RU2844716C1 - Anatabine compositions in powder form - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: powdered anatabine compositions contain sugar or an adhesion-reducing compound, and are suitable for inhalation, and methods for preparing them are presented. Sugar and the anatabinic compound can be spray-dried to form an anatabinic composition in the form of a dry powder. Anatabine powder may have a particle size of about 20 micrometres or less, 10 micrometres or less, or from about 1 to about 4 micrometres, measured as the mass median aerodynamic diameter. Powder may include a plurality of particles containing an anatabinic compound, sugar and an adhesion-reducing compound, and a plurality of particles having a particle size ranging from about 20 mcm to about 200 mcm, measured as a mass median aerodynamic diameter.

EFFECT: powdered anatabine compositions are disclosed.

15 cl, 1 dwg, 1 tbl, 2 ex

Description

The present invention relates to anatabine powder compositions with a sugar or an adhesion reducing compound that may be suitable for inhalation, and to methods for producing the same. The sugar and anatabine compound may be spray dried to form an anatabine dry powder composition for inhalation.

Dry powder inhalers (DPIs) are known and used to treat respiratory diseases by delivering a dry powder containing a pharmaceutically active compound in the form of an aerosol by inhalation into the respiratory tract of patients. In pharmaceutical dry powders, the active pharmaceutical ingredient (API) typically forms agglomerates on the surface of larger carrier particles, such as lactose. DPIs operate through complex mechanisms to ensure that such agglomerates are dispersed, disintegrated or broken down before the API is inhaled into the lungs.

It would be desirable to provide an anatabine composition in powder form that is free-flowing and efficiently formed. It would be desirable to provide an anatabine composition in powder form that is of a size that allows it to be delivered to the lungs or respiratory tract of a user by inhalation. It would be desirable to provide an anatabine composition in powder form that has a long shelf life.

According to an aspect of the present invention, an inhalable dry powder composition comprises a plurality of particles comprising an anatabine compound with a sugar or an adhesion reducing compound.

According to another aspect of the present invention, a powder composition comprises a plurality of particles comprising an anatabine compound with a sugar or an adhesion reducing compound, and the particles are characterized by a particle size of about 20 micrometers or less, or about 10 micrometers or less, or from about 1 to about 4 micrometers, measured as mass median aerodynamic diameter.

According to another aspect of the present invention, a powder composition comprises a plurality of particles comprising an anatabine compound with a sugar or an adhesion reducing compound, and wherein the plurality of particles are characterized by a particle size of from about 20 micrometers to about 200 micrometers, measured as mass median aerodynamic diameter.

According to another aspect of the present invention, the composition in powder form comprises a plurality of particles comprising an anatabine compound and a sugar, preferably an amorphous sugar.

According to another aspect of the present invention, the powder composition comprises a plurality of particles comprising an anatabine compound and an adhesion reducing compound, preferably an amino acid or a peptide.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles having a size of about 20 micrometers or less, or about 10 micrometers or less, or from about 1 to about 4 micrometers, measured as mass median aerodynamic diameter.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles having a size of from about 20 micrometers to about 200 micrometers, measured as mass median aerodynamic diameter.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a first dimension, and then micronizing the plurality of particles characterized by the first dimension to a reduced size.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a first dimension, and then micronizing the plurality of particles characterized by the first dimension to a reduced size in the range of about 20 micrometers or less, or about 10 micrometers or less, or about 1 to about 4 micrometers, measured as mass median aerodynamic diameter.

According to another aspect of the present invention, a method for forming a composition in powder form comprises combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a first dimension, and then micronizing the plurality of particles characterized by the first dimension to a reduced size in the range of from about 20 micrometers to about 200 micrometers, or from about 50 to about 150 micrometers, measured as the mass median aerodynamic diameter.

Advantageously, the anatabine powder composition is a free-flowing powder. Advantageously, the anatabine powder composition is free-flowing and can be sized for delivery to the lungs or respiratory tract of a user by inhalation. The anatabine powder composition can be stable and have a long shelf life. The methods result in anatabine particles in dry powder form that are free-flowing and can be suitable, for example, for inhalation. The method can provide high throughput in the production of the anatabine powder composition without deteriorating the physical and chemical properties of the anatabine powder composition.

Using spray drying methods, composite particles of anatabine are formed, each of which comprises anatabine and a matrix compound such as sugar. The composite particles of anatabine form the powder compositions described in the present invention. Anatabine can be dispersed within a sugar matrix. Preferably, anatabine is a solid salt at 25°C.

By spray drying methods, composite particles of anatabine are formed, each of which comprises anatabine and a matrix compound, such as a sugar, and a coating of a compound that reduces adhesion, preferably an amino acid. Anatabine can be dispersed in a sugar matrix, and an amino acid, such as leucine, can coat or encapsulate each composite particle of anatabine to form a free-flowing composition with composite particles of anatabine. Preferably, anatabine is a solid salt at 25 ° C.

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 marketed dietary supplement anatabolic antagonist, 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 an X-ray powder diffraction pattern (CuKα) comprising 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 an X-ray powder 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 a powder X-ray 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 solvent preferably includes 2-methyltetrahydrofuran, acetonitrile and/or ethyl acetate. More preferably, the solvent includes 2-methyltetrahydrofuran.

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

In step a), anatabine glutarate may 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 contacting 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 are combined to form a reaction mixture, followed by precipitation and recovery of the glutarate salt of anatabine from the mixture. Glutaric acid may 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°C to 25°C). The concentration of glutaric acid present in such a reaction mixture is preferably a concentration 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 naturally or be induced, for example, by introducing seed crystals. The reaction mixture can be stirred before, during or after precipitation.

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

The resulting precipitate can be recovered by 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 have 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 properties. In addition, anatabine glutarate recrystallizes as a crystalline salt even after exposure to moisture, if the moisture is removed by suitable means, such as drying under vacuum.

Anatabine (e.g., anatabine glutarate) can be administered to a human for the treatment of disorders involving an inflammatory component, including chronic low-grade inflammation. Anatabine can be administered to a human to reduce a symptom or disorder involving an NFKB-mediated inflammatory component and/or to reduce the risk of developing such a disorder. An NFKB-mediated inflammatory component can be associated with chronic inflammation that occurs, for example, in thyroiditis, cancer, arthritis, Alzheimer's disease, and multiple sclerosis. An inhalable powder comprising anatabine can have a monoamine oxidase (MAO) inhibitory effect. Additionally or alternatively, an inhalable powder comprising anatabine can have a STAT3 phosphorylation inhibiting effect.

In some embodiments, anatabine is formulated as a salt. Any pharmaceutically acceptable salt may 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 ("hydrate"), 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 a glutarate, such as anatabine glutarate. Preferably, the anatabine salt is anatabine glutarate. Preferably, the anatabine glutarate is a polymorphic form as described above.

Anatabine or anatabine compound may be present in the composition as a powder in an amount of 0.1 to 30% of the anatabine compound by weight or 0.5 to 20% of the anatabine compound by weight. Anatabine or anatabine compound may be present in the composition as a powder in an amount of 1 to 10% of the anatabine compound by weight. Anatabine or anatabine compound may be present in the composition as a powder in an amount of 10 to 20% of the anatabine compound by weight. Anatabine or anatabine compound may be present in the composition as a powder in an amount of 1 to 5% of the anatabine compound by weight. Anatabine or anatabine compound may be present in the composition as a powder in an amount of 5 to 15% of the anatabine compound by weight.

The plurality of particles may include sugar. The sugar may form a matrix for dispersing anatabine in the particles forming the powder composition. The sugar and anatabine may form a composite particle.

The sugar may preferably be an amorphous sugar. The plurality of particles may include a monosaccharide, a disaccharide, a polysaccharide, or mixtures thereof. The plurality of particles may include lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, or combinations thereof. The plurality of particles may preferably include trehalose.

The plurality of particles (or each particle) may comprise from 50 to 99% sugar by weight. The plurality of particles (or each particle) may comprise from 70 to 90% sugar by weight. The plurality of particles (or each particle) may comprise from 70 to 80% sugar by weight. The plurality of particles (or each particle) may comprise from 80 to 90% sugar by weight. The plurality of particles (or each particle) may comprise from 80 to 85% sugar by weight.

The powder composition may contain an adhesion reducing compound to reduce particle agglomeration and allow or promote free flow of the powder composition. The adhesion reducing compound may reduce the adhesion or cohesion that occurs between particles of the powder composition. The additive may interfere with weak bonding forces between small particles, helping to keep the particles separate and reducing the adhesion of such particles to each other, to other particles in the composition, and to the internal surfaces of the corresponding inhaler device.

The adhesion reducing compound may include a phospholipid or a derivative thereof, such as lecithin.

The adhesion reducing compound may comprise a metal stearate or a derivative thereof, such as sodium stearyl fumarate or sodium stearyl lactylate. Suitable metal stearates include, for example, zinc stearate, magnesium stearate, calcium stearate, sodium stearate or lithium stearate. Preferably, the adhesion reducing compound comprises magnesium stearate.

The adhesion reducing compound may comprise or consist of one or more surface-active materials, in particular materials that are surface-active in the solid state, which may be water-soluble or water-dispersible, such as lecithin, in particular soya lecithin, or substantially water-insoluble, such as fatty acids in the solid state, such as oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid or derivatives thereof (such as esters and salts), such as glyceryl behenate. Specific examples of such materials are: phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols and other examples of natural and synthetic pulmonary surfactants; lauric acid and its salts, such as sodium lauryl sulfate, magnesium lauryl sulfate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general. Alternatively, the additive may be cholesterol.

Other possible adhesion reducing compounds include sodium benzoate, hydrogenated oils that are solid at room temperature, talc, titanium dioxide, aluminum dioxide, silicon dioxide, and starch.

The adhesion reducing compound may comprise an amino acid or a peptide (containing, for example, three amino acids). The amino acid may comprise 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 comprises leucine, alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, or a combination thereof. Preferably, the amino acid comprises leucine, such as L-leucine. Preferably, the peptide, if present, comprises trileucine.

The anatabine-containing particles may be coated with an adhesion-reducing compound such as an amino acid or a peptide or a metal stearate. The anatabine-containing particles may include an adhesion-reducing compound such as an amino acid or a peptide or a metal stearate dispersed in the particles to form a powder composition.

An amino acid or adhesion reducing compound, such as an amino acid or a peptide or a metal stearate, can be added to the anatabine-containing particles after spray drying. For example, particles formed by spray drying can be mixed with an adhesion reducing compound and the mixture can be co-milled (e.g., micronized). Co-milling can allow the amino-containing adhesion reducing compound to coat the anatabine-containing particles. Co-milling can further provide a desired final particle size (e.g., reduce the particle size from about 50 μm to about 2 μm).

The anatabine-containing particles may contain 5 wt. % or more or 10 wt. % or more of an adhesion-reducing compound and 30 wt. % or less or 25 wt. % or less of an adhesion-reducing compound, by weight of the anatabine-containing particles. The plurality of particles may include from 0.5 to 20% of an adhesion-reducing compound, by weight. The plurality of particles may include from 1 to 15% of an adhesion-reducing compound, by weight. The plurality of particles may include from 1 to 10% of an adhesion-reducing compound, by weight.

The anatabine-containing particles may comprise 5 wt. % or more or 10 wt. % or more of an amino acid or peptide and 30 wt. % or less or 25 wt. % or less of an amino acid or peptide by weight of the anatabine-containing particles. The plurality of particles may comprise from 0.5 to 20% of an amino acid or peptide by weight. The plurality of particles may comprise from 1 to 15% of an amino acid by weight. The plurality of particles may comprise from 1 to 10% of an amino acid by weight.

By providing an adhesion reducing compound, such as an amino acid, preferably L-leucine, to the particles containing anatabine, the adhesive forces of the particles containing anatabine can be reduced, and the attraction between the particles can be reduced, and thus the agglomeration of the particles can be further reduced. Similarly, in powder systems comprising other particles, such as a plurality of second particles that can include a flavor additive, the adhesive forces with the other particles can also be reduced, thus the agglomeration of the particles containing anatabine with the other particles is also reduced. The other particles, such as a plurality of second particles that can include a flavor additive, if present, can include an adhesion reducing compound, such as an amino acid, preferably L-leucine, to further reduce the adhesive forces of the particles containing anatabine and the other particles. Thus, the powder system described in this document may be a free-flowing material and have a stable relative particle size of each component of the powder even when anatabine-containing particles and other particles are combined.

The anatabine-containing particles may comprise 0.5 to 20% anatabine glutarate, 70 to 90% sugar, and 0 to 20% adhesion-reducing compound, all by weight. The anatabine-containing particles may preferably comprise 0.5 to 20% anatabine glutarate, 70 to 90% sugar, and 1 to 20% adhesion-reducing compound, all by weight. The anatabine-containing particles may preferably comprise 1 to 10% anatabine glutarate, 70 to 90% sugar, and 1 to 10% adhesion-reducing compound, all by weight.

The anatabine-containing particles may comprise 0.5 to 20% anatabine glutarate, 70 to 90% sugar, and 0 to 20% leucine, all by weight. The anatabine-containing particles may preferably comprise 0.5 to 20% anatabine glutarate, 70 to 90% sugar, and 1 to 20% leucine, all by weight. The anatabine-containing particles may preferably comprise 1 to 10% anatabine glutarate, 70 to 90% sugar, and 1 to 10% leucine, all by weight.

The anatabine-containing particles may have a particle size of 20 micrometers or less, 10 micrometers or less, or 5 micrometers or less, or 0.1 micrometers or more, 0.2 micrometers or more, or 0.5 micrometers or more, or in the range of 0.5 micrometers to 10 micrometers or 0.75 micrometers to 5 micrometers. The desired particle size range may be achieved by spray drying, milling, sieving, or a combination thereof. This size range may be suitable for respiratory deposition, such as deep lung deposition of anatabine-containing particles.

The anatabine-containing particles may have a particle size of 20 micrometers or less, 10 micrometers or less, or 5 micrometers or less, or 1 micrometer or more, 2 micrometers or more, or 5 micrometers or more, or in the range of 5 micrometers to 10 micrometers or 7.5 micrometers to 10 micrometers. The desired particle size range may be achieved by spray drying, milling, sieving, or a combination thereof. This size range may be suitable for respiratory deposition, such as deep deposition of anatabine-containing particles in the bronchi.

The anatabine-containing particles may have a particle size of 20 micrometers or greater, or 20 to 200 micrometers, or 50 to 200 micrometers, or 50 to 150 micrometers. The desired particle size range may be achieved by spray drying, milling, sieving, or a combination thereof. This size range may be suitable for deposition of anatabine-containing particles in the upper respiratory tract, such as deposition upon sinus or buccal administration.

The anatabine-containing particles may have a specific particle size distribution. In illustrative examples, about 90%, or about 95%, or about 98% of the anatabine-containing particles are about 5 micrometers or less, or about 4.5 micrometers or less, or about 4.2 micrometers or less, and about 50% of the particles are about 2.5 micrometers or less, or about 2.1 micrometers or less. In many of these examples, about 10% of the anatabine-containing particles are about 820 nanometers or less. The anatabine-containing particles in the composition may have a mass median aerodynamic diameter that ranges from about 1 to about 4 micrometers. Essentially all of the anatabine-containing particles may have a particle size in the range from about 500 nanometers to about 5 micrometers. The percentages of particle size distribution described in this document are determined on a volume distribution basis (volume %).

The anatabine-containing particles may be further mixed or combined with a second plurality of particles. In some embodiments, the second plurality of particles has a particle size different from the anatabine-containing particles and forms a second plurality of particles that are larger than the anatabine-containing particles. The second plurality of particles may be useful in controlling or assisting in the delivery of anatabine particles. The second plurality of particles may include a flavoring compound. The second plurality of particles may have any suitable size distribution for delivery by inhalation selectively to the oral or buccal cavity of the user. For example, the second plurality of particles may have a particle size of about 20 micrometers or more, or about 50 micrometers or more, 200 micrometers or less, 150 micrometers or less, or in the range of 50 micrometers to 200 micrometers, or 50 micrometers to 150 micrometers. Alternatively, if the anatabine particles are of a suitable size to be deposited in the oral or buccal cavity, they may contain flavouring compounds.

The powder system may provide a weight ratio of the first plurality of particles containing anatabine and the second plurality of particles from about 1:1 to about 10:1, or from about 2:1 to about 8:1, or from about 2:1 to about 6:1, or from about 3:1 to about 5:1, preferably about 4:1. By selecting the weight ratio of the first plurality of particles containing anatabine and the second plurality of particles, it is possible to improve the delivery of the contents of a container (such as a capsule) containing the powder system over a series of inhalations providing a similar amount of powder.

The powder system may provide a weight ratio of the first plurality of particles containing anatabine and the second plurality of particles of the flavoring substance from about 1:1 to about 10:1, or from about 2:1 to about 8:1, or from about 2:1 to about 6:1, or from about 3:1 to about 5:1, preferably about 4:1. By selecting the weight ratio of the first plurality of particles containing anatabine and the second plurality of particles of the flavoring substance, it is possible to improve the delivery of the contents of a container (such as a capsule) containing the powder system over a series of inhalations providing a similar amount of powder.

The powder system is preferably free-flowing. The first plurality of anatabine-containing particles is preferably free-flowing. The second plurality of particles is preferably free-flowing. The powder system contained in the container or capsule is preferably free-flowing. The first plurality of anatabine-containing particles contained in the container or capsule is preferably free-flowing. The second plurality of particles contained in the container or capsule is preferably free-flowing. The powder system may have a stable size distribution. The powder system is preferably not agglomerated.

The second plurality of particles may not contain anatabine. The second plurality of particles may include a flavor additive. Suitable flavors include, but are not limited to, any natural or synthetic flavor such as tobacco, smoke, menthol, mint (such as peppermint and spearmint), chocolate, licorice, citrus and other fruit flavors, gamma-octalactone, vanillin, ethyl vanillin, breath freshening flavors, spicy flavors such as cinnamon, methyl salicylate, linalool, bergamot oil, geranium oil, lemon oil, ginger oil, and the like. Other suitable flavor additives may include flavor compounds selected from the group consisting of an acid, an alcohol, an ester, an aldehyde, a ketone, a pyrazine, combinations or mixtures thereof, and the like. Suitable flavor compounds may be selected, for example, from the group consisting of phenylacetic acid, solanone, megastigmatrienone, 2-heptanone, benzyl alcohol, cis-3-hexenyl acetate, valeric acid, valeraldehyde, an ester, a terpene, a sesquiterpene, nutcatone, maltol, damascenone, pyrazine, lactone, anethole, valeric acid isomers, combinations thereof, and the like.

Flavors or flavoring agents may be in the form of a solid flavoring substance (at room temperature of approximately 22 degrees Celsius and one atmosphere of pressure) and may include flavoring compounds, flavoring-containing materials, and flavoring precursors. A flavoring agent may include one or more natural flavoring agents, one or more synthetic flavoring agents, or a combination of natural and synthetic flavoring agents.

The flavor compound/component may be derived from natural flavors, nature-identical flavors, or artificial flavors. Non-limiting examples of flavor components or flavors include banana, cherry, cinnamon, fruit, grape, orange, peach, pineapple, vanilla, wintergreen, strawberry, and mint. In one embodiment, the flavor additive is menthol. In one embodiment, the flavor additive is mint. One skilled in the art will appreciate that mint generally includes, but is not limited to, any and all flavors associated with a genus of plants in the Lamiaceae family. In one embodiment, the mint is a natural extract. In another embodiment, the mint is a commercially available formulation, such as Coolmint Trusil Flavoring Powder available from International Flavors & Fragrances. In one embodiment, the mint is a single 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-mentha-1,8-diene. Preferably, the second plurality of particles comprises menthol or mint.

The second plurality of particles may include a compound for reducing adhesive forces or surface energy and any resulting agglomeration. The second plurality of particles may be surface modified with an adhesion-reducing compound to form coated particles. The adhesion-reducing compound may include an amino acid or peptide as described above, or magnesium stearate, or combinations thereof.

The amino acid for reducing the adhesive forces or surface energy and any resulting agglomeration in the second plurality of particles 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 comprises leucine, alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan or a combination thereof. Preferably, the amino acid comprises leucine, such as L-leucine. Preferably, the peptide comprises trileucine. The amino acid or peptide may preferably coat the particle forming the second plurality of particles. The amino acid or peptide may preferably coat the flavor particle.

One preferred adhesion reducing compound is magnesium stearate. By providing an adhesion reducing compound such as magnesium stearate to the second plurality of particles, in particular by coating the second plurality of particles, it is possible to reduce the adhesive forces of the second plurality of particles, which may contain a flavor additive, and it is possible to reduce the attraction between the particles and thus reduce the formation of particle agglomerates. The agglomeration of the second plurality of particles with the anatabine-containing particles can also be reduced. The powder system can have a stable relative size of the anatabine-containing particles and the second plurality of particles, even if the anatabine-containing particles and the second plurality of particles are combined. The powder system can preferably be free-flowing.

The anatabine-containing particles and the second plurality of particles may be combined in any suitable relative amount. If the second plurality of particles contain a flavor additive, they may be combined in any suitable relative amount so that the flavor particles are detected by the user when ingested together with the anatabine-containing particles. Preferably, the anatabine-containing 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 powder system may further comprise an excipient which is any pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, thickener, solvent or encapsulating material involved in carrying or transporting a compound useful in the present invention within or to a subject so that it can perform its intended function. In one embodiment, the formulation further comprises a stabilizing agent. Each material must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation, including anatabine, and is not deleterious to the subject. Some materials that may be useful in the formulation of the present invention include pharmaceutically acceptable carriers, for example, 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 cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol and polyethyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surface active agents; amino acids such as leucine, L-leucine, D-leucine, DL-leucine, isoleucine, lysine, valine, arginine, aspartic acid, threonine, methionine, phenylalanine; alginic acid; amino acid derivatives such as an amino acid derivative, for example, aspartame or acesulfame K; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions and other non-toxic compatible substances used in pharmaceutical formulations. Other pharmaceutically 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 anatabine or any other compound useful in the present invention and are physiologically acceptable to the subject.

The powder composition may have a pH (in solution) in the range recommended for human consumption. In some embodiments, the inhalable powder has a pH of 6 or less, 7 or less, or 8 or less, or 4 to 8, or 4 to 6 if dissolved in water. The pH of the powder composition may be tested by preparing a 1.0 mg/mL solution of the powder in water and measuring the pH of the solution. The powder composition may be formulated without the use of an additional buffer. Additional buffering agents may 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 particles containing the active agent. The powder composition may not contain surfactants.

The powder composition may be provided in a suitable dosage form. For example, the powder composition may be provided as a capsule. The dosage form (e.g., a capsule) may be adapted for use in a suitable inhaler or delivery device. For example, the capsule may be used in an inhaler device having a capsule cavity. Directing air flow through the capsule cavity of the inhaler device may result in rotation of the capsule contained therein during inhalation and consumption. The capsule may comprise anatabine particles and optionally a plurality of second particles that may comprise a flavor additive (also referred to as "flavor particles"). Rotation of the punctured capsule may result in suspension and aerosolization of the powder composition released from the punctured capsule into the inhaled air moving through the inhaler device. The plurality of second particles that may contain a flavor additive may be larger than the particles containing anatabine and may facilitate the transport of anatabine particles to the user's lungs, while the plurality of second particles that may contain a flavor additive preferably remain in the user's oral or buccal cavity. The particles containing anatabine and the optional plurality of second particles that may contain a flavor additive may be delivered by the inhaler at inhalation rates or air flow rates that are within the range of inhalation rates or air flow rates in a normal smoking regime.

The capsule containing the powder composition or powder system may be formed from an air-impermeable material that can be pierced or punctured by a piercing element, which may be separate from or integrated with the inhaler. The capsule may be formed from a metal or polymeric material that serves to prevent contaminants from entering the capsule, but may be pierced or punctured by the piercing element before consuming the anatabine particles inside the capsule. The capsule may be made of a polymeric material. The polymeric material may be hydroxypropyl methylcellulose (HPMC). The capsule may be a size 0-5 capsule, or a size 2 capsule, or a size 3 capsule, or a size 4 capsule. The capsule may contain from 20 mg to 80 mg of inhalable powder, or from 40 mg to 60 mg of inhalable powder, or 50 mg of inhalable powder.

The term "particle size" as used herein refers 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 properties as the particle being characterized.

In particular, for a powder system, the mass median aerodynamic diameter (MMAD) is usually referred to, one of the metrics most widely accepted as a single numerical parameter of the aerodynamic particle size distribution. The MMAD is a statistically derived index for a sample of particles: as an example, an MMAD of 5 micrometers means that 50 percent of the total mass of the sample will be present in particles with an aerodynamic diameter of less than 5 micrometers, and the remaining 50 percent of the total mass of the sample 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 that are widely used to sample and separate airborne particles to determine the aerodynamic size classification of aerosol particles. In practice, cascade impactors separate an incoming sample into discrete fractions based on the inertia of the particles, which is a function of particle size, density, and velocity. A cascade impactor typically consists of a number of stages, each of which includes a plate with a specific arrangement of nozzles and a collecting surface. Since both the nozzle size and the total nozzle area decrease with increasing number of stages, the velocity of the air laden with sample increases as it passes through the instrument. At each stage, particles with sufficient inertia are released from the prevailing air flow and impact the collection surface. Thus, for any given flow velocity, each stage is associated with a cutoff diameter, a measure of 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. The cut-off diameter associated with a given stage is therefore a function of the air flow rate used for testing. To reflect the efficiency of use, nebulizers are typically tested at 15 L/min, while dry powder inhalers may 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, having 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, the measurements are carried out at 20 ± 3 degrees Celsius and a relative humidity of 35 ± 5 percent.

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

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 the 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 indicates otherwise.

In the context of this document, the conjunction "or" is generally used in its meaning, including "and/or", unless the content clearly indicates otherwise. The term "and/or" means one or all of the listed elements or a combination of any two or more of the listed elements.

In the context of this document, the words "have", "having", "include", "including", "contain", "containing" 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", etc., belong to the category of "comprising", etc.

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 other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention, including the claims.

In the context of 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%. In the context of 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", i.e. 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 of the features of these examples may be combined with any one or more features of another example, embodiment or aspect described herein.

Example Ex1. A composition in powder form comprises a plurality of particles containing an anatabine compound.

Example Ex2. A composition in powder form comprises a plurality of particles containing an anatabine compound and sugar.

Example Ex3. A composition in powder form comprises a plurality of particles containing an anatabine compound and an adhesion reducing compound.

Example Ex4. A composition in powder form comprises a plurality of particles containing an anatabine compound, and a sugar, and an adhesion reducing compound.

Example Ex5. A powder composition comprises a plurality of particles comprising an anatabine compound, wherein the plurality of particles is characterized by a particle size of about 20 micrometers or less, or about 10 micrometers or less, or from about 1 to about 4 micrometers, measured as the mass median aerodynamic diameter.

Example Ex6. A powder composition comprises a plurality of particles comprising an anatabine compound and a sugar, wherein the plurality of particles is characterized by a particle size of approximately 20 micrometers or less, or approximately 10 micrometers or less, or from approximately 1 to approximately 4 micrometers, measured as the mass median aerodynamic diameter.

Example Ex7. A powder composition comprises a plurality of particles comprising an anatabine compound and an adhesion reducing compound, wherein the plurality of particles is characterized by a particle size of approximately 20 micrometers or less, or approximately 10 micrometers or less, or from approximately 1 to approximately 4 micrometers, measured as the mass median aerodynamic diameter.

Example Ex8. A powder composition comprises a plurality of particles comprising an anatabine compound and a sugar and an adhesion reducing compound, wherein the plurality of particles is characterized by a particle size of approximately 20 micrometers or less, or approximately 10 micrometers or less, or from approximately 1 to approximately 4 micrometers, measured as the mass median aerodynamic diameter.

Example Ex9. A composition in powder form comprises a plurality of particles comprising an anatabine compound, wherein the plurality of particles are characterized by a particle size of from about 20 micrometers to about 200 micrometers, measured as the mass median aerodynamic diameter.

Example Ex10. A composition in powder form comprises a plurality of particles comprising an anatabine compound and a sugar, wherein the plurality of particles are characterized by a particle size of from about 20 micrometers to about 200 micrometers, measured as the mass median aerodynamic diameter.

Example Ex11. A composition in powder form comprises a plurality of particles comprising an anatabine compound and an adhesion reducing compound, wherein the plurality of particles are characterized by a particle size of from about 20 micrometers to about 200 micrometers, measured as the mass median aerodynamic diameter.

Example Ex12. A composition in powder form comprises a plurality of particles comprising an anatabine compound and a sugar and an adhesion reducing compound, wherein the plurality of particles is characterized by a particle size of from about 20 micrometers to about 200 micrometers, measured as the mass median aerodynamic diameter.

Example Ex13. A powder composition according to any of the previous examples, wherein the plurality of particles comprises an anatabine compound and an amorphous sugar.

Example Ex14. A powder composition according to any of the previous examples, wherein the plurality of particles comprises an anatabine compound and an amino acid or peptide.

Example Ex15. A powder composition according to any of the previous examples, wherein the anatabine compound comprises an anatabine salt.

Example Ex16. A powder composition according to any of the previous examples, wherein the anatabine compound comprises anatabine glutarate.

Example Ex17. A powder composition according to any of the previous examples, wherein the sugar comprises a monosaccharide, a disaccharide, a polysaccharide or mixtures thereof.

Example Ex18. A powder composition according to Ex17, wherein the sugar comprises lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose or combinations thereof, preferably the sugar comprises trehalose.

Example Ex19. A powder composition according to any of the previous examples, wherein the plurality of particles comprises an amino acid.

Example Ex20. A powder composition according to Ex19, wherein the plurality of particles comprises 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 wherein the amino acid preferably comprises leucine.

Example Ex21. A powder composition according to Ex19, wherein the plurality of particles comprises trileucine.

Example Ex22. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 50 to 99% sugar by weight, or from 70 to 90% sugar by weight, or from 70 to 80% sugar by weight, or from 80 to 90% sugar by weight, or from 80 to 85% sugar by weight.

Example Ex23. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 0.5 to 20% by weight of anatabine compound, or from 1 to 10% by weight of anatabine compound, or from 10 to 20% by weight of anatabine compound, or from 1 to 5% by weight of anatabine compound, or from 5 to 15% by weight of anatabine compound.

Example Ex24. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 0.5 to 20% by weight of an adhesion-reducing compound, or from 1 to 15% by weight of an adhesion-reducing compound, or from 1 to 10% by weight of an adhesion-reducing compound.

Example Ex25. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 0.5 to 20% amino acid by weight, or from 1 to 15% amino acid by weight, or from 1 to 10% amino acid by weight.

Example Ex26. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 0.5 to 20% anatabine glutarate, from 70 to 90% sugar and from 0 to 20% leucine, all values being by weight.

Example Ex27. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 0.5 to 20% anatabine glutarate, from 70 to 90% sugar and from 1 to 20% leucine, all values being by weight.

Example Ex28. A powder composition according to any of the previous examples, wherein the plurality of particles comprises from 1 to 10% anatabine glutarate, from 70 to 90% sugar and from 1 to 10% leucine, all values being by weight.

Example Ex29. A powder composition according to any of the previous examples, wherein 90%, or 95%, or 95%, or 98% of the particles have a size of 5 micrometers or less, or 4.5 micrometers or less, or 4.2 micrometers or less, and 50% of the particles have a size of 2.5 micrometers or less, or 2.1 micrometers or less.

Example Ex30. A powder composition according to any of the previous examples, wherein 90% of the plurality of particles have a particle size of 4.5 micrometers or less, and 50% of the plurality of particles have a particle size of less than 2.5 micrometers.

Example Ex31. A powder composition according to any of the previous examples, further comprising a second plurality of particles characterized by a particle size of 20 micrometers or greater or from 50 micrometers to 200 micrometers.

Example Ex32. A powder composition according to Ex31, wherein the weight ratio of the first plurality of particles and the second plurality of particles is from 1:1 to 10:1, or from 2:1 to 6:1, or from 3:1 to 5:1, preferably 4:1.

Example Ex33. A powder composition according to Ex31 or Ex32, wherein the second plurality of particles comprises a flavouring additive, wherein the flavouring additive may comprise menthol.

Example Ex34. A powder composition according to any of the previous examples, wherein the inhalable powder is contained within a capsule.

Example Ex35. A powder composition according to Ex34, wherein the capsule may be a size 2 to 4 capsule or a size 3 capsule and contains from 20 mg to 80 mg of inhalable powder, or from 40 mg to 60 mg of inhalable powder, or 50 mg of inhalable powder.

Example Ex36. A method of forming a composition in powder form comprising combining an anatabine compound in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles.

Example Ex37. A method of forming a composition in powder form comprising combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles.

Example Ex38. A method for forming a composition in powder form, comprising: combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a first dimension, and then micronizing the plurality of particles characterized by the first dimension to a reduced size.

Example Ex39. A method of forming a composition in powder form, comprising: combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a size in the range of from about 20 micrometers or less, or from about 10 micrometers or less, or from about 1 to about 4 micrometers, measured as mass median aerodynamic diameter.

Example Ex40. A method of forming a composition in powder form, comprising: combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a size in the range of from about 20 micrometers to about 200 micrometers or from about 50 to about 150 micrometers, measured as mass median aerodynamic diameter.

Example Ex41. A method of forming a composition in powder form, comprising: combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a first dimension, and then micronizing the plurality of particles characterized by the first dimension to a reduced size in the range of about 20 micrometers or less, or about 10 micrometers or less, or about 1 to about 4 micrometers, measured as mass median aerodynamic diameter.

Example Ex42. A method of forming a composition in powder form, comprising: combining an anatabine compound and a sugar in a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a plurality of particles characterized by a first dimension, and then micronizing the plurality of particles characterized by the first dimension to a reduced size in the range of from about 20 micrometers to about 200 micrometers or from about 50 to about 150 micrometers, measured as the mass median aerodynamic diameter.

Example Ex43. The method according to one of Ex36-Ex42, wherein the plurality of particles comprises an anatabine compound and an adhesion reducing compound.

Example Ex44. The method according to one of Ex36 to Ex42, wherein the plurality of particles comprises an anatabine compound and an amino acid or a peptide.

Example Ex45. The method according to one of Ex36 to Ex44, wherein the anatabine compound comprises a salt of anatabine.

Example Ex46. The method according to one of Ex36 to Ex45, wherein the anatabine compound comprises anatabine glutarate.

Example Ex47: The method according to one or more of Ex36-Ex46, wherein the sugar comprises an amorphous sugar.

Example Ex48. The method according to one or more of Ex36-Ex47, wherein the sugar comprises a monosaccharide, a disaccharide, a polysaccharide or mixtures thereof.

Example Ex49. The method according to one or more of Ex36-Ex48, wherein the sugar comprises lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose or combinations thereof, preferably the sugar comprises trehalose.

Example Ex50: The method according to one or more of Ex36-Ex49, wherein the plurality of particles comprises an amino acid.

Example Ex51. The method according to Ex50, wherein the plurality of particles comprises 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 wherein the amino acid preferably comprises leucine.

Example Ex52. The method according to Ex44, wherein the plurality of particles comprises trileucine.

Example Ex53. The method according to one or more of Ex36-Ex52, wherein the plurality of particles comprises from 50 to 99% sugar by weight, or from 70 to 90% sugar by weight, or from 70 to 80% sugar by weight, or from 80 to 90% sugar by weight, or from 80 to 85% sugar by weight.

Example Ex54. The method according to one or more of Ex36-Ex53, wherein the plurality of particles comprises from 0.5 to 20% by weight of anatabine compound, or from 1 to 10% by weight of anatabine compound, or from 10 to 20% by weight of anatabine compound, or from 1 to 5% by weight of anatabine compound, or from 5 to 15% by weight of anatabine compound.

Example Ex55. The method according to one or more of Ex36-Ex54, wherein the plurality of particles comprises from 0.5 to 20% by weight of an amino acid, or from 1 to 15% by weight of an amino acid, or from 1 to 10% by weight of an amino acid.

Example Ex56. The method according to one or more of Ex36-Ex55, wherein the plurality of particles comprises from 0.5 to 20% anatabine glutarate, from 70 to 90% sugar and from 0 to 20% leucine, all values being by weight.

Example Ex57. The method according to one or more of Ex36-Ex56, wherein the plurality of particles comprises from 0.5 to 20% anatabine glutarate, from 70 to 90% sugar and from 1 to 20% leucine, all values being by weight.

Example Ex58. The method according to one or more of Ex36-Ex57, wherein the plurality of particles comprises from 1 to 10% anatabine glutarate, from 70 to 90% sugar and from 1 to 10% leucine, all values being by weight.

Example Ex59. The method according to any of Ex36-Ex58, wherein 90%, or 95%, or 95%, or 98% of the particles are characterized by a size of 5 micrometers or less, or 4.5 micrometers or less, or 4.2 micrometers or less, and 50% of the particles are characterized by a size of 2.5 micrometers or less, or 2.1 micrometers or less.

Example Ex60. The method according to one or more of Ex36-Ex59, wherein 90% of the plurality of particles have a particle size of 4.5 micrometers or less, and 50% of the plurality of particles have a particle size of less than 2.5 micrometers.

Example Ex61. A powder composition or method according to one or more of Ex.1 to Ex.60, wherein the anatabine compound provides a polymorphic form characterized by a powder X-ray diffraction pattern (CuKα) comprising 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.

Example Ex62. A powder composition or method according to one or more of Ex.1 to Ex.60, wherein the anatabine compound provides a polymorphic form 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.

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.

Schematic graphics are provided for illustrative purposes and not for limitation purposes.

EXAMPLES

Obtaining anatabine glutarate

Anatabine free base was converted to 1:1 anatabine glutarate by the following methods.

a) To a solution of glutaric acid (16.5 g, 125 mmol, 1.00 equiv.) in acetonitrile (500 mL) was added dropwise anatabine (20.0 g, 125 mmol, 1.00 equiv.) at 25 °C and the mixture was stirred at 25 °C for 1 h. Consumption of anatabine was observed by TLC (dichloromethane:methanol=20:1) (Rf=0.5). The mixture was filtered. The filter cake was collected and concentrated to dryness to give anatabine glutarate (30.0 g, 103 mmol, yield 82.2%, purity 100%) as an off-white solid.

b) Glutaric acid (9.6 g, 72 mmol) was added to a solution of anatabine (11.6 g, 72 mmol) in acetonitrile (700 mL). The reaction mixture became cloudy. The reaction mixture was then heated to give a clear yellow solution. The mixture was allowed to cool to room temperature (20 °C) and stirred for 2 h. This gave a sticky solid, which was scraped off with a spatula. The mixture was stirred for an additional 30 min, and the resulting pale yellow solid was filtered under argon, washed with acetonitrile (500 mL), and dried under reduced pressure at 45 °C for 45 min to give anatabine glutarate (18.3 g, 87%) as a pale yellow solid.

¹ H NMR (D ₂ O), δ: 8.84-8.45 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 7.59-7.55 (m, 1H), 6.08 (d, J=8.4 Hz, 1H), 5.85 (d, J=10.4 Hz, 1H), 4.63-4.59 (m, 1H), 3.97-3.87 (m, 1H), 3.81-3.70 (m, 1H), 2.80-2.53 (m, 2H), 2.25 (t, J=7.6 Hz, 4H), 1.82-1.74 (m, 2H). The chemical purity of anatabine glutarate was assessed using a Waters Acquity UPLC H-class with a PDA detector and SQD mass spectrometer, BEH C18 column, 2.1 x 50 mm, 1.7 μM, running a gradient with detection at 261 nM. The retention time of anatabine glutarate was 1.125 min and the purity was 99.41%, [M+H] ⁺ 161.0. Comparison of the FTIR spectra of anatabine glutarate and anatabine free base indicates a change in the NH band, confirming the formation of a salt.

Anatabine glutarate obtained in this manner was recrystallized from 2.5 ml of acetonitrile by cooling after heating under reflux. The solid phase was reduced and dried.

Anatabine glutarate salt was analyzed by X-ray diffraction (XRPD) in the range 2-40° 2θ using zero background silicon wafers (9 mm cavities). Its purity was found to be greater than 99% by uHPLC. Figure 1 shows the CuKα powder X-ray diffraction pattern of the preferred polymorph of anatabine glutarate.

Obtaining anatabine compositions in powder form

Anatabine glutarate is a solid salt. The use of such a solid salt in spray drying allows limiting losses, stabilizing the resulting powder and allowing the production of powders with a high effective content of anatabine glutarate.

Two different batches of anatabine spray dried powder formulation were prepared and the results are presented below.

The following raw materials were used to prepare these spray dried formulations.

1) Solid anatabine glutarate salt; a 2% (effective) anatabine formulation (3.62% anatabine glutarate) (i.e. for multiple inhalation administration => i.e. 50 mg powder to deliver 1 mg anatabine) and a 10% (effective) anatabine formulation (18.17% anatabine glutarate) (i.e. for single direct inhalation administration => i.e. 10 mg powder in a capsule to deliver 1 mg) were prepared. The stoichiometric ratio of anatabine to glutaric acid is 1:1.

2) L-Leucine; its use is beneficial for ensuring powder flowability, but is not essential. It is possible to prepare anatabine powder formulation with/without leucine (optional). 10% w/w L-leucine.

3) Trehalose dihydrate; 86.35% w/w trehalose or 71.76% w/w trehalose was used as an excipient.

Spray drying stock solutions were prepared in deionized (DI) water and spray dried immediately after preparation. Spray drying was performed using a Buchi B-290 spray dryer equipped with a Buchi two-fluid nozzle and a standard Buchi cyclone. Stock solutions were protected from light during processing. All powders were processed at reduced humidity (<30% RH) and stored in sealed amber glass jars at 2-8°C.

Spray drying conditions on a Buchi B-290 spray dryer. Spray pressure 6 bar. Set outlet temperature 80°C. Aspirator 100%. Feed rate 3 g/min.

Particle size analysis of the spray-dried powders was performed using a Sympatec HELOS particle size analyzer equipped with an R3 lens (range 0.5 to 175 micrometers) and an ASPIROS dispersion unit. Dispersion was performed using compressed air at 1 bar. Measurements were performed in triplicate and average data values were reported.

Mixing and fine grinding. 6.500 g of the spray-dried composition was mixed with 1.147 g of leucine for five minutes at 36 rpm using a turbulent mixer. The resulting mixture, 85% w/w spray-dried composition and 15% w/w leucine, was finely ground using an Atritor M3 jet mill under the following conditions. Venturi pressure 8.0 bar. Grinding pressure 3-4 bar. Feed rate 2.4 g/min.

Two spray dryer feed solutions were prepared according to Table 1 below. Trehalose was added as trehalose dihydrate, the loss of water of hydration during processing was compensated for in all calculations.

Table 1

Example Total solids (g) Deionized water (ml) Anatabine glutarate (g) L-leucine (g) Trehalose (g) 1 25 250 0.912 2.5 23.9 2 25 250 4,561 2.5 19.8

Results

Example Compound X ₁₀ (µm) X ₅₀ (µm) X ₉₀ (µm) VMD (µm) 1 Anatabine glutarate (3.65%); leucine (10%); trehalose (86.35%) 0.99 2.89 6.04 3.31 2 Anatabine glutarate (18.24%); leucine (10%); trehalose (71.76%) 0.99 2.77 5.63 3.09

Both Example 1 and Example 2 were spray dried successfully with post-process recovery of approximately 85%. The spray dried materials of Example 1 and Example 2 were noted to be fine, free-flowing white powder.

For the purposes of the present specification 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 maximum and minimum points disclosed and include any intermediate ranges therebetween that may or may not be specifically listed herein. Therefore, in this context, the number "A" is understood to mean A ± 2% A. In this context, the number A may 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 vary by the percentages listed above, provided that the amount by which A varies does not materially affect the fundamental and novel characteristic(s) of the claimed invention. Also, all ranges include the maximum and minimum points disclosed and include any intermediate ranges therebetween that may or may not be specifically listed herein.

Claims (18)

1. An inhalable powder composition comprising: a plurality of particles comprising an anatabine compound, a sugar, and an adhesion reducing compound, wherein the plurality of particles are characterized by a particle size of from about 0.1 to about 10 micrometers, measured as mass median aerodynamic diameter. 2. An inhalable powder composition comprising: a plurality of particles comprising an anatabine compound, a sugar and an adhesion reducing compound, wherein the plurality of particles are characterized by a particle size of from about 20 micrometers to about 200 micrometers, measured as mass median aerodynamic diameter. 3. An inhalable powder composition according to claim 1 or 2, wherein the anatabine compound comprises an anatabine salt. 4. An inhalable powder composition according to claim 1 or 2, wherein the anatabine compound comprises anatabine glutarate. 5. An inhalable powder composition according to any preceding claim, wherein a plurality of particles comprise an amorphous sugar. 6. The inhalable powder composition of claim 5, wherein the sugar comprises lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, or combinations thereof, preferably the sugar comprises trehalose. 7. An inhalable powder composition according to any preceding claim, wherein the adhesion reducing compound comprises an amino acid or a peptide. 8. An inhalable powder composition according to any preceding claim, wherein the adhesion reducing compound comprises 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 comprises leucine. 9. An inhalable powder composition according to any preceding claim, wherein the plurality of particles comprise from 50 to 99% sugar by weight, or from 70 to 90% sugar by weight, or from 70 to 80% sugar by weight, or from 80 to 90% sugar by weight, or from 80 to 85% sugar by weight. 10. An inhalable powder composition according to any preceding claim, wherein the plurality of particles comprise from 0.5 to 20% by weight of an anatabine compound, or from 1 to 10% by weight of anatabine compound, or from 10 to 20% by weight of anatabine compound, or from 1 to 5% by weight of anatabine compound, or from 5 to 15% by weight of anatabine compound. 11. An inhalable powder composition according to any preceding claim, wherein the plurality of particles comprise from 0.5 to 20% by weight of an amino acid, or from 1 to 15% by weight of an amino acid, or from 1 to 10% by weight of an amino acid. 12. An inhalable powder composition according to any preceding claim, wherein the plurality of particles comprise from 0.5 to 20% anatabine glutarate, from 70 to 90% sugar, and from 0 to 20% leucine, all values being by weight. 13. An inhalable powder composition according to any preceding claim, wherein the plurality of particles comprises from 0.5 to 20% anatabine glutarate, from 70 to 90% sugar and from 1 to 20% leucine, all values by weight, preferably the plurality of particles comprises from 1 to 10% anatabine glutarate, from 70 to 90% sugar and from 1 to 10% leucine, all values by weight. 14. An inhalable powder composition according to any preceding claim, further comprising a second plurality of particles having a particle size of from 50 to 200 micrometers, wherein the second plurality of particles comprises a flavor additive. 15. A method for forming an inhalable composition in the form of a powder, comprising: combining the anatabine compound and the sugar and the adhesion reducing compound in a liquid carrier to form a liquid mixture; and spray drying the liquid mixture to form a plurality of particles to form an inhalable powder composition according to claim 1 or 2, or spray drying the liquid mixture to form a plurality of particles, and then micronizing the plurality of particles to form the inhalable powder composition of claim 1 or 2.