, 200 μm or less, 150 μm or less, or in the range of 50 μm to 200 μm, or 50 μm to 150 μm. The second plurality of flavor particles may have any suitable size distribution for delivery upon inhalation selectively to the oral or buccal cavity of the user. A larger second plurality of flavor particles may facilitate the delivery of the crystalline dry powder particles into the inhaled air stream for the user.

The crystalline dry powder particles and the second plurality of flavor particles may be combined in any suitable relative amount, whereby the second plurality of flavor particles is perceived by the user upon consumption of the crystalline dry powder particles. Preferably, the crystalline dry powder particles and the second plurality of flavor particles comprise at least about 90 wt.%, or at least about 95 wt.%, or at least about 99 wt.%, or 100 wt.% of the total weight of the powder system.

Crystalline particles of a dry powder or powder system can be provided in a suitable dosage form. For example, crystalline particles of a dry powder or powder system can be provided in the form of a capsule. The dosage form (e.g., a capsule) can be adapted for use in a suitable inhaler. For example, the capsule can be used in an inhaler device having a capsule cavity. Directing airflow through the capsule cavity of the inhaler device can cause the capsule to rotate during inhalation and consumption. The capsule can contain crystalline particles of a dry powder or powder system.

According to an embodiment, the crystalline particles of the dry powder or powder system are formulated to exhibit reduced hygroscopicity and a reduced tendency to agglomerate or stick together upon contact with water or moisture. Rotation of the punctured capsule can result in the suspension and aerosolization of the crystalline particles of the dry powder or powder system, released from the punctured capsule into the inhaled air moving through the inhaler device. Optional flavor particles can be larger than the crystalline particles of the dry powder and can facilitate the transport of the crystalline particles of the dry powder to the user, while the flavor particles are preferentially deposited in the user's oral or buccal cavity. The crystalline dry powder particles and optional flavor particles may be delivered by an inhaler device at inhalation rates or airflow rates that are within the range of inhalation rates or airflow rates in normal smoking.

Crystalline dry powder particles may contain a therapeutically effective dose of an active agent, such as anatabine glutarate. Anatabine (e.g., anatabine glutarate) may be administered to a human to reduce a symptom or disorder involving an NFκB-mediated inflammatory component and/or to reduce the risk of developing such a disorder. An NFκB-mediated inflammatory component may be associated with chronic inflammation, such as that seen in thyroiditis, cancer, arthritis, Alzheimer's disease, and multiple sclerosis. Crystalline dry powder particles containing anatabine may have a monoamine oxidase (MAO) inhibitory effect. Additionally or alternatively, crystalline dry powder particles containing anatabine may inhibit STAT3 phosphorylation.

The sugar alcohol may be selected from erythritol, myo-inositol, adonitol, xylitol, mannitol, their stereoisomers, or combinations thereof. The sugar or sugar alcohol may be a non-reducing sugar or sugar alcohol, preferably a sugar alcohol or a combination of sugar alcohols. Preferably, the sugar alcohol is selected from erythritol, myo-inositol, adonitol, mannitol, and xylitol. Preferably, the sugar alcohol is selected from erythritol, myo-inositol, and mannitol. Preferably, the sugar alcohol is erythritol or myo-inositol.

A sugar or sugar alcohol may have a glass transition temperature of 100°C or less, 75°C or less, or 50°C or less. A sugar or sugar alcohol may have a solubility of 75 g or less, 60 g or less, 50 g or less, or 30 g or less in 100 g of water at 25°C. A sugar alcohol may have a glass transition temperature of 100°C or less, 75°C or less, or 50°C or less. A sugar alcohol may have a solubility of 75 g or less, 60 g or less, 50 g or less, or 30 g or less in 100 g of water at 25°C.

The crystalline dry powder particles may exhibit a hygroscopicity of approximately 5% or less. The crystalline dry powder particles may exhibit a hygroscopicity of approximately 4% or less. The crystalline dry powder particles may exhibit a hygroscopicity of approximately 3% or less. The crystalline dry powder particles may exhibit a hygroscopicity of approximately 2.5% or less. The crystalline dry powder particles may exhibit a hygroscopicity of approximately 2% or less. The crystalline dry powder particles may exhibit a hygroscopicity of approximately 1.5% or less. The crystalline dry powder particles may exhibit a hygroscopicity of approximately 1% or less. The crystalline dry powder particles may exhibit a hygroscopicity in the range of 0% to approximately 5%, or 0% to approximately 4%, or 0% to approximately 3%, or 0% to approximately 2%.

Hygroscopicity can be measured by measuring the absorption or adsorption of water (increase in weight percent) of a sample under tropical conditions (in an atmosphere with 75% relative humidity and 30 degrees Celsius) for 20 minutes. Before exposure to tropical conditions, the sample is equilibrated at 0% relative humidity and 25 degrees Celsius for 24 hours to reduce or remove unbound water from the sample. Hygroscopicity is measured using an SPSx-1u high-capacity vapor sorption analyzer manufactured by ProUmid GmbH & Co. KG, as described in the examples below.

Crystalline dry powder particles can be prepared by mixing an active agent with an acid or base, a sugar or sugar alcohol, and a liquid carrier into a flowable liquid mixture and spray-drying the flowable mixture. Crystalline dry powder particles can be prepared by mixing an active agent with an acid or base, a sugar alcohol, and a liquid carrier into a flowable liquid mixture and spray-drying the flowable mixture. The use of an acid or base can result in the formation of a salt of the active agent that is solid at room temperature. This can be advantageous since it allows the incorporation of active agents that are not solid at room temperature or can provide a solid with preferable physical properties. The method can further include adding an amino acid to the crystalline dry powder particles or flowable liquid mixture. The method can further include combining the amino acid with the sugar, active agent, and acid to form a mixture. The method can further include adding the amino acid to both the liquid mixture and the particles.

Crystalline dry powder particles can be prepared by mixing the active agent with an acid, a sugar or sugar alcohol, and a liquid carrier into a flowable liquid mixture and spray-drying the flowable mixture. Crystalline dry powder particles can be prepared by mixing the active agent with an acid, a sugar alcohol, and a liquid carrier into a flowable liquid mixture and spray-drying the flowable mixture. The use of an acid can result in the formation of a salt of the active agent that is solid at room temperature. This can be advantageous because it allows the incorporation of active agents that are not solid at room temperature or can provide a solid with preferred physical properties. This has been found to be particularly useful if the active agent is an alkaloid, particularly if the active agent is nicotine, anatabine, or anabasine. The acid can be selected to reduce any loss of the active agent during spray-drying. Malate salts have been found to be particularly effective in reducing such alkaloid losses, particularly nicotine, during spray drying. The method may further comprise adding an amino acid to the crystalline particles of the dry powder. The method may further comprise combining the amino acid with a sugar, an active agent, and an acid to form a mixture. The method may further comprise adding the amino acid to both the liquid mixture and the crystalline particles of the dry powder.

Preferably, at least each of the selected crystalline particles of the dry powder comprises a solid alkaloid salt dispersed in a mannitol crystalline matrix, an erythritol crystalline matrix, or a myo-inositol crystalline matrix.

Preferably, at least each of the selected crystalline particles of the dry powder comprises a solid nicotine salt dispersed in a crystalline mannitol matrix, a crystalline erythritol matrix, or a crystalline myo-inositol matrix.

Preferably, at least each of the selected crystalline dry powder particles comprises a solid anatabine salt dispersed in a mannitol crystalline matrix, an erythritol crystalline matrix, or a myo-inositol crystalline matrix.

The crystalline dry powder particles may contain nicotine aspartate; mannitol, myo-inositol or erythritol, and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine aspartate, from 70% to 99% by weight of mannitol, myo-inositol, or erythritol, and from 0% to 29% by weight of leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine aspartate, from 70% to 80% by weight of mannitol, myo-inositol, or erythritol, and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain nicotine bitartrate; mannitol, myo-inositol or erythritol, and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine bitartrate, from 70% to 80% by weight of mannitol, myo-inositol, or erythritol, and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain nicotine glutarate; mannitol, myo-inositol or erythritol, and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine glutarate, from 70% to 80% by weight of mannitol, myo-inositol, or erythritol, and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain nicotine malate; mannitol, myo-inositol or erythritol, and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine glutarate, from 70% to 80% by weight of mannitol, myo-inositol, or erythritol, and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain anatabine glutarate; mannitol, myo-inositol or erythritol, and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of anatabine glutarate, from 70% to 80% by weight of mannitol, myo-inositol, or erythritol, and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain nicotine aspartate; erythritol and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine aspartate, from 70% to 99% by weight of erythritol and from 0% to 29% by weight of leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine aspartate, from 70% to 80% by weight of erythritol and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain nicotine bitartrate; erythritol and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight nicotine bitartrate, from 70% to 80% by weight erythritol and from 15% to 25% by weight leucine.

The crystalline dry powder particles may contain nicotine glutarate; erythritol and leucine. The crystalline dry powder particles may contain from 1% to 10% by weight of nicotine glutarate, from 70% to 80% by weight of erythritol and from 15% to 25% by weight of leucine.

The crystalline dry powder particles may contain nicotine malate; erythritol and leucine. The crystalline dry powder particles may contain from 1 wt.% to 10 wt.% nicotine glutarate, from 70 wt.% to 80 wt.% erythritol and from 15 wt.% to 25 wt.% leucine.

The crystalline dry powder particles may contain anatabine glutarate; erythritol and leucine. The crystalline dry powder particles may contain from 1 wt.% to 10 wt.% anatabine glutarate, from 70 wt.% to 80 wt.% erythritol and from 15 wt.% to 25 wt.% leucine.

In some embodiments, the crystalline dry powder particles may not contain mannitol if the active agent is aspartate.

The crystalline particles of the dry powder of the present invention create a matrix of crystalline sugar or crystalline sugar alcohol, which helps protect the active agent from environmental factors such as high temperature and humidity. The crystalline sugar or crystalline sugar alcohol matrix also helps minimize agglomeration and maintain good flowability and aerodynamic properties of the inhaled powder. However, once the inhaled powder reaches the user's lungs, the particles dissolve rapidly, facilitating rapid absorption of the active agent.

The lower hygroscopicity of crystalline dry powder particles can help minimize composition loss due to agglomeration, stickiness, or liquefaction. This can provide improved control over the particle size of the crystalline dry powder particles, the dose size, and the chemical composition of the crystalline dry powder particles delivered to the consumer. In addition to lower hygroscopicity and thus an increased shelf life, crystalline dry powder particles may advantageously have improved aerodynamic properties. For example, a consumer may be able to consume more than half of the crystalline dry powder particles contained in a cartridge or capsule. Because crystalline dry powder particles do not readily absorb water, the consumer can obtain a greater number of use sessions or puffs from a single cartridge or capsule. Crystalline dry powder particles can also be supplied in larger dosage forms, such as cartridges or capsules, due to the fact that the quality of the crystalline dry powder particles does not deteriorate shortly after opening the package.

The term "particle size" is used herein to refer to the mass median aerodynamic diameter (MMAD) of a particle or set of particles, unless otherwise noted. Such values are based on the distribution of particle aerodynamic diameters, defined as the diameter of a sphere with a density of 1 g/ ^cm3 that has the same aerodynamic characteristics as the particle being characterized.

Specifically, for a powder system, the mass median aerodynamic diameter (MMAD) is commonly referred to, one of the metrics most widely accepted as a single numerical parameter of the aerodynamic particle size distribution. MMAD is a statistically derived metric for a particle sample: as an example, an MMAD of 5 micrometers means that 50 percent of the total sample mass will be present in particles with an aerodynamic diameter of less than 5 micrometers, and the remaining 50 percent of the total sample mass will be present in particles with an aerodynamic diameter greater than 5 micrometers. In the context of the present invention, when describing a powder system, the term "particle size" preferably refers to the MMAD of the powder system.

The MMAD of a powder system is preferably measured using a cascade impactor. Cascade impactors are instruments widely used for sampling and separating airborne particles to determine aerodynamic size classification of aerosol particles. In practice, cascade impactors separate the incoming sample into discrete fractions based on particle inertia, which is a function of particle size, density, and velocity. A cascade impactor typically consists of a series of stages, each of which includes a plate with a specific nozzle arrangement and a collecting surface. Because both the nozzle size and the total nozzle area decrease with increasing number of stages, the velocity of the air saturated with the sample increases as it passes through the instrument. At each stage, particles with sufficient inertia break away from the prevailing airflow and strike the collection surface. Thus, at any given flow velocity, each stage is associated with a cutoff diameter, a parameter that determines the size of the particles being collected. As the number of stages increases, the velocity increases, and therefore the cutoff diameter of the stages decreases. Thus, the cutoff diameter associated with a given stage is a function of the airflow rate used for testing. To reflect efficiency, nebulizers are typically tested at 15 L/min, while dry powder inhalers can be tested at values up to 100 L/min.

Preferably, in the context of the present invention, the MMAD of the powder system is measured using a Next Generation Impactor (NGI) 170 (available from Copley Scientific AG). The NGI is a high-performance, high-precision cascade impactor with particle classification, comprising seven stages plus a micro-diaphragm collector (MOC). The characteristics and operating principle of the NGI are described, for example, in Marple et al. , Journal of Aerosol Medicine - Volume 16, Number 3 (2003). More preferably, measurements are performed at 20 ± 3 degrees Celsius and a relative humidity of 35 ± 5 percent.

The dry powder composition typically contains moisture in an amount less than or equal to about 15 percent by weight, preferably less than or equal to about 10 percent by weight, and even more preferably less than or equal to about 6 percent by weight. Most preferably, the dry powder composition contains moisture in an amount less than or equal to about 5 percent by weight, or even less than or equal to about 3 percent by weight, or even less than or equal to about 1 percent by weight.

All values given as percentages are assumed to be weight percentages based on total weight.

All scientific and technical terms used in this document have the meanings commonly used in the art unless otherwise specified. The definitions provided in this document are intended to facilitate understanding of certain terms frequently used in this document.

As used herein, the singular forms "a", "an", and "the" include embodiments with plural references unless the content clearly dictates otherwise.

In the context of this document, the conjunction "or" is generally used to include "and/or," unless the context clearly indicates otherwise. The term "and/or" refers to one or all of the listed elements, or a combination of any two or more of the listed elements.

As used in this document, the words "have," "having," "include," "including," "contain," "comprising," or the like are used in their broad sense and generally mean "including, but not limited to." It will be understood that the expressions "consisting essentially of," "consisting of," and the like are included within the category of "comprising," and the like.

The words "preferred" and "preferably" refer to embodiments of the present invention that may provide certain advantages under certain circumstances. However, other embodiments may also be preferred under the same or different circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention, including the claims.

As used in this document, the term "substantially" has the same meaning as "significantly" and may be understood as modifying the relevant term by at least approximately 90%, at least approximately 95%, or at least approximately 98%. As used in this document, the term "not substantially" has the same meaning as "insignificantly" and may be understood as having the inverse meaning of the term "substantially", that is, modifying the relevant term by no more than 10%, no more than 5%, or no more than 2%.

The present invention is defined in the claims. However, a non-exhaustive list of non-limiting examples is provided below. Any one or more features of these examples may be combined with any one or more features of another example, embodiment, or aspect described herein.

Example Ex1. The inhaled powder comprises crystalline dry powder particles. The crystalline dry powder particles comprise a solid alkaloid salt and a sugar alcohol.

Example Ex2. The inhalable powder of Ex1, wherein the sugar alcohol is mannitol, erythritol, myo-inositol, adonitol, xylitol, or a combination thereof.

Example Ex3. An inhalable powder according to any of the previous examples, wherein the sugar alcohol is mannitol, erythritol, myo-inositol, or a combination thereof.

Example Ex4. An inhalable powder according to any of the previous examples, wherein the sugar alcohol is mannitol.

Example Ex5. An inhalable powder according to any of the previous examples, wherein the sugar alcohol is erythritol.

Example Ex6. An inhalable powder according to any of the previous examples, wherein the sugar alcohol is myo-inositol.

Example Ex7. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt is a nicotine salt.

Example Ex8. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt comprises nicotine bitartrate, nicotine aspartate, nicotine malate, or nicotine glutarate.

Example Ex9. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt is nicotine bitartrate.

Example Ex10. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt is nicotine aspartate.

Example Ex11. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt is nicotine glutarate.

Example Ex12. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt is nicotine malate.

Example Ex13. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt comprises anatabine salt.

Example Ex14. An inhalable powder according to any of the previous examples, wherein the solid alkaloid salt is anatabine glutarate.

Example Ex15. An inhalable powder according to any of the preceding examples, wherein the solid alkaloid salt is anabasine.

Example Ex16. An inhalable powder according to any of the previous examples, wherein the crystalline particles of the dry powder comprise a solid alkaloid salt, a sugar alcohol, and an amino acid.

Example Ex17. An inhalable powder according to any of the previous examples, wherein the crystalline particles of the dry powder comprise a solid alkaloid salt, a sugar alcohol, and leucine.

Example Ex18. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, nicotine aspartate, nicotine malate or nicotine glutarate, a sugar alcohol and leucine.

Example Ex19. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, nicotine aspartate, nicotine malate or nicotine glutarate, mannitol and leucine.

Example Ex20. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, nicotine aspartate, nicotine malate or nicotine glutarate, erythritol and leucine.

Example Ex21. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, nicotine aspartate, nicotine malate or nicotine glutarate, myo-inositol and leucine.

Example Ex22. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, mannitol and leucine, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine bitartrate is dispersed in the matrix of mannitol.

Example Ex23. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, erythritol and leucine, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine bitartrate is dispersed in the erythritol matrix.

Example Ex24. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine bitartrate, myo-inositol and leucine, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine bitartrate is dispersed in the myo-inositol matrix.

Example Ex25. An inhalable powder according to any of the previous examples, wherein the crystalline dry powder particles comprise nicotine aspartate, mannitol and leucine, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine aspartate is dispersed in the matrix of mannitol.

Example Ex26. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine aspartate, erythritol and leucine, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine aspartate is dispersed in the erythritol matrix.

Example Ex27. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine aspartate, myo-inositol and leucine, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine aspartate is dispersed in the myo-inositol matrix.

Example Ex28. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine glutarate, mannitol and leucine, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine glutarate is dispersed in the matrix of mannitol.

Example Ex29. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine glutarate, erythritol and leucine, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine glutarate is dispersed in the erythritol matrix.

Example Ex30. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine glutarate, myo-inositol and leucine, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine glutarate is dispersed in the myo-inositol matrix.

Example Ex31. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine malate, mannitol and leucine, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine malate is dispersed in the matrix of mannitol.

Example Ex32. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine malate, erythritol and leucine, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine malate is dispersed in the erythritol matrix.

Example Ex33. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise nicotine malate, myo-inositol and leucine, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine malate is dispersed in the myo-inositol matrix.

Example Ex34. The inhalable powder of any of the previous examples, wherein the crystalline particles of the dry powder comprise about 60% by weight or more of a sugar alcohol and 10% or more of an amino acid and from about 1% to about 10% by weight of a solid alkaloid salt.

Example Ex35. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise approximately 60% by weight or more of a sugar alcohol and 10% or more of an amino acid and from approximately 1% to approximately 10% by weight of a solid alkaloid salt, and at least each of the selected crystalline dry powder particles comprises a sugar alcohol matrix, and the solid alkaloid salt is dispersed in the sugar alcohol matrix.

Example Ex36. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% erythritol, from 15% to 25% leucine and from 1% to 10% nicotine bitartrate, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine bitartrate is dispersed in the erythritol matrix.

Example Ex37. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% erythritol, from 15% to 25% leucine and from 1% to 10% nicotine aspartate, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine aspartate is dispersed in the erythritol matrix.

Example Ex38. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% erythritol, from 15% to 25% leucine and from 1% to 10% nicotine glutarate, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine glutarate is dispersed in the erythritol matrix.

Example Ex39. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% erythritol, from 15% to 25% leucine and from 1% to 10% nicotine malate, and at least each of the selected crystalline dry powder particles comprises an erythritol matrix, and the nicotine malate is dispersed in the erythritol matrix.

Example Ex40. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% myo-inositol, from 15% to 25% leucine and from 1% to 10% nicotine bitartrate, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine bitartrate is dispersed in the myo-inositol matrix.

Example Ex41. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% myo-inositol, from 15% to 25% leucine and from 1% to 10% nicotine aspartate, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine aspartate is dispersed in the myo-inositol matrix.

Example Ex42. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% myo-inositol, from 15% to 25% leucine and from 1% to 10% nicotine glutarate, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine glutarate is dispersed in the myo-inositol matrix.

Example Ex43. The inhalable powder of any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% myo-inositol, from 15% to 25% leucine and from 1% to 10% nicotine malate, and at least each of the selected crystalline dry powder particles comprises a myo-inositol matrix, and the nicotine malate is dispersed in the myo-inositol matrix.

Example Ex44. An inhalable powder according to any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% mannitol, from 15% to 25% leucine and from 1% to 10% nicotine bitartrate, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine bitartrate is dispersed in the matrix of mannitol.

Example Ex45. An inhalable powder according to any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% mannitol, from 15% to 25% leucine and from 1% to 10% nicotine aspartate, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine aspartate is dispersed in the matrix of mannitol.

Example Ex46. An inhalable powder according to any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% mannitol, from 15% to 25% leucine and from 1% to 10% nicotine glutarate, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine glutarate is dispersed in the matrix of mannitol.

Example Ex46. An inhalable powder according to any of the previous examples, wherein the crystalline dry powder particles comprise from 70% to 80% mannitol, from 15% to 25% leucine and from 1% to 10% nicotine malate, and at least each of the selected crystalline dry powder particles comprises a matrix of mannitol, and the nicotine malate is dispersed in the matrix of mannitol.

Example Ex.47. The respirable powder of any of the previous examples, wherein the crystalline particles of the dry powder are characterized by a hygroscopicity of 5% or less, or 4% or less, or 3% or less, or 2% or less.

Example Ex.48. A respirable powder system comprising a first plurality of crystalline dry powder particles of the powder of any one or more of the preceding examples and a second plurality of particles having a particle size greater than the particle size of the first plurality of particles.

Example Ex.49. The respirable powder system of Ex.48, wherein the first plurality of crystalline dry powder particles is characterized by a particle size of from about 1 micrometer to about 5 micrometers, and the second plurality of particles is characterized by a particle size of from 20 micrometers to 200 micrometers.

Below, the examples will be further described with reference to figures in which:

Fig. 1 shows the powder X-ray diffraction pattern (CuKα) of the preferred polymorph of anatabine glutarate.

Fig. 2 shows a schematic representation of an illustrative product in the form of an inhaler.

Fig. 3 shows the powder X-ray diffraction pattern for the amorphous trehalose powder composition Comp Ex described below.

Figure 4 shows the powder X-ray diffraction pattern for the crystalline myo-inositol powder composition sample B described below.

Fig. 5 shows the X-ray powder diffraction pattern for the crystalline erythritol powder composition sample C described below.

Fig. 6 shows the powder X-ray diffraction pattern for the sample D of the crystalline powder composition of adonite described below.

Fig. 7 shows the powder X-ray diffraction pattern for the crystalline mannitol powder composition sample A described below.

Fig. 8 shows the powder X-ray diffraction pattern for the sample E of the crystalline xylitol powder composition described below.

Fig. 9 shows a graph of the hygroscopicity test data described in the examples below.

The exemplary inhaler article 10 in Fig. 2 includes an elongated cylindrical body extending from the mouthpiece end 11 to the distal end 12. A cavity for a capsule 20 is formed within the elongated cylindrical body. A capsule 30 is contained in the cavity for the capsule 20. The crystalline dry powder particles described herein may be contained in the capsule 30. The capsule 30 may be punctured to form an opening in the body of the capsule 30, and inhaled air may pass through the inhaler article 10 with the release of the crystalline dry powder particles from the punctured capsule 30 and into the inhaled air stream and from the mouthpiece end 11.

The diagrammatic drawings are not necessarily to scale and are presented for illustrative purposes only, not limiting. The drawings depict one or more aspects described in the present invention. However, it will be understood that other aspects not shown in the drawings are within the scope and spirit of the present invention.

EXAMPLES

The first liquid mixture was formed by combining 2.5% nicotine free base, 20% leucine, 73.4% mannitol, and 4.1% aspartic acid in water. The first liquid mixture was fed into a spray dryer (Buchi B-290) operated at the first set point (1.0 bar, 50°C, and a feed rate of 2.5 g/min) and the second set point (3.0 bar, 50°C, and a feed rate of 2.5 g/min) to form crystalline dry powder particles.

The crystalline dry powder particles obtained in the first established mode were fine, free-flowing white powder. This powder was characterized by a particle size distribution of _X10 = 1.78 micrometers, _X50 = 7.13 micrometers, _X90 = 14.56 micrometers, and VMD = 7.82 micrometers. These crystalline dry powder particles were then co-micronized (jet milled) with leucine at a ratio of 85:15 (crystalline dry powder particles:leucine). This co-micronized powder was characterized by a particle size distribution of _X10 = 0.64 micrometers, _X50 = 1.29 micrometers, _X90 = 2.81 micrometers, and VMD = 1.54 micrometers.

The crystalline dry powder particles obtained in the second set of conditions were a fine, free-flowing white powder. This powder had a particle size distribution of _X10 = 1.10 micrometers, _X50 = 2.88 micrometers, _X90 = 6.13 micrometers, and VMD = 3.37 micrometers.

Additional crystalline dry powder particles were formed (using the formulations listed in Table 1 below) using the second set of spray-drying conditions described above. All samples and comparative examples had particle size distributions of approximately X ₅₀ = 2-4 micrometers and X ₉₀ = 5-6 micrometers.

Table 1

Sample Nicotine, % Aspartic acid, % Leucine, % Sugar or sugar alcohol, % A 2.5 4.1 20 73.4 - mannitol, Tg=13°C B 2.5 4.1 20 73.4 - myo-inositol, Tg=<50°C C 2.5 4.1 20 73.4 - erythritol, Tg=-44°C D 2.5 4.1 20 73.4 - adonite, Tg=-21°C E 2.5 4.1 20 73.4 - xylitol, Tg=-29°C

The comparative sample "Comp Ex" was prepared using amorphous trehalose sugar (Tg=106°C and solubility of 69 g/100 ml water at 25°C) using a comparative liquid mixture formed by combining 2.5% nicotine free base, 10% leucine, 86.25% trehalose, 1.25% lactic acid in water. The comparative liquid mixture was fed into a spray dryer (Buchi B-290) operated at the first setting (5.5 bar, 70°C and feed rate of 3 g/min) to form amorphous dry powder particles.

Powder X-ray diffraction measurements were performed using a PANalytical X'Pert Pro diffractometer equipped with a CuKα electromagnetic radiation source (λ = 1.5432 nm, 40 kV, 40 mA) in Bragg-Brentano geometry using standard sample holders. Six 30-minute scans were performed for each sample. The resulting diffraction patterns or graphs from these powder X-ray diffraction measurements are shown in Figs. 3–8.

Figure 3 shows the X-ray powder diffraction pattern for the trehalose powder formulation Comp Ex. This diffraction pattern indicates that Comp Ex was primarily amorphous.

Figure 4 shows the X-ray powder diffraction pattern for sample B of the crystalline myo-inositol powder composition. This diffraction pattern indicates that sample B was crystalline.

Figure 5 shows the X-ray powder diffraction pattern for sample C of the crystalline erythritol powder composition. This diffraction pattern indicates that sample C was crystalline.

Fig. 6 shows the X-ray powder diffraction pattern for sample D of the crystalline powder composition of adonite. This diffraction pattern indicates that sample D was crystalline.

Fig. 7 shows the X-ray powder diffraction pattern for sample A of the crystalline mannitol powder composition. This diffraction pattern indicates that sample A was crystalline.

Fig. 8 shows the X-ray powder diffraction pattern for sample E of the crystalline xylitol powder composition. This diffraction pattern indicates that sample E was crystalline.

As shown in Fig. 9, each 100-milligram sample (samples A-E and Comp Ex) was placed in the measuring chamber of the ProUmid vapor sorption apparatus and equilibrated at 0% relative humidity and 25 degrees Celsius for 24 hours 1450 minutes. The temperature of the apparatus was then increased to 30 degrees Celsius and 75% relative humidity. Measurements were taken approximately every 6 minutes.

The trehalose-based sample (Comp Ex) showed the highest rate of mass increase (moisture absorption) of over 7% within 20 minutes and over 10% within 30 minutes.

All mannitol-based (sample A), myo-inositol-based (sample B), erythritol-based (sample C), adonitol-based (sample D), and xylitol-based (sample E) samples showed an increase of 2% or less at 20 minutes and 3% or less at 30 minutes. Table 2 below shows the hygroscopicity from 1450 min to 1500 min (50-minute duration).

Table 2. % increase in mass depending on time

Time (min) Comp Ex
Trehalose Sample A
Mannitol Sample B
Myo-inositol Sample C
Erythritol Sample D
Adonite Sample E
Xylitol 0 0 0 0 0 0 0 10 2.3 0.8 0.9 1.0 1.2 0.6 20 7 1.6 1.9 1.6 2.0 1.5 30 10 1.9 2.3 1.9 2.9 2.3 40 10 2.1 2.7 2.2 3.6 3.0 50 9.5 2.5 3.5 3.0 5.4 4.8

All samples were then tested using a tropical aerosol generation test. Approximately 50 grams of powder from each sample was loaded into a capsule, which was then inserted into the inhaler and punctured. Inhaled air (75% relative humidity and 30 degrees Celsius) was passed through the inhaler at a puff rate of 80 ml every two seconds for a total of 20 puffs. The entire inhaler device was weighed before and after the aerosol generation test to determine the amount of each sample released from the capsule. The preferred target amount of released substance was found to be at least 25 grams.

The amount of released sample A (based on mannitol) was 30 grams. The amount of released sample B (based on myo-inositol) was 34 grams. The amount of released sample C (based on erythritol) was 30 grams. All of these samples met the target amount of released target substance.

The amount of sample D (based on adonitol) released was 9 grams. The amount of sample E (based on xylitol) released was 14 grams. These samples did not meet the target amount of released target substance.

The comparison sample "Comp Ex" (trehalose based) actually increased in weight by 0.1 grams, indicating that more water was absorbed than released by the sample.

Although adonitol and xylitol powders did not achieve the target release value, they still provided a significant improvement over amorphous trehalose powder.

For the purposes of the present description and the appended claims, except where otherwise indicated, all numbers expressing quantities, amounts, percentages, etc., are to be understood as modified in all instances by the term "about." Also, all ranges include the disclosed maximum and minimum points and include any intermediate ranges therebetween, which may or may not be specifically listed herein. Thus, in this context, the number A is understood as A ±2% A. In this context, the number A can be considered to include numerical values that are within the normal standard error for measuring the property that the number A modifies. The number A, in some instances, when used in the appended claims, may deviate by the percentages listed above, provided that the amount by which A deviates does not materially affect the fundamental and novel characteristic(s) of the claimed invention. Also, all ranges include the disclosed maximum and minimum points and include any intermediate ranges therebetween, which may or may not be specifically listed herein.

Claims (16)

1. Inhalable powder containing: crystalline particles of dry powder containing a solid alkaloid salt, wherein the alkaloid salt is a solid at 25°C; and a sugar alcohol selected from erythritol, myo-inositol, adonitol, xylitol, or a combination thereof. 2. The inhalable powder of claim 1, wherein the solid alkaloid salt comprises nicotine bitartrate, nicotine aspartate, nicotine malate, or nicotine glutarate. 3. The inhalable powder of claim 1 or 2, wherein the solid alkaloid salt comprises anatabine glutarate. 4. The inhalable powder of any preceding claim, wherein the crystalline particles of the dry powder further comprise an amino acid. 5. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise a sugar alcohol, an amino acid, and a solid alkaloid salt, and at least each of the selected crystalline dry powder particles comprises a sugar alcohol matrix and a solid alkaloid salt dispersed in the sugar alcohol matrix. 6. An inhalable powder according to any preceding paragraph, wherein the sugar alcohol is erythritol or myo-inositol. 7. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise 60% by weight or more of a sugar alcohol, and 10% or more of an amino acid, and from 1 to 10% by weight of a solid alkaloid salt, and at least each of the selected crystalline dry powder particles comprises a sugar alcohol matrix, and the solid alkaloid salt is dispersed in the sugar alcohol matrix. 8. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise erythritol or myo-inositol, and leucine, and nicotine bitartrate, and at least each of the selected crystalline dry powder particles comprises a matrix of erythritol or myo-inositol, and the nicotine bitartrate is dispersed in the matrix of erythritol or myo-inositol. 9. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise erythritol or myo-inositol, and leucine, and nicotine aspartate, and at least each of the selected crystalline dry powder particles comprises a matrix of erythritol or myo-inositol, and the nicotine aspartate is dispersed in the matrix of erythritol or myo-inositol. 10. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise erythritol or myo-inositol, and leucine, and nicotine glutarate, and at least each of the selected crystalline dry powder particles comprises a matrix of erythritol or myo-inositol, and the nicotine glutarate is dispersed in the matrix of erythritol or myo-inositol. 11. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise erythritol or myo-inositol, and leucine, and nicotine malate, and at least each of the selected crystalline dry powder particles comprises a matrix of erythritol or myo-inositol, and the nicotine malate is dispersed in the matrix of erythritol or myo-inositol. 12. The inhalable powder of any preceding claim, wherein the crystalline dry powder particles comprise from 70 to 80% erythritol, from 15 to 25% leucine, and from 1 to 10% by weight of nicotine bitartrate, nicotine aspartate, nicotine malate, or nicotine glutarate. 13. An inhalable powder system comprising a first plurality of crystalline dry powder particles of a powder according to any one of claims 1-12 and a second plurality of flavoring particles characterized by a particle size greater than that of the first plurality of particles. 14. The inhalable powder system of claim 13, wherein the first plurality of crystalline dry powder particles are characterized by a particle size corresponding to an MMAD of from 1 to 5 μm, and the second plurality of particles are characterized by a particle size corresponding to an MMAD of from 20 to 200 μm.