Low-hygroscopic active powder composition

Abstract

An inhalable powder includes crystalline dry powder particles. The crystalline dry powder particles include a solid salt of an alkaloid and a sugar alcohol. The salt is solid at 25 °C. The sugar alcohol can include mannitol, erythritol, inositol, ribitol, xylitol, or combinations thereof. The inhalable powder can be part of a powder system that also includes a second population of particles having a particle size greater than the crystalline dry powder particles.

Description

Technical Field

[0001] This disclosure relates to active powder compositions exhibiting low hygroscopicity. Sugars or sugar alcohols and active agents form crystalline, dry particles. Background Technology

[0002] Active powder compositions with amorphous structures have been described. Amorphous structures lack the long-range order characteristic of crystalline forms. These amorphous powder compositions typically exhibit higher water solubility than their crystalline counterparts and may show shortened shelf life or delivery due to absorption of ambient moisture.

[0003] When exposed to humid conditions, such as relative humidity equal to or higher than about 40% and temperature equal to or higher than about 25°C, amorphous powder compositions tend to be hygroscopic and may agglomerate, become sticky, or even liquefy. Tropical conditions, such as relative humidity equal to or higher than about 60% and temperature equal to or higher than about 30°C, may exacerbate these problems. The transport and storage of these amorphous powder compositions may require sealed packaging to maintain their stability. Once the seal is compromised (e.g., when the packaging is opened by a consumer), the contents may rapidly absorb moisture. Additionally, delivery of amorphous powder compositions to a consumer's lungs may require separating moisture from the inhaled airflow, leading to increased complexity and cost of the associated inhaler device or article.

[0004] It is desirable to provide active powder compositions that exhibit reduced hygroscopicity. It is desirable to provide active powder compositions that resist water or moisture absorption when exposed to humid or tropical conditions. It is desirable to provide active powder compositions that exhibit reduced agglomeration when exposed to humid or tropical conditions. It is desirable to provide active powder compositions that are stable and have a long shelf life. Summary of the Invention

[0005] According to one aspect of the invention, an inhalable powder composition comprising crystalline dried powder particles is provided. The crystalline dried powder particles comprise sugar or sugar alcohol and an active agent. Preferably, the crystalline dried powder particles are dried powder particles comprising a solid salt of sugar alcohol and an alkaloid.

[0006] Advantageously, the inhalable powder exhibits low or reduced hygroscopicity. When exposed to humid or tropical conditions, the inhalable powder does not readily absorb water or moisture. It also does not readily agglomerate when exposed to humid or tropical conditions. Furthermore, the inhalable powder is advantageously stable and has a long shelf life.

[0007] The term "spray drying temperature" refers to the temperature of the liquid mixture leaving the nozzle of the spray dryer. The spray drying temperature is preferably less than about 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.

[0008] The term "crystalline" refers to the solid form of a compound that exhibits long-range order in its microscopic lattice. Technicians can identify crystalline materials by examining their X-ray diffraction (XRD) patterns, such as powder X-ray diffraction (pXRD) traces. For example, in this paper… Figure 1 and Figures 4-8 The image shows the XRD pattern of the crystals. Crystalline materials may exhibit a certain degree of amorphous structure.

[0009] The term "crystallized dry powder particles" refers to a free-flowing particulate composition containing crystalline material.

[0010] The term "activator" refers to an alkaloid or other pharmaceutically active ingredient. "Activator" always refers only to the active component of a compound. Preferably, the activator can be a salt of an activator.

[0011] The term "low hygroscopicity" refers to a measured hygroscopicity value of 5% by weight or less, or 4% or less, or 3% or less, or 2.5% or less, or 2% or less. Hygroscopicity can be determined by measuring the water absorption or water uptake (increase by weight) of a sample after exposure to tropical conditions (75% relative humidity and 30°C atmosphere) for a duration of 20 minutes. Before exposure to tropical conditions, the sample is equilibrated for 24 hours at 0% relative humidity and 25°C atmosphere to reduce or remove non-bound water from the sample. Hygroscopicity values ​​can be measured using a "Vapor SorptionAnalyzer SPSx-1u High Load" manufactured by ProUmid GmbH & Co. KG, as described in the examples below.

[0012] Methods for forming crystalline, dry powder particles may include 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 include alkaloids such as nicotine, neonicotinoids, or nifedipine, provided as a free base and combined with an acid to form a pharmaceutically acceptable salt.

[0013] Any pharmaceutically acceptable salt can be used to form the active agent salt. In a preferred embodiment, the alkaloid salt may be solid at room temperature (e.g., solid at 25°C). Suitable salts include, for example, salts of aspartic acid (“aspartate”), salts of gentianic acid (“gentianate”), salts of benzoic acid (“benzoate”), salts of lactic acid (“lactate”), salts of malic acid (“malate”), salts of fumaric acid (“fumarate”), salts of maleic acid (“maleate”), salts of mucoconic acid (“mucoconate”), salts of hydrochloric acid (“hydrochloride”), salts of α-dihydroxybenzoic acid (“α-dihydroxybenzoate”), salts of β-dihydroxybenzoic acid (“β-dihydroxybenzoate”), salts of oxalic acid (“oxalate”), salts of p-anisinic acid (“anisate”), salts of tartaric acid (“bitate”), or salts of glutaric acid (“glutarate”). Preferably, the salt includes aspartate, tartrate, malate, or glutarate.

[0014] The preferred alkaloid is nicotine. Nicotine may preferably be a nicotine salt. Nicotine salts include, for example, nicotine aspartate, nicotine tartrate, nicotine glutarate, nicotine lactate, nicotine gentianate, nicotine benzoate, nicotine fumarate, nicotine hydrochloride, nicotine α-dihydroxybenzoate, nicotine β-dihydroxybenzoate, nicotine oxalate, nicotine malate, and nicotine anisylate. Preferred nicotine salts are selected from one or more of nicotine tartrate, nicotine aspartate, nicotine malate, and nicotine glutarate.

[0015] Another preferred alkaloid is neonicotinoid. Neonicotinoid can preferably be a neonicotinoid salt. A preferred neonicotinoid salt is neonicotinoid glutarate. Neonicotinoid glutarate is described, for example, in WO2020 / 127225A1.

[0016] Neonicotinine is an alkaloid found in tobacco and in low concentrations in various foods, including green tomatoes, green potatoes, ripe red peppers, prunes, and dried tomatoes. For example, the preparation of isolated forms of neonicotinine is described in WO 2011 / 119722.

[0017] Neonicotinoids are also known as 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine. The enantioselective synthesis of the S- and R-enantiomers of neonicotinoids is described, for example, in Ayers, JT; Xu, R.; Dwoskin, LP; Crooks, PA. A general procedure for the enantioselective synthesis of the minor Tobacco alkaloids nornicotine, anabasine, and anatabine. The AAPS Journal 2005; 7(3) Article 75.

[0018] As used herein, the term "neonicotin" may refer to (1) a racemic mixture of neonicotin (R,S); (2) a purified form of S-(-)-neonicotin; or (3) a purified form of R-(+)-neonicotin. Preferred neonicotin compounds are neonicotin salts such as neonicotin glutarate or 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridin glutarate. Preferably, the 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridin glutarate has a molar ratio of 1:1 of 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine to glutarate.

[0019] Pharmaceutically acceptable salts of neonicotinoids are described in U.S. Patents 8,207,346 and 8,557,999. In particular, Example 6 of U.S. Patent 8,207,346 and Example 6 of U.S. Patent 8,557,999 describe the preparation of neonicotinoid tartrate and neonicotinoid citrate by adding tartaric acid or citric acid to a solution of neonicotinoids in acetone.

[0020] It should be understood that any reference in this document to “3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate” or “neotoxin glutarate” should also be understood to refer to any pharmaceutically acceptable solvate thereof.

[0021] 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridineglutarate has a chemical structure represented by the following formula (I):

[0022] .

[0023] In a preferred embodiment, 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine glutarate may therefore have the following formula (Ia):

[0024]

[0025] Preferably, neonicotinoid glutarate is a specific polymorph (also referred to herein as the polymorphic form) of 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridinium glutarate, particularly a specific polymorph of 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridinium glutarate crystals. The polymorph preferably has generally the following characteristics: Figure 1 The X-ray powder diffraction pattern (CuKα) shown is illustrated. The polymorph preferably has an X-ray powder diffraction pattern (CuKα) including 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 preferably has an X-ray powder diffraction pattern (CuKα) including 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.

[0026] More preferably, the polymorph preferably has an X-ray powder diffraction pattern (CuKα) including 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 preferably has an X-ray powder diffraction pattern (CuKα) including 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.

[0027] More specifically, the polymorph preferably has one or more of the following morphologies: 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 ± X-ray powder diffraction pattern of the peak at 0.2 °2θ (CuKα). More particularly, the polymorph preferably has one or more of the following morphologies: 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 ± X-ray powder diffraction pattern of the peak at 0.1 °2θ (CuKα). The above-mentioned form of neonicotinoid glutarate can be prepared using a method comprising the following steps:

[0028] a) Prepare a solution containing 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine, glutaric acid, and a solvent.

[0029] b) This results in the formation of a salt of 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine with glutaric acid, and

[0030] c) Recovery of 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine glutarate.

[0031] In the preparation of a solution of 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine, glutaric acid, and a solvent, the solvent preferably comprises 2-methyltetrahydrofuran, acetonitrile, and / or ethyl acetate. More preferably, the solvent comprises 2-methyltetrahydrofuran.

[0032] The method may further include step d) recrystallizing 3-[1,2,3,6-tetrahydropyridin-2-yl]pyridine glutarate. Suitable solvents for this recrystallization include acetonitrile.

[0033] In step a), neonicotinoid glutarate can be prepared by combining neonicotinoid free base, solvent, and glutaric acid to produce a reaction mixture. Neonicotinoid glutarate is typically formed in such a reaction mixture by contact between neonicotinoid free base and glutaric acid. Preferably, the neonicotinoid free base is combined with glutaric acid in a 1 to 5% by mass acetonitrile solution.

[0034] Preferably, a solution or suspension of neonicotinoid free base, a solvent, and glutaric acid are combined to form a reaction mixture, from which neonicotinoid glutarate is then precipitated and recovered. Glutaric acid may be added either as a solid or as a solution or suspension in a solvent.

[0035] The solvent is preferably selected from alkanols containing 1 to 8 carbon atoms, aliphatic esters containing 3 to 8 carbon atoms, aliphatic linear or cyclic ethers containing 3 to 8 carbon atoms, aliphatic ketones containing 3 to 8 carbon atoms, and C644. 6-12 Aromatic hydrocarbons (such as benzene and naphthalene), acetonitrile, water, and any mixture thereof. Preferably, the solvent is selected from aliphatic esters containing 3 to 8 carbon atoms, aliphatic cyclic ethers containing 3 to 8 carbon atoms, acetonitrile, and mixtures thereof. More preferably, the solvent is selected from ethyl acetate, acetonitrile, 2-methyltetrahydrofuran, and any mixture thereof. Even more preferably, the solvent contains acetonitrile. Still more preferably, the solvent is acetonitrile.

[0036] The neonicotinic alkaloid, glutaric acid, and at least one solvent are preferably combined at approximately room temperature (i.e., preferably in the range of 15°C to 25°C) to form a reaction mixture. 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). Neonicotinic glutarate typically precipitates from the mixture. Precipitation can occur spontaneously or, for example, by the introduction of seed crystals. The reaction mixture can be stirred before, during, or after precipitation.

[0037] The reaction mixture can be heated and then cooled to promote the precipitation of neonicotinoid glutarate. Heating can be carried out at any temperature in the range from room temperature to the boiling temperature of the solvent (e.g., from about 50°C to about 80°C). Subsequently, cooling is typically carried out to below 40°C, preferably from about 30°C to about 20°C, more preferably room temperature (i.e., preferably in the range of 15°C to 25°C) to promote precipitation.

[0038] The resulting precipitate can be recovered using various techniques such as filtration. The precipitate can be dried under ambient pressure or at reduced and / or elevated temperatures.

[0039] Neonicotin glutarate, and particularly the aforementioned polymorphic forms, possess advantageous properties such as high crystallinity, morphology, thermal and mechanical stability to polymorphic transformation and / or dehydration, storage stability, low residual solvent content, low hygroscopicity, flowability, and favorable processing and handling characteristics. Furthermore, when moisture is removed by suitable measures such as vacuum drying, neonicotin glutarate recrystallizes into a crystalline salt even after exposure to moisture.

[0040] Neonicotinic acid (e.g., neonicotinic acid glutarate) can be administered to individuals to treat conditions containing inflammatory components, including chronic, low-level inflammation. Neonicotinic acid can be administered to individuals to reduce symptoms of conditions containing NFKB-mediated inflammatory components and / or reduce the risk of developing such conditions. NFKB-mediated inflammatory components may be associated with chronic inflammation occurring, for example, in thyroiditis, cancer, arthritis, Alzheimer's disease, and multiple sclerosis. Inhalable powders containing neonicotinic acid may have a monoamine oxidase (MAO) inhibitory effect. Alternatively or additionally, inhalable powders containing neonicotinic acid may have a STAT3 phosphorylation inhibitory effect.

[0041] In some embodiments, neonicotinoids are formulated as salts. Any pharmaceutically acceptable salt can be used. Preferably, the neonicotinoid salt is a solid at room temperature (e.g., a solid at 25°C). Suitable salts include, for example, salts of aspartic acid (“aspartate”), salts of gentianic acid (“gentianate”), salts of benzoic acid (“benzoate”), salts of fumaric acid (“fumarate”), salts of hydrochloric acid (“hydrochloride”), salts of α-dihydroxybenzoic acid (“α-dihydroxybenzoate”), salts of β-dihydroxybenzoic acid (“β-dihydroxybenzoate”), salts of oxalic acid (“oxalate”), salts of p-anisolic acid (“anisate”), or salts of glutaric acid (“glutarate”). Preferably, the salt includes glutarate, such as neonicotinoid glutarate. Preferably, the neonicotinoid salt is neonicotinoid glutarate. Preferably, neonicotinoid glutarate is in the above-described polymorphic form.

[0042] Another preferred alkaloid is hesperidin. Hesperidin can be preferably hesperidin salt. Hesperidin is a pyridine and piperidine alkaloid found in the tobacco tree plant.

[0043] Other pharmaceutically active ingredients include, for example: antiviral compounds such as acyclovir; anti-inflammatory compounds such as salicylic acid, aceclofenac, or ketoprofen; antidiabetic compounds such as metformin or glipizide; antihypertensive compounds such as oxenolol; antiemetic compounds such as promethazine; antidepressant compounds such as seroxetine; anticoagulant compounds such as pyrcotahistine; bronchodilators such as clenbuterol; or anticancer compounds such as β-lapaquinone.

[0044] Beneficial crystallinity and reduced hygroscopicity can be achieved by selecting one or more parameters of the composition and the method of preparing the inhalable powder. For example, the surfactant can be selected such that it is a solid at room temperature (e.g., a solid at 25°C). The surfactant can be a solid at or below 30°C or at 25°C. The sugar or sugar alcohol can be selected to have a suitable glass transition temperature (Tg) such that the desired crystallinity can be achieved via spray drying.

[0045] The sugar or sugar alcohol may be selected to have a 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 75g or less, 60g or less, 50g or less, or 30g or less in 100g of water at 25°C.

[0046] The crystalline dry powder particles described herein can be formed by spray drying or freeze drying. In either method, a liquid mixture can 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. The crystalline dry powder particles may each contain a crystalline sugar or crystalline sugar alcohol matrix and an active agent (such as an alkaloid) dispersed within the crystalline sugar or crystalline sugar alcohol matrix.

[0047] 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 above 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 the spray drying process. The glass transition temperature of the sugar or sugar alcohol is lower than the temperature encountered by the particles during the spray drying process to ensure the necessary molecular migration of the sugar or sugar alcohol molecules, thereby enabling 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 about 50°C or less.

[0048] Composite particles are formed by spray drying or freeze drying, each containing an active agent and a sugar or sugar alcohol. The active agent may be dispersed within 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 located within a sugar or sugar alcohol crystalline matrix forming the particles or composite particles.

[0049] Preferably, the sugar or sugar alcohol is a sugar alcohol. Sugar alcohols include, for example, the following compounds and their stereoisomers: erythritol, ribitol, xylitol, arabinitol, mannitol, sorbitol, inositol, etc. Preferably, the sugar alcohol is selected from erythritol (Tg=-44℃), mannitol (Tg=13℃), inositol (Tg=50℃), their stereoisomers, and combinations thereof. Preferably, the sugar alcohol is erythritol, mannitol, or inositol.

[0050] Dry powder particles formed by spray drying or freeze drying can be ground or micronized to obtain the desired final particle size (e.g., from about 50 micrometers to about 2 micrometers). The final particle size of inhalable powder or crystalline dry powder particles can be in the range of about 1 micrometer to about 5 micrometers, or about 1 micrometer to about 3 micrometers, or about 1.5 micrometers to about 2.5 micrometers.

[0051] The inhalable powder may also contain amino acids. Amino acids can be added to the surfactant and sugar or sugar alcohol prior to the spray drying or freeze drying step. Amino acids can be added to the crystalline dried powder particles after the spray drying or freeze drying step. For example, the crystalline dried powder particles formed by spray drying or freeze drying can be co-milled with amino acid particles (e.g., jet milling). Co-milling allows the amino acids to at least partially coat the crystalline dried powder particles. The crystalline dried powder particles can be coated with amino acids. Co-milling can also obtain the desired final particle size (e.g., from about 50 micrometers to about 2 micrometers).

[0052] The merging step may include merging a sugar or sugar alcohol with an active agent, amino acids, and a liquid carrier to form a liquid mixture, and then spray-drying or freeze-drying the liquid mixture at a specific temperature to form crystalline dry powder particles. The spray-drying temperature is higher than the glass transition temperature of the sugar or sugar alcohol. At least selected dry powder particles each contain amino acids coating the crystalline dry powder particles, which contain a solid active agent dispersed within a crystalline sugar matrix or a crystalline sugar alcohol matrix.

[0053] Amino acids may include histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, pyrrolidone, proline, selenocysteine, serine, tyrosine, or combinations thereof. Preferably, the amino acid includes leucine, such as L-leucine.

[0054] Based on the weight of the crystalline dried powder particles, the crystalline dried powder particles may contain 5% or more, or 10% or more, of amino acids and 30% or less, or 25% or less, of amino acids. Based on the weight of the crystalline dried powder particles, the crystalline dried powder particles may contain 5% to 30% by weight, 10% to 30% by weight, or 15% to 25% by weight of amino acids.

[0055] Preferably, the crystalline dried powder particles may contain 5% or more, or 10% or more, of leucine, and 30% or less, or 25% or less of leucine, calculated by weight of the crystalline dried powder particles. Alternatively, the crystalline dried powder particles may contain 5% to 30% by weight, 10% to 30% by weight, or 15% to 25% by weight of leucine, calculated by weight of the crystalline dried powder particles.

[0056] Providing amino acids such as L-leucine to crystalline dry powder particles can reduce the adhesion of the crystalline dry powder particles and reduce the attraction between particles, thus further reducing particle aggregation.

[0057] The crystalline dried powder particles or crystalline dried powder particles can preferably form a uniform particle group, wherein each particle contains an active agent, a sugar or sugar alcohol, and optionally an amino acid. The crystalline dried powder particles may each contain about 1% to about 10% of an active agent, 99% to about 50% of a sugar or sugar alcohol, and optionally 1% to about 40% of an amino acid. Preferably, the crystalline dried powder particles may each contain about 1% to about 10% of an active agent, 80% to about 70% of a sugar alcohol, and 15% to about 25% of an amino acid.

[0058] The crystalline, dried powder particles may contain about 60% by weight or more sugar alcohols, 10% by weight or more amino acids, and about 1% by weight to about 10% by weight of solid salts of alkaloids. At least selected particles each contain a sugar alcohol matrix and the solid salts of alkaloids are dispersed within the sugar alcohol matrix.

[0059] The crystalline dry powder particles may each contain about 1% to about 10% of an active agent, 99% to about 60% of a sugar or sugar alcohol, and optionally 10% to about 30% of an amino acid. Preferably, the crystalline dry powder particles may each contain about 1% to about 10% of an active agent, 85% to about 65% of a sugar alcohol, and 10% to about 30% of an amino acid.

[0060] The crystalline dry powder particles may each contain about 1% to about 10% nicotine, 99% to about 60% sugar or sugar alcohol, and optionally 10% to about 30% amino acids. Preferably, the crystalline dry powder particles may each contain about 1% to about 10% nicotine, 85% to about 65% sugar alcohol, and 10% to about 30% amino acids.

[0061] According to one aspect of the invention, the crystalline dry powder particles comprise about 60% or more sugar alcohol, 10% or more amino acids, and about 1% to about 10% solid alkaloid salts.

[0062] According to one aspect of the invention, the crystalline dry powder particles may contain a solid salt of an alkaloid and a sugar alcohol, said sugar alcohol including mannitol, erythritol, inositol, ribitol, xylitol or combinations thereof.

[0063] According to one aspect of the invention, the crystalline dry powder particles may contain a solid salt of an alkaloid and a sugar alcohol, including mannitol, erythritol, inositol, or a combination thereof.

[0064] According to one aspect of the invention, the crystalline dried powder particles may comprise a solid salt of an alkaloid; a sugar alcohol, including mannitol, erythritol, inositol, or a combination thereof; and leucine.

[0065] According to one aspect of the invention, the crystalline dried powder particles may contain nicotine aspartate; sugar alcohols, including mannitol, erythritol, inositol, or combinations thereof; and leucine.

[0066] According to one aspect of the invention, the crystalline dried powder particles may contain nicotine tartrate; sugar alcohols, including mannitol, erythritol, inositol, or combinations thereof; and leucine.

[0067] According to one aspect of the invention, the crystalline dry powder particles may comprise nicotine glutarate; sugar alcohols, including mannitol, erythritol, inositol, or combinations thereof; and leucine.

[0068] According to one aspect of the invention, the crystalline dried powder particles may contain nicotine malate; sugar alcohols, including mannitol, erythritol, inositol, or combinations thereof; and leucine.

[0069] According to one aspect of the invention, the crystalline dried powder particles may comprise neonicotinoid glutarate; sugar alcohols, including mannitol, erythritol, inositol, or combinations thereof; and leucine.

[0070] Spray drying or freeze drying methods produce dry, crystalline powder particles containing surfactants and suitable for inhalation. Advantageously, the crystalline dry powder particles exhibit low or reduced hygroscopicity. The crystalline dry powder particles do not readily absorb water or moisture when exposed to humid or tropical conditions. The crystalline dry powder particles do not readily agglomerate when exposed to humid or tropical conditions. Furthermore, the crystalline dry powder particles are stable and have a long shelf life.

[0071] This disclosure describes inhalable powders having various active agents. Preferably, for example, the active agents include alkaloids such as nicotine, neonicotinoids, or nifedipine. Preferably, the active agents include solid salts of alkaloids.

[0072] Salts may be formed during the process (during the merging step) or may be formed prior to the merging step. For example, the free base activator may be mixed with aspartic acid, gentianic acid, benzoic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, mucoconic acid, hydrochloric acid, α-dihydroxybenzoic acid, β-dihydroxybenzoic acid, oxalic acid, p-anisolic acid, glutaric acid, or combinations thereof, preferably aspartic acid, tartaric acid, or glutaric acid. Acids may be mixed with the free base activator in any suitable ratio depending on the desired salt form and reaction rate. For example, monoprotic acids such as benzoic acid may be merged with nicotine in a molar ratio of about 1:1 to provide unprotonated nicotine salts.

[0073] The amount of surfactant can be selected based on the desired or intended use of the inhalable powder. For example, the amount of surfactant can be between 0.5% by weight and 10% by weight of the total weight of the crystalline dry powder particles. In some embodiments, the crystalline dry powder particles contain 0.5% by weight or more, 1% by weight or more, 2% by weight or more, or 3% by weight or more of surfactant, and contain 12% by weight or less, 10% by weight or less, 9% by weight or less, 8% by weight or less, or 7% by weight or less of surfactant, or contain 0.5% by weight to 10% by weight, 1% by weight to 8% by weight, 1.5% by weight to 6% by weight, or 2% by weight to 5% by weight of surfactant.

[0074] In some embodiments, the crystalline dry powder particles contain 0.5% or more, 1% or more, 2% or more, or 3% or more of nicotine, and contain 12% or less, 10% or less, 9% or less, 8% or less, or 7% or less of nicotine, or contain 0.5% to 10% of nicotine, 1% to 8% of nicotine, 1.5% to 6% of nicotine, or 2% to 5% of nicotine.

[0075] The amount of active agent can also be selected on a per-dose basis. Inhalable powder can be packaged in single-dose or multi-dose form. For example, each dose of 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. Each dose of 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. In some embodiments, each dose of inhalable powder contains 0.01 to 10 mg of neonicotinoids or nicotine or chenopogonin, each dose contains 0.05 to 5 mg of neonicotinoids or nicotine or chenopogonin, or each dose contains 0.1 to 1 mg of neonicotinoids or nicotine or chenopogonin.

[0076] The inhalable powder composition can be prepared by combining a sugar or sugar alcohol with an active agent and a liquid carrier to form a liquid mixture. This liquid mixture can be spray-dried or freeze-dried to form crystalline, dry powder particles. Preferably, the liquid carrier is aqueous. Preferably, the liquid carrier is water. Preferably, the liquid carrier is at least about 95% water, or at least 99% water, or 100% water (based on the total weight of the liquid carrier).

[0077] The liquid carrier may also contain organic solvents such as alkanols containing 1 to 8 carbon atoms, aliphatic esters containing 3 to 8 carbon atoms, aliphatic straight-chain or cyclic ethers containing 3 to 8 carbon atoms, aliphatic ketones containing 3 to 8 carbon atoms, methanol, ethanol, acetone, or acetonitrile.

[0078] Liquid mixtures can be spray-dried at spray-drying temperatures above the glass transition temperature of sugars or sugar alcohols. Spray-drying temperatures 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 surfactant. Such spray-drying temperatures can be used to prepare nicotine powder and minimize nicotine loss or degradation during drying. The spray-drying temperature is the outlet temperature of the spray nozzle of the spray dryer. The spray-drying temperature can also be the maximum temperature experienced by any given droplet during the spray-drying process.

[0079] As a result of spray drying or freeze drying of a liquid mixture of surfactant and sugar or sugar alcohol, the crystalline dried powder particles contain surfactant dispersed throughout the particles in a sugar or sugar alcohol matrix. The matrix of crystalline sugar or sugar alcohol helps protect the surfactant from environmental factors such as high temperature and humidity. The matrix of crystalline sugar or sugar alcohol also helps minimize agglomeration and maintain good flowability and aerodynamic properties of the crystalline dried powder particles. However, once the crystalline dried powder particles reach the user's lungs, they dissolve rapidly, which facilitates rapid uptake of the surfactant.

[0080] The crystalline dried powder particles can have a particle size ranging from 20 µm or smaller, 10 µm or smaller, or 5 µm or smaller, or 0.1 µm or larger, 0.2 µm or larger, or 0.5 µm or larger, or within 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, grinding, sieving, or a combination thereof.

[0081] The crystalline dried powder particles may have a pH (in solution) within the recommended range for human consumption. In some embodiments, when dissolved in water, the crystalline dried powder particles have a pH of 6 or less, 7 or less, 8 or less, between 3 and 8, between 3 and 6, or between 6 and 8. The pH of the crystalline dried powder particles can be measured by resolving 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 dried powder particles can be formulated without the use of additional buffers. Additional buffers can be considered compounds capable of buffering (e.g., salts, acids, bases, and combinations thereof) other than acids that form salts with surfactants or amino acids contained in the crystalline dried powder particles. The crystalline dried powder particles may be surfactant-free.

[0082] The crystalline dry powder particles can be further mixed with a second particle group to form a powder system. Preferably, the second particle group has a different particle size or a larger particle size than the crystalline dry powder particles. For example, the second particle group can have a particle size in the range of about 20 µm or larger, or about 50 µm or larger, 200 µm or smaller, 150 µm or smaller, or in the range of 50 µm to 200 µm, or 50 µm to 150 µm. The second particle group can have any useful size distribution suitable for selective inhalation and delivery to the user's oral cavity or buccal cavity. A larger second flavoring particle group can help deliver the crystalline dry powder particles to the user's inhalation airflow.

[0083] The crystalline dry powder particles and the second particle group can be combined in any useful relative amount such that the second particle group is detectable by the user when consumed together with the crystalline dry powder particles. Preferably, the crystalline dry powder particles and the second particle group form at least about 90% by weight, at least about 95% by weight, at least about 99% by weight, or 100% by weight of the total weight of the powder system.

[0084] The crystalline, dry powder particles can be further mixed with a second group of flavoring particles to form a powder system. Preferably, the second group of flavoring particles has a different particle size or a larger particle size than the crystalline, dry powder particles. For example, the flavoring particles can have a particle size in the range of about 20 µm or larger, or about 50 µm or larger, 200 µm or smaller, 150 µm or smaller, or in the range of 50 µm to 200 µm, or 50 µm to 150 µm. The second group of flavoring particles can have any useful size distribution suitable for selective inhalation and delivery to the user's oral cavity or buccal cavity. A larger group of second flavoring particles can help deliver the crystalline, dry powder particles to the user's inhalation airflow.

[0085] The crystalline dry powder particles and the second flavoring particle group can be combined in any useful relative amount such that the second flavoring particle group is detectable by the user when consumed together with the crystalline dry powder particles. Preferably, the crystalline dry powder particles and the second flavoring particle group form at least about 90% by weight, at least about 95% by weight, at least about 99% by weight, or 100% by weight of the total weight of the powder system.

[0086] Crystalline dry powder particles or powder systems can be provided in suitable dosage forms. For example, crystalline dry powder particles or powder systems can be provided in capsules. The dosage form (e.g., capsules) can be configured for use in a suitable inhaler. For example, capsules can be used in an inhaler device having a capsule cavity. Airflow management through the capsule cavity of the inhaler device allows the capsule contained therein to rotate during inhalation and consumption. The capsule can contain crystalline dry powder particles or powder systems.

[0087] According to one embodiment, the crystalline dry powder particles or powder system are formulated to have reduced hygroscopicity and a reduced tendency to agglomerate or clump together when in contact with water or moisture. Rotation of the punctured capsule can suspend and atomize the crystalline dry powder particles or powder system released from the punctured capsule into the inhaled air moving through the inhaler device. Optional flavor particles may be larger than the crystalline dry powder particles and may facilitate delivery of the crystalline dry powder particles to the user, while the flavor particles preferentially deposit in the user's oral cavity or buccal cavity. The crystalline dry powder particles and optional flavor particles can be delivered using the inhaler device at an inhalation rate or airflow rate within the range of conventional smoking inhalation rates or airflow rates.

[0088] Crystalline, dry powder particles may contain therapeutically effective doses of an active agent, such as neonicotinoid glutarate. Neonicotinoids (e.g., neonicotinoid glutarate) may be administered to an individual to alleviate symptoms or conditions containing NFKB-mediated inflammatory components and / or reduce the risk of developing such conditions. NFKB-mediated inflammatory components may be associated with chronic inflammation, such as that occurring in thyroiditis, cancer, arthritis, Alzheimer's disease, and multiple sclerosis. Crystalline, dry powder particles containing neonicotinoids may have a monoamine oxidase (MAO) inhibitory effect. Alternatively or additionally, crystalline, dry powder particles containing neonicotinoids may have a STAT3 phosphorylation inhibitory effect.

[0089] The sugar alcohol may be selected from erythritol, inositol, ribitol, 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, inositol, ribitol, mannitol, and xylitol. More preferably, the sugar alcohol is selected from erythritol, inositol, and mannitol. More preferably, the sugar alcohol is erythritol or inositol.

[0090] Sugars or sugar alcohols can have glass transition temperatures of 100°C or less, 75°C or less, or 50°C or less. At 25°C, sugars or sugar alcohols can have a solubility of 75g or less, 60g or less, 50g or less, or 30g or less in 100g of water. Sugar alcohols can have glass transition temperatures of 100°C or less, 75°C or less, or 50°C or less. At 25°C, sugar alcohols can have a solubility of 75g or less, 60g or less, 50g or less, or 30g or less in 100g of water.

[0091] Crystalline dry powder particles may exhibit hygroscopicity of about 5% or less. Crystalline dry powder particles may exhibit hygroscopicity of about 4% or less. Crystalline dry powder particles may exhibit hygroscopicity of about 3% or less. Crystalline dry powder particles may exhibit hygroscopicity of about 2.5% or less. Crystalline dry powder particles may exhibit hygroscopicity of about 2% or less. Crystalline dry powder particles may exhibit hygroscopicity of about 1.5% or less. Crystalline dry powder particles may exhibit hygroscopicity of about 1% or less. Crystalline dry powder particles may exhibit hygroscopicity in the range of 0% to about 5%, or 0% to about 4%, or 0% to about 3%, or 0% to about 2%.

[0092] Hygroscopicity can be measured by measuring the amount of water absorbed or the percentage increase in weight of water by a sample over a 20-minute period under tropical conditions (75% relative humidity and 30°C atmosphere). Before exposure to tropical conditions, the sample is equilibrated for 24 hours at 0% relative humidity and 25°C atmosphere to reduce or remove non-bound water from the sample. Hygroscopicity values ​​were measured using a “Vapor Sorption Analyzer SPSx-1u High Load” manufactured by ProUmid GmbH & Co. KG, as described in the examples below.

[0093] 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 to form a flowable liquid mixture and then 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 because it allows for the incorporation of an active agent that is not solid at room temperature or can provide a solid with preferred physical properties. The method may also include adding amino acids to the crystalline dry powder particles or the flowable liquid mixture. The method may also include combining the amino acids with sugar, the active agent, and the acid to form a mixture. The method may also include adding amino acids to both the liquid mixture and the particles.

[0094] Crystalline dry powder particles can be prepared by mixing an active agent with an acid, sugar or sugar alcohol, and a liquid carrier to form a flowable liquid mixture and then spray-drying the flowable mixture. The use of an acid can lead to the formation of a salt of the active agent, which is solid at room temperature. This can be advantageous because it allows for the incorporation of an active agent that is not solid at room temperature or can provide a solid with preferred physical properties. This has been found particularly useful when the active agent is an alkaloid, especially when the active agent is nicotine, neonicotinoid, or chenopodium. The acid can be selected to reduce any loss of active ingredient during the spray-drying process. Malates have been found to be particularly effective in reducing such loss of alkaloids, especially nicotine, during spray-drying. The method may also include adding amino acids to the crystalline dry powder particles. The method may also include combining the amino acids with sugar, active agent, and acid to form a mixture. The method may also include adding amino acids to both the liquid mixture and the crystalline dry powder particles.

[0095] Preferably, at least selected crystalline dry powder particles each contain a solid alkaloid salt dispersed within a crystalline mannitol matrix, a crystalline erythritol matrix, or a crystalline inositol matrix.

[0096] Preferably, at least selected crystalline dry powder particles each contain a solid nicotine salt dispersed within a crystalline mannitol matrix, a crystalline erythritol matrix, or a crystalline inositol matrix.

[0097] Preferably, at least selected crystalline dry powder particles each contain a solid neonicotinoid salt dispersed within a crystalline mannitol matrix, a crystalline erythritol matrix, or a crystalline inositol matrix.

[0098] The crystalline dried powder particles may contain nicotine aspartate; mannitol, inositol or erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine aspartate, 70% to 99% by weight of mannitol, inositol or erythritol, and 0% to 29% by weight of leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine aspartate, 70% to 80% by weight of mannitol, inositol or erythritol, and 15% to 25% by weight of leucine.

[0099] The crystalline dried powder particles may contain nicotine tartrate; mannitol, inositol or erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine tartrate, 70% to 80% by weight of mannitol, inositol or erythritol, and 15% to 25% by weight of leucine.

[0100] The crystalline dried powder particles may contain nicotine glutarate; mannitol, inositol or erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine glutarate, 70% to 80% by weight of mannitol, inositol or erythritol, and 15% to 25% by weight of leucine.

[0101] The crystalline dried powder particles may contain nicotine malate; mannitol, inositol or erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine glutarate, 70% to 80% by weight of mannitol, inositol or erythritol, and 15% to 25% by weight of leucine.

[0102] The crystalline dried powder particles may contain neonicotinoid glutarate; mannitol, inositol or erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight neonicotinoid glutarate, 70% to 80% by weight mannitol, inositol or erythritol and 15% to 25% by weight leucine.

[0103] The crystalline dried powder particles may contain nicotine aspartate; erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine aspartate, 70% to 99% by weight of erythritol, and 0% to 29% by weight of leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine aspartate, 70% to 80% by weight of erythritol, and 15% to 25% by weight of leucine.

[0104] The crystalline dried powder particles may contain nicotine tartrate; erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine tartrate, 70% to 80% by weight of erythritol, and 15% to 25% by weight of leucine.

[0105] The crystalline dried powder particles may contain nicotine glutarate; erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine glutarate, 70% to 80% by weight of erythritol, and 15% to 25% by weight of leucine.

[0106] The crystalline dried powder particles may contain nicotine malate, erythritol, and leucine. The crystalline dried powder particles may contain 1% to 10% by weight of nicotine glutarate, 70% to 80% by weight of erythritol, and 15% to 25% by weight of leucine.

[0107] The crystalline dried powder particles may contain neonicotinoid glutarate; erythritol; and leucine. The crystalline dried powder particles may contain 1% to 10% by weight neonicotinoid glutarate, 70% to 80% by weight erythritol, and 15% to 25% by weight leucine.

[0108] In some implementations, when the activator is an aspartate salt, the crystalline dry powder particles may not contain mannitol.

[0109] The crystalline, dried powder particles of this disclosure produce a matrix of crystalline sugars or crystalline sugar alcohols, which helps protect the active agent from environmental factors such as high temperature and humidity. The matrix of crystalline sugars or crystalline sugar alcohols also helps minimize agglomeration and maintain good flowability and aerodynamic properties of the inhalable powder. However, once the inhalable powder reaches the user's lungs, the particles dissolve rapidly, which helps provide rapid uptake of the active agent.

[0110] The lower hygroscopicity of crystalline dry powder particles can help minimize composition loss due to agglomeration, adhesion, or liquefaction. This provides improved control over the particle size, dosage, and chemical composition of the crystalline dry powder particles delivered to the consumer. In addition to lower hygroscopicity and thus increased shelf life, crystalline dry powder particles can advantageously have improved aerodynamic properties. For example, consumers 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, consumers may be able to obtain more usage time or more pumps from a single cartridge or capsule. Since the quality of crystalline dry powder particles is not quickly compromised after opening the packaging, crystalline dry powder particles can also be supplied in larger dosage forms such as cartridges or capsules.

[0111] Unless otherwise stated, the term "particle size" is used herein to refer to the mass median aerodynamic diameter (MMAD) of a particle or aggregate of particles. Such values ​​are based on a mass median aerodynamic diameter (MMAD) of 1 gm / cm², defined as having the same aerodynamic behavior as the particle being characterized. 3 The distribution of the density of the sphere's diameter and the diameter of the aerodynamic particles.

[0112] Specifically, for powder systems, the mass median aerodynamic diameter (MMAD) is typically referenced, as it is the most widely used metric as a single numerical descriptor of aerodynamic particle size distribution. MMAD is a statistically derived graph of a particle sample: for example, an MMAD of 5 micrometers means that 50% of the total sample mass will be present in particles with an aerodynamic diameter of less than 5 micrometers, and the remaining 50% of the total sample mass will be present in particles with an aerodynamic diameter greater than 5 micrometers. In the context of this invention, when describing powder systems, the term "particle size" preferably refers to the MMAD of the powder system.

[0113] MMAD for powder systems is preferably measured using a cascade impactor. Cascade impactors are instruments widely used to sample and separate airborne particles to determine the aerodynamic size classification of aerosol particles. Essentially, a cascade impactor separates an incoming sample into discrete parts based on particle inertia, which varies with particle size, density, and velocity. A cascade impactor typically comprises a series of stages, each including a plate with a specific nozzle arrangement and collection surface. The velocity of the sample-carrying air increases as the number of stages increases, while the nozzle size and total nozzle area decrease with increasing stage number. At each stage, particles with sufficient inertia detach from the main airflow to impact the collection surface. Therefore, at any given flow rate, each stage is associated with a cutoff diameter, which numerically defines the size of the collected particles. As the number of stages increases, the velocity increases, and thus the stage cutoff diameter decreases. Therefore, the cutoff diameter associated with a given stage is a function of the airflow rate used for testing. To reflect in-service performance, aerosol inhalers are routinely tested at 15 L / min, and dry powder inhalers can be tested at flow rates up to 100 L / min.

[0114] Preferably, in the context of this invention, the MMAD of the powder system is measured using a Next-Generation Impactor (NGI) 170 (purchased from Copley Scientific AG). The NGI is a high-performance, precise particle sorting cascade impactor with seven stages plus a micropore collector (MOC). The characteristics and operating principle of the NGI are described, for example, in... Marple et al. As described in the Journal of Aerosol Medicine, Volume 16, No. 3 (2003). More preferably, the measurements were performed at 20 ± 3 degrees Celsius and 35 ± 5% relative humidity.

[0115] Dry powder formulations typically contain less than or equal to about 15% by weight of water, preferably less than or equal to about 10% by weight, and even more preferably less than or equal to about 6% by weight. Most preferably, the dry powder formulation contains less than or equal to about 5% by weight of water, or even less than or equal to about 3% by weight of water, or even less than or equal to about 1% by weight of water.

[0116] All values ​​reported as percentages are assumed to be weight percentages based on total weight.

[0117] All scientific and technical terms used in this article have their common meanings in the field, unless otherwise specified. The definitions provided are for ease of understanding of certain terms used frequently in this article.

[0118] As used herein, unless the content explicitly indicates otherwise, the singular forms “a” and “the” cover embodiments having plural references.

[0119] As used herein, unless otherwise expressly indicated by the content, "or" is generally used in its meaning as including "and / or". The term "and / or" means one or all of the listed elements or any combination of two or more of the listed elements.

[0120] As used in this text, "having," "containing," "including," etc., are used in their open sense and generally mean "including (but not limited to)." It should be understood that phrases such as "basically composed of," "composed of," etc., fall under the category of "including."

[0121] The terms "preferred" and "ideally" refer to embodiments of the invention that provide certain benefits in certain circumstances. However, other embodiments may also be preferred in the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are useless, and is not intended to exclude other embodiments from the scope of this disclosure, including the claims.

[0122] As used herein, the term “substantially” has the same meaning as “significantly” and can be understood as modifying the relevant term by at least about 90%, at least about 95%, or at least about 98%. As used herein, the term “substantially not” has the same meaning as “significantly not” and can be understood as having the opposite meaning to “substantially”, i.e., modifying the relevant term by no more than 10%, no more than 5%, or no more than 2%.

[0123] The 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.

[0124] Example Ex1. An inhalable powder comprises crystalline, dry powder particles. The crystalline, dry powder particles comprise a solid salt of an alkaloid and a sugar alcohol.

[0125] Example Ex2. The inhalable powder of Ex1, wherein the sugar alcohol is mannitol, erythritol, inositol, ribitol, xylitol or a combination thereof.

[0126] Example Ex3. An inhalable powder of any of the preceding examples, wherein the sugar alcohol is mannitol, erythritol, inositol, or a combination thereof.

[0127] Example Ex4. An inhalable powder of any of the preceding examples, wherein the sugar alcohol is mannitol.

[0128] Example Ex5. An inhalable powder of any of the preceding examples, wherein the sugar alcohol is erythritol.

[0129] Example Ex6. An inhalable powder of any of the preceding examples, wherein the sugar alcohol is inositol.

[0130] Example Ex7. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is a nicotine salt.

[0131] Example Ex8. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid comprises nicotine tartrate, nicotine aspartate, nicotine malate, or nicotine glutarate.

[0132] Example Ex9. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is nicotine tartrate.

[0133] Example Ex10. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is nicotine aspartate.

[0134] Example Ex11. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is nicotine glutarate.

[0135] Example Ex12. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is nicotine malate.

[0136] Example Ex13. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid comprises neonicotinoid salt.

[0137] Example Ex14. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is neonicotinoid glutarate.

[0138] Example Ex15. An inhalable powder of any of the preceding examples, wherein the solid salt of the alkaloid is chenopogonin.

[0139] Example Ex16. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise a solid salt of an alkaloid, a sugar alcohol, and an amino acid.

[0140] Example Ex17. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise a solid salt of an alkaloid, a sugar alcohol, and leucine.

[0141] Example Ex18. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, nicotine aspartate, nicotine malate or nicotine glutarate, as well as sugar alcohol and leucine.

[0142] Example Ex19. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, nicotine aspartate, nicotine malate or nicotine glutarate, as well as mannitol and leucine.

[0143] Example Ex20. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, nicotine aspartate, nicotine malate or nicotine glutarate, as well as erythritol and leucine.

[0144] Example Ex21. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, nicotine aspartate, nicotine malate or nicotine glutarate, as well as inositol and leucine.

[0145] Example Ex22. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, mannitol and leucine, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine tartrate is dispersed within the mannitol matrix.

[0146] Example Ex23. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, erythritol and leucine, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine tartrate is dispersed within the erythritol matrix.

[0147] Example Ex24. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine tartrate, inositol and leucine, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine tartrate is dispersed within the inositol matrix.

[0148] Example Ex25. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine aspartate, mannitol and leucine, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine aspartate is dispersed within the mannitol matrix.

[0149] Example Ex26. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine aspartate, erythritol and leucine, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine aspartate is dispersed within the erythritol matrix.

[0150] Example Ex27. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine aspartate, inositol and leucine, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine aspartate is dispersed within the inositol matrix.

[0151] Example Ex28. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine glutarate, mannitol and leucine, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine glutarate is dispersed within the mannitol matrix.

[0152] Example Ex29. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine glutarate, erythritol and leucine, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine glutarate is dispersed within the erythritol matrix.

[0153] Example Ex30. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise nicotine glutarate, inositol and leucine, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine glutarate is dispersed within the inositol matrix.

[0154] Example Ex31. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise nicotine malate, mannitol and leucine, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine malate is dispersed within the mannitol matrix.

[0155] Example Ex32. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise nicotine malate, erythritol and leucine, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine malate is dispersed within the erythritol matrix.

[0156] Example Ex33. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise nicotine malate, inositol and leucine, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine malate is dispersed within the inositol matrix.

[0157] Example Ex34. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise about 60% or more sugar alcohols, 10% or more amino acids, and about 1% to about 10% solid alkaloid salts.

[0158] Example Ex35. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise about 60% or more sugar alcohol, and 10% or more amino acids and about 1% to about 10% solid alkaloid salts, and at least selected crystalline dry powder particles each comprise a sugar alcohol matrix and the solid alkaloid salts are dispersed within the sugar alcohol matrix.

[0159] Example Ex36. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% erythritol, 15% to 25% leucine and 1% to 10% nicotine tartrate, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine tartrate is dispersed within the erythritol matrix.

[0160] Example Ex37. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise 70% to 80% erythritol, 15% to 25% leucine and 1% to 10% nicotine aspartate, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine aspartate is dispersed within the erythritol matrix.

[0161] Example Ex38. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% erythritol, 15% to 25% leucine and 1% to 10% nicotine glutarate, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine glutarate is dispersed within the erythritol matrix.

[0162] Example Ex39. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% erythritol, 15% to 25% leucine and 1% to 10% nicotine malate, and at least selected crystalline dry powder particles each comprise an erythritol matrix and the nicotine malate is dispersed within the erythritol matrix.

[0163] Example Ex40. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% inositol, 15% to 25% leucine and 1% to 10% nicotine tartrate, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine tartrate is dispersed within the inositol matrix.

[0164] Example Ex41. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise 70% to 80% inositol, 15% to 25% leucine and 1% to 10% nicotine aspartate, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine aspartate is dispersed within the inositol matrix.

[0165] Example Ex42. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% inositol, 15% to 25% leucine and 1% to 10% nicotine glutarate, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine glutarate is dispersed within the inositol matrix.

[0166] Example Ex43. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% inositol, 15% to 25% leucine and 1% to 10% nicotine malate, and at least selected crystalline dry powder particles each comprise an inositol matrix and the nicotine malate is dispersed within the inositol matrix.

[0167] Example Ex44. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% mannitol, 15% to 25% leucine and 1% to 10% nicotine tartrate, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine tartrate is dispersed within the mannitol matrix.

[0168] Example Ex45. An inhalable powder of any of the foregoing examples, wherein the crystalline dry powder particles comprise 70% to 80% mannitol, 15% to 25% leucine and 1% to 10% nicotine aspartate, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine aspartate is dispersed within the mannitol matrix.

[0169] Example Ex46. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise 70% to 80% mannitol, 15% to 25% leucine and 1% to 10% nicotine glutarate, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine glutarate is dispersed within the mannitol matrix.

[0170] Example Ex46. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles comprise 70% to 80% mannitol, 15% to 25% leucine and 1% to 10% nicotine malate, and at least selected crystalline dry powder particles each comprise a mannitol matrix and the nicotine malate is dispersed within the mannitol matrix.

[0171] Example Ex.47. An inhalable powder of any of the preceding examples, wherein the crystalline dry powder particles have hygroscopicity of 5% or less, or 4% or less, or 3% or less, or 2% or less.

[0172] Example Ex. 48. An inhalable powder system comprising a first group of dried powder particles of crystalline form of any one or more of the powders of the foregoing examples and a second group of particles with a particle size larger than the first group of particles.

[0173] Example Ex.49. Ex.48: An inhalable powder system wherein a first group of crystalline dry powder particles has a particle size of about 1 micrometer to about 5 micrometers and a second group of particles has a particle size of 20 micrometers to 200 micrometers. Attached Figure Description

[0174] The embodiments will now be described further with reference to the accompanying drawings, in which:

[0175] Figure 1 X-ray powder diffraction pattern of the preferred polymorph of neonicotinoid glutarate (CuK) ).

[0176] Figure 2 This is a schematic diagram of an inhaler product.

[0177] Figure 3 The following is a powder X-ray diffraction pattern of the Comp Ex amorphous trehalose powder formulation described below.

[0178] Figure 4 The following is the powder X-ray diffraction pattern of sample B, a crystalline inositol powder formulation.

[0179] Figure 5 The following is the powder X-ray diffraction pattern of the crystalline erythritol powder formulation of sample C described below.

[0180] Figure 6 The following is the powder X-ray diffraction pattern of sample D, a crystalline ribitol powder formulation.

[0181] Figure 7 The following is a powder X-ray diffraction pattern of the crystalline mannitol powder formulation of sample A described below.

[0182] Figure 8 The following is the powder X-ray diffraction pattern of sample E, a crystalline xylitol powder formulation, as described below.

[0183] Figure 9 The graph below shows the hygroscopicity test data described in the examples below.

[0184] Figure 2 The illustrative inhaler article 10 includes an elongated cylindrical body extending from a mouthpiece end 11 to a distal end 12. A capsule cavity 20 is defined within the elongated cylindrical body. A capsule 30 is housed within the capsule cavity 20. The crystalline dry powder particles described herein may be contained within the capsule 30. The capsule 30 may be punctured to form an opening through the body of the capsule 30, and inhaled air may flow through the inhaler article 10 to release the crystalline dry powder particles from the punctured capsule 30, into the inhaled airflow, and out from the mouthpiece end 11.

[0185] The illustrations are not necessarily to scale and are presented for illustrative rather than limiting purposes. The accompanying drawings depict one or more aspects described in this disclosure. However, it should be understood that other aspects not depicted in the drawings fall within the scope and spirit of this disclosure. Detailed Implementation

[0186] Example

[0187] A first liquid mixture was formed by combining 2.5% free nicotine, 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) operating under first conditions (1.0 bar, 50°C, and a feed rate of 2.5 g / min) and second conditions (3.0 bar, 50°C, and a feed rate of 2.5 g / min) to form crystalline dried powder particles.

[0188] The dried powder particles produced by the first set of conditions result in a fine, free-flowing white powder. This powder has the following particle size distribution: X 10 =1.78 micrometers, X 50 =7.13 micrometers, X 90 =14.56 micrometers, and VMD=7.82 micrometers. These crystalline dry powder particles were then co-finished with leucine at a ratio of 85:15 (crystalline dry powder particles: leucine) using a fluid energy mill. The co-finished powder has the following particle size distribution: X 10 =0.64 micrometers, X 50 =1.29 micrometers, X 90 =2.81 micrometers, and VMD=1.54 micrometers.

[0189] The dried powder particles produced by the second set of conditions result in a fine, free-flowing white powder. This powder has the following particle size distribution: X 10 =1.10 micrometers, X 50 =2.88 micrometers, X 90 =6.13 micrometers, and VMD=3.37 micrometers.

[0190] Additional crystalline dried powder particles were formed using the second spray drying condition group described above (using the formulations listed in Table 1 below). All samples and comparative examples had approximately the following particle size distribution: X 50 =2-4 micrometers, X 90 =5-6 micrometers.

[0191] Table 1

[0192]

[0193] The amorphous sugar trehalose (Tg = 106 °C and solubility of 69 g / 100 ml water at 25 °C) was used. A comparative sample, “Comp Ex”, was prepared by combining a comparative liquid mixture in water containing 2.5% free nicotine, 10% leucine, 86.25% trehalose, and 1.25% lactic acid. The comparative liquid mixture was fed into a spray dryer (Buchi B-290) operating under the first set of conditions (5.5 bar, 70 °C, and a feed rate of 3 g / min) to form amorphous dried powder particles.

[0194] Using CuK Radiation source ( Powder X-ray diffraction measurements were performed using a PANalytical X'Pert Pro diffractometer (1.5432 nm, 40 kV, 40 mA) with Bragg-Brentano geometry and a standard sample holder. Six 30-minute scans were performed on each sample. Figure 3-8 The resulting spectra or patterns from X-ray diffraction measurements of these powders.

[0195] Figure 3 This is the powder X-ray diffraction pattern of the Comp Ex trehalose powder formulation. The pattern indicates that Comp Ex is largely amorphous.

[0196] Figure 4 The image shows the powder X-ray diffraction pattern of crystalline inositol powder formulation B. This pattern indicates that sample B is crystalline.

[0197] Figure 5 The image shows the powder X-ray diffraction pattern of crystalline erythritol powder formulation of sample C. This pattern indicates that sample C is crystalline.

[0198] Figure 6 The image shows the powder X-ray diffraction pattern of crystalline ribitol powder formulation of sample D. This pattern indicates that sample D is crystalline.

[0199] Figure 7 This is the powder X-ray diffraction pattern of crystalline mannitol powder formulation of sample A. The pattern indicates that sample A is crystalline.

[0200] Figure 8 The image shows the powder X-ray diffraction pattern of sample E, a crystalline xylitol powder formulation. This pattern indicates that sample E is crystalline.

[0201] like Figure 9 As shown, 100 mg samples (samples AE and Comp Ex) were placed in the measurement chamber of the ProUmid vapor adsorption instrument and equilibrated for 24 hours (1450 minutes) at 0% relative humidity and 25°C. The instrument temperature was then raised to 30°C and 75% relative humidity. Measurements were taken approximately every 6 minutes.

[0202] The trehalose-based sample (Comp Ex) showed the greatest rate of increase in mass (hygroscopicity), exceeding 7% at 20 minutes and exceeding 10% at 30 minutes.

[0203] The mannitol-based sample (sample A), the inositol-based sample (sample B), the erythritol-based sample (sample C), the ribitol-based sample (sample D), and the xylitol-based sample (sample E) showed an increase of 2% or less at 20 minutes and an increase of 3% or less at 30 minutes. Table 2 below illustrates the hygroscopicity from 1450 minutes to 1500 minutes (50-minute duration).

[0204] Table 2 – Mass % increasing over time

[0205]

[0206] Next, all samples were tested using an aerosol generation test under tropical conditions. Approximately 50 grams of each sample powder was loaded into capsules, which were then placed in the inhaler device and punctured. Inhaled air (75% relative humidity and 30°C) was passed through the inhaler at a rate of 80 ml per two seconds for a total of 20 inhalations. The entire inhaler device was weighed before and after the aerosol generation test to determine the amount of each sample released from the capsules. A preferred target release of at least 25 grams was established.

[0207] Sample A (mannitol-based) released 30 grams. Sample B (inositol-based) released 34 grams. Sample C (erythritol-based) released 30 grams. All these samples met the target release amount.

[0208] Sample D (ribitol-based) released 9 grams. Sample E (xylitol-based) released 14 grams. These samples did not meet the target release amount.

[0209] The comparison sample “Comp Ex” (based on trehalose) actually increased in weight by 0.1 grams, indicating that it absorbed more water than the sample released.

[0210] Although ribitol and xylitol powders did not reach the target release values, they still showed a significant improvement over amorphous trehalose powder.

[0211] For the purposes of this specification and the appended claims, unless otherwise stated elsewhere, all figures representing quantities, quantities, percentages, etc., shall be understood to be modified by the term "about" in all cases. Furthermore, all ranges include the disclosed maximum and minimum points, and include any intermediate ranges that may be specifically listed or not listed herein. Thus, in this context, the numeral A is understood to be A ± 2%A. Within this context, the numeral A can be considered as a value within the general standard error for the measurement of the attribute modified by the numeral A. In certain instances used in the appended claims, the numeral A may deviate from the percentages listed above, provided that the amount of deviation from A does not materially affect the essential and novel features of the claimed invention. Furthermore, all ranges include the disclosed maximum and minimum points, and include any intermediate ranges that may be specifically listed or not listed herein.

Claims

1. An inhalable powder, said inhalable powder comprising: Crystallized dry powder particles, the crystalline dry powder particles comprising: A solid salt of an alkaloid, wherein the solid salt of the alkaloid is solid at 25°C, wherein the alkaloid is nicotine; and Sugar alcohols, including erythritol, inositol, ribitol, xylitol, or combinations thereof, The crystalline dry powder particles absorb 5% by weight or less of water over a duration of 20 minutes at 75% relative humidity and 30 degrees Celsius. The dried powder particles of the crystals also contain amino acids, specifically leucine.

2. The inhalable powder according to claim 1, wherein the solid salt of the alkaloid comprises nicotine tartrate, nicotine aspartate, nicotine malate, or nicotine glutarate.

3. The inhalable powder according to claim 1, wherein the crystalline dry powder particles comprise solid salts of sugar alcohols, amino acids and alkaloids, and the crystalline dry powder particles comprise a sugar alcohol matrix and the solid salts of the alkaloids are dispersed within the sugar alcohol matrix.

4. The inhalable powder according to claim 1, wherein the sugar alcohol is erythritol or inositol.

5. The inhalable powder according to claim 1, wherein the crystalline dry powder particles comprise 60% or more sugar alcohol, 10% or more amino acids, and 1% to 10% solid salts of alkaloids, and the crystalline dry powder particles comprise a sugar alcohol matrix and the solid salts of the alkaloids are dispersed within the sugar alcohol matrix.

6. The inhalable powder according to claim 1, wherein the crystalline dry powder particles comprise erythritol or inositol and leucine and nicotine tartrate, and the crystalline dry powder particles comprise an erythritol or inositol matrix and the nicotine tartrate is dispersed within the erythritol or inositol matrix.

7. The inhalable powder according to claim 1, wherein the crystalline dry powder particles comprise erythritol or inositol and leucine and nicotine aspartate, and the crystalline dry powder particles comprise an erythritol or inositol matrix and the nicotine aspartate is dispersed within the erythritol or inositol matrix.

8. The inhalable powder according to claim 1, wherein the crystalline dry powder particles comprise erythritol or inositol and leucine and nicotinic acid glutarate, and the crystalline dry powder particles comprise an erythritol or inositol matrix and the nicotinic acid glutarate is dispersed within the erythritol or inositol matrix.

9. The inhalable powder of claim 1, wherein the crystalline dry powder particles comprise erythritol or inositol, leucine, and nicotine malate, and the crystalline dry powder particles comprise an erythritol or inositol matrix and the nicotine malate is dispersed within the erythritol or inositol matrix.

10. The inhalable powder according to claim 1, wherein the crystalline dry powder particles comprise 70% to 80% by weight of erythritol, 15% to 25% by weight of leucine, and 1% to 10% by weight of nicotine tartrate, nicotine aspartate, nicotine malate, or nicotine glutarate.

11. An inhalable powder system comprising a first particle group of dried powder particles of the powder as described in any one of claims 1-10 and a second particle group with a particle size larger than the first particle group.

12. The inhalable powder system of claim 11, wherein the first group of crystalline dry powder particles has an MMAD particle size of 1 micrometer to 5 micrometers and the second group of particles has an MMAD particle size of 20 micrometers to 200 micrometers.

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