Niclosamide particles and their use

Abstract

The present disclosure provides a composition comprising particles comprising at least 30% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the particles have a density of (i) 0.40 g / cm 3 (ii) an average bulk density (untapped) of less than 0.55 g / cm 3 and / or (iii) an average tap density of at least 3.6 m 2 The present invention provides compositions, as well as methods for using the compositions, having one or more specific surface areas (SSA) of 1000 nm to 1000 nm / g.

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 075424, filed on 8 September 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Niclosamide is an FDA-approved oral medication for treating helminthic infections and has been shown to inhibit multiple viruses, including but not limited to SARS- and MERS-CoV, influenza, Ebola, Lassa, Zika, and SARS-CoV-2. Niclosamide is a potent inhibitor of the TMEM16A cell membrane ion channel, which is expressed in airway epithelial cells, a key cell type infected with SARS-CoV-2, the virus that causes coronavirus infection 2019 (COVID-19), and affects their physiology. By blocking TMEM16A-mediated cellular calcium signaling, niclosamide potently dilates the airways, inhibits mucus secretion, and reduces airway inflammation, making it a promising novel treatment, particularly for uncontrolled asthma and COPD among its indications. However, a major limitation of niclosamide therapy is that high-dose oral formulations result in low systemic drug concentrations, making this pathway unwieldy for treating respiratory infections. [Overview of the project]

[0003] In one embodiment, the present disclosure provides a composition comprising particles comprising at least 30% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the particles are (i) 0.40 g / cm³ 3 Average bulk density less than (without tapping), (ii) 0.55 g / cm³ 3 Less than average tap density, and / or (iii) at least 3.6m 2 Specific surface area (SSA) of / g It has one or more of the following.

[0004] In one embodiment, the particles have an average bulk density (without tapping) of less than 0.20 g / cm 3 and an average tapped density of less than 0.20 g / cm 3 In another embodiment, the particles have an average bulk density (without tapping) of less than 0.15 g / cm 3 and an average tapped density of less than 0.15 g / cm 3 In a further embodiment, the particles have (a) an average bulk density (without tapping) of about 0.02 g / cm 3 to 0.30 g / cm 3 and an average tapped density of about 0.02 g / cm 3 to 0.30 g / cm 3 , (b) an average bulk density (without tapping) of about 0.03 g / cm 3 to 0.30 g / cm 3 and an average tapped density of about 0.03 g / cm 3 to 0.30 g / cm 3 , (c) an average bulk density (without tapping) of about 0.04 g / cm 3 to 0.30 g / cm 3 and an average tapped density of about 0.04 g / cm 3 to 0.30 g / cm 3 , or (d) an average bulk density (without tapping) of about 0.05 g / cm 3 to 0.30 g / cm 3 and an average tapped density of about 0.05 g / cm 3 to 0.30 g / cm 3 In one embodiment, the particles have a specific surface area (SSA) of at least about 5 m 2 / g. In another embodiment, the particles have a specific surface area (SSA) of 3.6 m 2 / g to about 50 m 2 / g.

[0005] In one embodiment, the particles are (i) having an average bulk density (without tapping) of less than 0.40 g / cm 3 , (ii) having an average tapped density of less than 0.55 g / cm 3 , and (iii) having a specific surface area of at least 3.6 m2 Specific surface area (SSA) of / g It holds.

[0006] In another embodiment, the particles are (i) 0.40 g / cm³ 3 Average bulk density less than (without tapping), (ii) 0.55 g / cm³ 3 Less than average tap density, and (iii) at least 5m 2 Specific surface area (SSA) of / g It holds.

[0007] In further embodiments, the particles have average particle diameters with volume distributions of approximately 0.1 μm to 10.5 μm, 0.1 μm to 8 μm, 0.3 μm to 7 μm, and 0.5 μm to 6 μm.

[0008] In one embodiment, the particles contain at least 30% by weight of niclosamide. In another embodiment, the particles contain at least 95% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In a further embodiment, the particles contain a cocrystal of niclosamide with urea, nicotinamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, the cocrystal constituting at least 95% by weight of the particles. In one embodiment, the particles contain a cocrystal of niclosamide with urea or nicotinamide, the cocrystal constituting at least 95% by weight of the particles.

[0009] In one embodiment, the particles are (a) niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof (b) Urea or any pharmaceutically acceptable salt, hydrate, or solvate thereof It contains a co-crystal of The cocrystal constitutes at least 96%, 97%, 98%, 99%, or 100% by weight of the particles, and the molar ratio of urea:niclosamide present in the particles is 3:1 to 1:3.

[0010] In another embodiment, the particles are (a) niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof (b) Nicotinamide or any pharmaceutically acceptable salt, hydrate, or solvate thereof It contains a co-crystal of The cocrystal constitutes at least 96%, 97%, 98%, 99%, or 100% by weight of the particles, and the molar ratio of nicotinamide to niclosamide present in the particles is 3:1 to 1:3.

[0011] In one embodiment, the composition comprises a suspension further comprising a pharmaceutically acceptable aqueous carrier, and / or the composition further comprises one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol, and hydroxypropylmethylcellulose. In another embodiment, the composition is formulated for pulmonary, intramuscular, subcutaneous, or intraperitoneal administration. In a further embodiment, niclosamide particles or a suspension thereof are formulated as a dry powder inhalation aerosol, a spray suspension, or niclosamide particles or a suspension thereof are suspended in a suitable propellant system (including, but not limited to, hydrofluoroalkanes (HFAs)) containing at least one liquefied gas in a pressurized vessel sealed with a throttle valve.

[0012] In another aspect, the Disclosure relates to parasitic infections, viral infections (including, but not limited to, coronaviruses (SARS, MERS, SARS-CoV-2), influenza, Ebola virus, Lassa virus, Zika virus, Dengue virus, West Nile and Japanese encephalitis virus, Chikungunya virus, Sindbis virus, Ross River virus, Semryki Forest virus), yellow fever virus, rabies virus, herpes simplex virus, hepatitis C virus, rhinovirus, and coxsackivirus, bacterial infections (including drug-resistant Mycobacterium tuberculosis, Mycobacterium abscesses, methicillin-resistant Staphylococcus aureus and biofilms, Pseudomonas aeruginosa and biofilms, vancomycin-resistant enterococci, multidrug-resistant Gram-negative bacteria, and Bacillus anthrax). The present invention provides a method for treating or limiting the manifestation of disorders, including but not limited to, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, pulmonary and renal fibrosis, pulmonary hypertension, idiopathic pulmonary arterial hypertension (IPAH), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), eosinophilic esophagitis, stroke, ischemia / reperfusion injury, pain, psoriasis and atopic dermatitis, rheumatoid arthritis, graft-versus-host disease and systemic sclerosis, secretory diarrhea, diabetes mellitus, renal disease (including ADPKD), endometriosis, and suppression of uterine contractions in spontaneous early labor, comprising administering to a subject in need of it a composition or suspension of any embodiment or combination of embodiments of the present disclosure in an amount effective to treat or limit the manifestation of the disorder. In one embodiment, the composition is administered via a transpulmonary, intramuscular, or subcutaneous route. In one embodiment, transpulmonary administration includes dry powder inhalation using a suitable dry powder inhaler. In another embodiment, transpulmonary administration includes spraying, which results in transpulmonary delivery of aerosol droplets of particles or a suspension thereof to a subject.In further embodiments, particles or their suspension are aerosolized for administration, and aerosolization yields aerosol droplets having an aerodynamic median particle diameter (MMAD) of approximately 0.5 μm to 6 μm, or approximately 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 2 μm to 5 μm, 2 μm to 4 μm, or 2 μm to 3 μm.

[0013] In another aspect, the present disclosure relates to a method for producing compound particles, (a) (i) Introducing a solution comprising at least one solvent selected from the group consisting of acetone, ethanol, methanol, dichloromethane, hexafluoroisopropyl alcohol, trifluoroethanol, dimethyl sulfoxide, tetrahydrofuran (THF), dimethylformamide, or a combination thereof, and at least one solute comprising niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, either alone or in combination with urea, nicotinamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, into the nozzle inlet; (ii) Introducing a compressible fluid into the inlet of a vessel defining a pressurizable chamber; (b) A step of passing a solution through a nozzle opening into a pressurizable chamber to generate an output stream of spray droplets, wherein the nozzle opening is located 2 mm to 20 mm from a sound wave energy source located in the output stream, the sound wave energy source generates sound wave energy with an amplitude of 10% to 100% during passage, and the nozzle opening has a diameter of 20 μm to 125 μm. (c) The step of bringing the spray droplets into contact with a compressed fluid to deplete the solvent from the spray droplets and generate compound particles of any embodiment or combination of embodiments disclosed herein. Includes, Steps (a), (b), and (c) are performed under the supercritical temperature and supercritical pressure of the compressible fluid. Provide a method. [Brief explanation of the drawing]

[0014] [Figure 1] Scanning electron microscope images of the raw material niclosamide at (A) 2500X magnification and (B) 10000X magnification. [Figure 2] Scanning electron microscope images of SC13-low ultrasonic treatment small batch generation-1:1 acetone:ethanol-35 mg / mL at (A) 2500X magnification and (B) 10000X magnification. [Figure 3] Scanning electron microscope images of SC20-coprecipitation 1:1 nicotinamide:niclosamide-4 mg / mL at (A) 2500X magnification and (B) 10000X magnification. [Figure 4] Scanning electron microscope images of SC27-high ultrasonic treatment 3:2 urea:niclosamide-25 mg / mL at (A) 2500X magnification and (B) 10000X magnification. [Figure 5] Scanning electron microscope images of SC31-low-pressure nicrosamide ethanolamine at (A) 1000X magnification and (B) 5000X magnification. [Figure 6] Scanning electron microscope images of 10 gm of niclosamide in SC58-THF at (A) 1000X magnification and (B) 5000X magnification. [Modes for carrying out the invention]

[0015] All references are incorporated herein by reference in their entirety. Where used herein, the singular forms “a,” “an,” and “the” include the plural form unless the context specifically indicates otherwise. Unless the context specifically indicates otherwise, all embodiments of any aspect of this disclosure may be used in combination.

[0016] Where used herein, "approximately" means ±5% of the stated value.

[0017] In one embodiment, the present disclosure provides a particle composition comprising at least 30% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the particles (i) 0.40 g / cm³ 3 Average bulk density less than (without tapping), (ii) 0.55 g / cm³ 3 Less than average tap density, and / or (iii) at least 3.6m 2 Specific surface area (SSA) of / g It holds.

[0018] Niclosamide is poorly absorbed from the gastrointestinal tract and is substantially toxic when administered intravenously (Andrews et al., 1982; Schweizer et al., 2018). This disclosure provides unique low bulk density, high surface area niclosamide particles, either alone or in cocrystal form, that can be administered via, for example, transpulmonary, intramuscular, intraperitoneal, and subcutaneous routes, offering significantly improved solubility, enhanced residence time, and higher concentrations at target body sites, and are considered suitable for treating a given disease. Accordingly, this disclosure provides niclosamide particles and suspensions thereof having significantly improved therapeutic properties compared to previous niclosamide therapies.

[0019] As used herein, "niclosamide" includes any ionization state of niclosamide, including basic, acidic, and neutral states. In one embodiment, niclosamide is in a neutral state. [ka]

[0020] The particles contain at least 30% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In various embodiments, the particles contain at least 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or 95% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In other embodiments, the particles contain a cocrystal of niclosamide with urea, nicotinamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In these embodiments, the cocrystal constitutes at least 95% by weight of the particles. In various embodiments, the niclosamide, or the cocrystal of it with urea or nicotinamide, constitutes at least 96% by weight, 97% by weight, 98% by weight, 99% by weight, or 100% by weight of the particles.

[0021] In one embodiment, the particles are (a) niclosamide, its pharmaceutically acceptable salt, hydrate, or solvate, (b) Urea or any pharmaceutically acceptable salt, hydrate, or solvate thereof It contains a co-crystal of The cocrystal constitutes at least 96% by weight, 97% by weight, 98% by weight, 99% by weight, or 100% by weight of the particles.

[0022] In another embodiment, the particles are (a) Niclosamide and, (b) Urea and It contains a co-crystal of The cocrystal constitutes at least 96% by weight, 97% by weight, 98% by weight, 99% by weight, or 100% by weight of the particles.

[0023] In these embodiments, niclosamide and urea may be present in the particles in any molar ratio, as long as the particles contain at least 30% by weight of niclosamide. In various embodiments, the molar ratio of urea:niclosamide present in the particles may be 3:1 to 1:3, i.e., 1:1, 2:2, 3:1, 3:2, 1:2, 1:3, or 2:3.

[0024] In another embodiment, the particles are (a) niclosamide, its pharmaceutically acceptable salt, hydrate, or solvate, (b) Nicotinamide or any pharmaceutically acceptable salt, hydrate, or solvate thereof It contains a co-crystal of The cocrystal constitutes at least 96% by weight, 97% by weight, 98% by weight, 99% by weight, or 100% by weight of the particles.

[0025] In further embodiments, the particles are (a) Niclosamide and, (b) Nicotinamide and It contains a co-crystal of The cocrystal constitutes at least 96% by weight, 97% by weight, 98% by weight, 99% by weight, or 100% by weight of the particles.

[0026] In these embodiments, niclosamide and nicotinamide may be present in the particles in any molar ratio, as long as the particles contain at least 30% by weight of niclosamide. In various embodiments, the molar ratio of nicotinamide to niclosamide present in the particles may be 3:1 to 1:3, i.e., 1:1, 2:2, 3:1, 3:2, 1:2, 1:3, or 2:3.

[0027] The inventors unexpectedly found that it was 0.40 g / cm³. 3 Average bulk density less than 0.55 g / cm³ (without tapping), 0.55 g / cm³ 3 Average tap density less than 3.6m 2We were able to produce nicrosamide particles with a specific surface area (SSA) of 1 / g. The bulk density was significantly lower than that of the previous nicrosamide particles, while the SSA was significantly higher. The increased specific surface area and / or decreased bulk density of the nicrosamide particles result in a significant increase in dissolution rate compared to the micronized nicrosamide product used for comparison. Dissolution occurs only at the solid / liquid interface. Therefore, the increased specific surface area increases the dissolution rate by allowing more molecules on the particle surface to come into contact with the dissolving medium. Bulk density takes into account the macrostructure of the particles and the interparticle space. Parameters contributing to bulk density include particle size distribution, particle shape, and the affinity of particles to each other (i.e., aggregation). A lower powder bulk density results in a faster dissolution rate. This is due to the ability of the dissolving medium to penetrate more easily into the spaces within or between particles and to come into greater contact with the particle surface. Therefore, the increased specific surface area and decreased bulk density, respectively, result in a significant increase in the dissolution rate of the nicrosamide particles of this disclosure compared to the micronized nicrosamide product used for comparison.

[0028] As used herein, particle bulk density (untapped) is the ratio of mass to volume (including the volume of voids between particles) of an untapped powder sample.

[0029] As used herein, the tap density of particles is obtained by mechanically tapping a graduated cylinder containing the sample until little further volume change is observed.

[0030] In one embodiment, the particles of the present disclosure are 0.40 g / cm³ 3 It has an average bulk density of less than 0.38 g / cm³. In various embodiments, the particles are 0.38 g / cm³. 3 , 0.35 g / cm³ 3 , 0.33 g / cm³ 3 0.30 g / cm³ 3 , 0.28 g / cm³ 3 , 0.35 g / cm³ 3 , 0.23 g / cm³ 3, 0.20 g / cm³ 3 , 0.18 g / cm³ 3 , 0.15 g / cm³ 3 0.13 g / cm³ 3 , 0.10 g / cm³ 3 , 0.08 g / cm³ 3 , or 0.05 g / cm³ 3 It has an average bulk density of less than 0.02 g / cm³. In various further embodiments, the particles are about 0.02 g / cm³. 3 ~0.40g / cm 3 , about 0.02g / cm 3 ~0.38 g / cm³ 3 , about 0.02g / cm 3 ~0.35g / cm 3 , about 0.02g / cm 3 ~0.33g / cm 3 , about 0.02g / cm 3 ~0.30g / cm 3 , about 0.02g / cm 3 ~0.28 g / cm³ 3 , about 0.02g / cm 3 ~0.25g / cm 3 , about 0.02g / cm 3 ~0.23g / cm 3 , about 0.02g / cm 3 ~0.20 g / cm³ 3 , about 0.02g / cm 3 ~0.18 g / cm³ 3 , about 0.02g / cm 3 ~0.15g / cm 3 , about 0.02g / cm 3 ~0.13g / cm 3 , about 0.02g / cm 3 ~0.10 g / cm³ 3 , about 0.02g / cm 3 ~0.08 g / cm³ 3 , about 0.03g / cm 3 ~0.40g / cm 3 , about 0.03g / cm 3 ~0.38 g / cm³ 3 , about 0.03g / cm 3 ~0.35g / cm 3 , about 0.03g / cm 3 ~0.33g / cm3 Approximately 0.3 g / cm³ 3 ~0.30g / cm 3 Approximately 0.03 g / cm³ 3 ~0.28g / cm 3 Approximately 0.03 g / cm³ 3 ~0.25g / cm 3 Approximately 0.03 g / cm³ 3 ~0.23g / cm 3 Approximately 0.03 g / cm³ 3 ~0.20g / cm 3 Approximately 0.03 g / cm³ 3 ~0.18g / cm 3 Approximately 0.03 g / cm³ 3 ~0.15g / cm 3 Approximately 0.03 g / cm³ 3 ~0.13g / cm 3 Approximately 0.03 g / cm³ 3 ~0.10g / cm 3 Approximately 0.03 g / cm³ 3 ~0.08g / cm 3 0.04g / cm 3 ~0.40g / cm 3 Approximately 0.04 g / cm³ 3 ~0.38g / cm 3 Approximately 0.04 g / cm³ 3 ~0.35g / cm 3 Approximately 0.04 g / cm³ 3 ~0.33g / cm 3 Approximately 0.04 g / cm³ 3 ~0.30g / cm 3 Approximately 0.04 g / cm³ 3 ~0.28g / cm 3 Approximately 0.04 g / cm³ 3 ~0.25g / cm 3 Approximately 0.04 g / cm³ 3 ~0.23g / cm 3 Approximately 0.04 g / cm³ 3 ~0.20g / cm 3 Approximately 0.04 g / cm³ 3 ~0.18g / cm 3 Approximately 0.04 g / cm³ 3 ~0.15g / cm 3 Approximately 0.04 g / cm³ 3 ~0.13g / cm 3, about 0.04g / cm 3 ~0.10 g / cm³ 3 , about 0.04g / cm 3 ~0.08 g / cm³ 3 , 0.05 g / cm³ 3 ~0.40g / cm 3 , about 0.05g / cm 3 ~0.38 g / cm³ 3 , about 0.05g / cm 3 ~0.35g / cm 3 , about 0.05g / cm 3 ~0.33g / cm 3 , about 0.05g / cm 3 ~0.30g / cm 3 , about 0.05g / cm 3 ~0.28 g / cm³ 3 , about 0.05g / cm 3 ~0.25g / cm 3 , about 0.05g / cm 3 ~0.23g / cm 3 , about 0.05g / cm 3 ~0.20 g / cm³ 3 , about 0.05g / cm 3 ~0.18 g / cm³ 3 , about 0.05g / cm 3 ~0.15g / cm 3 , about 0.05g / cm 3 ~0.13g / cm 3 , or approximately 0.05 g / cm³ 3 ~0.10 g / cm³ 3 It has an average bulk density (without tapping).

[0031] In another embodiment, the particles of the present disclosure are 0.55 g / cm³ 3 It has an average tap density of less than 0.53 g / cm³. In various embodiments, the particles are 0.53 g / cm³. 3 , 0.50 g / cm³ 3 0.48 g / cm³ 3 0.45 g / cm³ 3 0.43 g / cm³ 3 , 0.40 g / cm³ 3 , 0.38 g / cm³ 3 , 0.35 g / cm³ 3 , 0.33 g / cm³ 30.30 g / cm³ 3 , 0.28 g / cm³ 3 , 0.25 g / cm³ 3 , 0.23 g / cm³ 3 , 0.20 g / cm³ 3 , 0.18 g / cm³ 3 0.53 g / cm³ 3 , 0.15 g / cm³ 3 0.13 g / cm³ 3 , 0.10 g / cm³ 3 , 0.08 g / cm³ 3 , or 0.05 g / cm³ 3 It has an average tap density of less than 0.02 g / cm³. In various further embodiments, the particles are about 0.02 g / cm³. 3 ~0.55 g / cm³ 3 , about 0.02g / cm 3 ~0.53 g / cm³ 3 , about 0.02g / cm 3 ~0.50g / cm 3 , about 0.02g / cm 3 ~0.47 g / cm³ 3 , about 0.02g / cm 3 ~0.45g / cm 3 , about 0.02g / cm 3 ~0.43g / cm 3 , about 0.02g / cm 3 ~0.40g / cm 3 , about 0.02g / cm 3 ~0.38 g / cm³ 3 , about 0.02g / cm 3 ~0.35g / cm 3 , about 0.02g / cm 3 ~0.33g / cm 3 , about 0.02g / cm 3 ~0.30g / cm 3 , about 0.02g / cm 3 ~0.28 g / cm³ 3 , about 0.02g / cm 3 ~0.25g / cm 3 , about 0.02g / cm 3 ~0.23g / cm 3 , about 0.02g / cm 3 ~0.20 g / cm³ 3 , about 0.02g / cm 3~0.18g / cm 3 Approximately 0.02 g / cm³ 3 ~0.15g / cm 3 Approximately 0.02 g / cm³ 3 ~0.13g / cm 3 Approximately 0.02 g / cm³ 3 ~0.10g / cm 3 Approximately 0.02 g / cm³ 3 ~0.08g / cm 3 Approximately 0.03 g / cm³ 3 ~0.55g / cm 3 Approximately 0.03 g / cm³ 3 ~0.53g / cm 3 Approximately 0.03 g / cm³ 3 ~0.50g / cm 3 Approximately 0.03 g / cm³ 3 ~0.47g / cm 3 Approximately 0.03 g / cm³ 3 ~0.45g / cm 3 Approximately 0.03 g / cm³ 3 ~0.43g / cm 3 Approximately 0.03 g / cm³ 3 ~0.40g / cm 3 Approximately 0.03 g / cm³ 3 ~0.38g / cm 3 Approximately 0.03 g / cm³ 3 ~0.35g / cm 3 Approximately 0.03 g / cm³ 3 ~0.33g / cm 3 Approximately 0.3 g / cm³ 3 ~0.30g / cm 3 Approximately 0.03 g / cm³ 3 ~0.28g / cm 3 Approximately 0.03 g / cm³ 3 ~0.25g / cm 3 Approximately 0.03 g / cm³ 3 ~0.23g / cm 3 Approximately 0.03 g / cm³ 3 ~0.20g / cm 3 Approximately 0.03 g / cm³ 3 ~0.18g / cm 3 Approximately 0.03 g / cm³ 3 ~0.15g / cm 3 Approximately 0.03 g / cm³ 3 ~0.13g / cm3 Approximately 0.03 g / cm³ 3 ~0.10g / cm 3 Approximately 0.03 g / cm³ 3 ~0.08g / cm 3 Approximately 0.04 g / cm³ 3 ~0.55g / cm 3 Approximately 0.04 g / cm³ 3 ~0.53g / cm 3 Approximately 0.04 g / cm³ 3 ~0.50g / cm 3 Approximately 0.04 g / cm³ 3 ~0.47g / cm 3 Approximately 0.04 g / cm³ 3 ~0.45g / cm 3 Approximately 0.04 g / cm³ 3 ~0.43g / cm 3 Approximately 0.04 g / cm³ 3 ~0.40g / cm 3 Approximately 0.04 g / cm³ 3 ~0.38g / cm 3 Approximately 0.04 g / cm³ 3 ~0.35g / cm 3 Approximately 0.04 g / cm³ 3 ~0.33g / cm 3 Approximately 0.04 g / cm³ 3 ~0.30g / cm 3 Approximately 0.04 g / cm³ 3 ~0.28g / cm 3 Approximately 0.04 g / cm³ 3 ~0.25g / cm 3 Approximately 0.04 g / cm³ 3 ~0.23g / cm 3 Approximately 0.04 g / cm³ 3 ~0.20g / cm 3 Approximately 0.04 g / cm³ 3 ~0.18g / cm 3 Approximately 0.04 g / cm³ 3 ~0.15g / cm 3 Approximately 0.04 g / cm³ 3 ~0.13g / cm 3 Approximately 0.04 g / cm³ 3 ~0.10g / cm 3 Approximately 0.05 g / cm³ 3 ~0.55g / cm 3, about 0.05g / cm 3 ~0.53 g / cm³ 3 , about 0.05g / cm 3 ~0.50g / cm 3 , about 0.05g / cm 3 ~0.47 g / cm³ 3 , about 0.05g / cm 3 ~0.45g / cm 3 , about 0.05g / cm 3 ~0.43g / cm 3 , about 0.05g / cm 3 ~0.40g / cm 3 , about 0.05g / cm 3 ~0.38 g / cm³ 3 , about 0.05g / cm 3 ~0.35g / cm 3 , about 0.05g / cm 3 ~0.33g / cm 3 , about 0.05g / cm 3 ~0.30g / cm 3 , about 0.05g / cm 3 ~0.28 g / cm³ 3 , about 0.05g / cm 3 ~0.25g / cm 3 , about 0.05g / cm 3 ~0.23g / cm 3 , about 0.05g / cm 3 ~0.20 g / cm³ 3 , about 0.05g / cm 3 ~0.18 g / cm³ 3 , about 0.05g / cm 3 ~0.15g / cm 3 , about 0.05g / cm 3 ~0.13g / cm 3 , or approximately 0.05 g / cm³ 3 ~0.10 g / cm³ 3 It has an average tap density of

[0032] As used herein, “specific surface area” is the total surface area of ​​nicrosamide particles per unit mass of nicrosamide, measured by the Brunauer-Emmett-Teller ("BET") isotherm (i.e., BET SSA). As those skilled in the art will understand, the SSA is determined per gram and takes into account both aggregated and unaggregated nicrosamide particles in the composition. The BET specific surface area test procedure is an official method included in both the United States Pharmacopeia and the European Pharmacopoeia. In one embodiment, the nicrosamide particles are at least 3.6 m². 2 It has a specific surface area (SSA) of 1 / g. In another embodiment, the niclosamide particles have at least 5 m 2 It has SSA of / g. In various further embodiments, the nicrosamide particles have at least 4.0m 2 / g, 4.5m 2 / g, 5.0m 2 / g, 5.5m 2 / g, 6m 2 / g, 6.5m 2 / g, 7m 2 / g, 7.5m 2 / g, 8m 2 / g, 8.5m 2 / g, 9m 2 / g, 9.5m 2 / g, 10m 2 / g, 10.5m 2 / g, 11m 2 / g, 11.5m 2 / g, 12m 2 / g, 12.5m 2 / g, 13m 2 / g, or 13.5m 2 It has SSA of / g. In further embodiments, the niclosamide particles are 3.6m 2 / g~about 50m 2 / g, 4m 2 / g~about 50m 2 / g, 4.5m 2 / g~about 50m 2 / g, 5m 2 / g~about 50m 2 / g, 5m 2 / g ~ approx. 45m 2 / g, 5m 2 / g~about 40m 2 / g、5m 2 / g~approximately 35m 2 / g、5m 2 / g~approximately 33m 2 / g、5m 2 / g~approximately 30m 2 / g、5m 2 / g~approximately 28m 2 / g、5m 2 / g~approximately 25m 2 / g、5m 2 / g~approximately 23m 2 / g、5m 2 / g~approximately 20m 2 / g、5m 2 / g~approximately 18m 2 / g、5m 2 / g~approximately 15m 2 / g、6m 2 / g~approximately 50m 2 / g、6m 2 / g~approximately 45m 2 / g、6m 2 / g~approximately 40m 2 / g、6m 2 / g~approximately 35m 2 / g、6m 2 / g~approximately 33m 2 / g、6m 2 / g~approximately 30m 2 / g、6m 2 / g~approximately 28m 2 / g、6m 2 / g~approximately 25m 2 / g、6m 2 / g~approximately 23m 2 / g、6m 2 / g~approximately 20m 2 / g、6m 2 / g~approximately 18m 2 / g、6m 2 / g~approximately 15m 2 / g、7m 2 / g~approximately 50m 2 / g、7m 2 / g~approximately 45m 2 / g、7m 2 / g~approximately 40m 2 / g、7m 2 / g~approximately 35m 2 / g、7m 2 / g~approximately 33m 2 / g、7m2 / g~approximately 30m 2 / g、7m 2 / g~approximately 28m 2 / g、7m 2 / g~approximately 25m 2 / g、7m 2 / g~approximately 23m 2 / g、7m 2 / g~approximately 20m 2 / g、7m 2 / g~approximately 18m 2 / g、7m 2 / g~approximately 15m 2 / g、8m 2 / g~approximately 50m 2 / g、8m 2 / g~approximately 45m 2 / g、8m 2 / g~approximately 40m 2 / g、8m 2 / g~approximately 35m 2 / g、8m 2 / g~approximately 33m 2 / g、8m 2 / g~approximately 30m 2 / g、8m 2 / g~approximately 28m 2 / g、8m 2 / g~approximately 25m 2 / g、8m 2 / g~approximately 23m 2 / g、8m 2 / g~approximately 20m 2 / g、8m 2 / g~approximately 18m 2 / g、8m 2 / g~approximately 15m 2 / g、9m 2 / g~approximately 50m 2 / g、9m 2 / g~approximately 45m 2 / g、9m 2 / g~approximately 40m 2 / g、9m 2 / g~approximately 35m 2 / g、9m 2 / g~approximately 33m 2 / g、9m 2 / g~approximately 30m 2 / g、9m 2 / g~approximately 28m 2 / g、9m 2 / g ~ approx. 25m 2 / g, 9m 2 / g ~ approx. 23m 2 / g, 9m 2 / g~about 20m 2 / g, 9m 2 / g ~ approx. 18m 2 / g, 9m 2 / g ~ approx. 15m 2 / g, 10m 2 / g~about 50m 2 / g, 10m 2 / g ~ approx. 45m 2 / g, 10m 2 / g~about 40m 2 / g, 10m 2 / g ~ approx. 35m 2 / g, 10m 2 / g ~ approx. 33m 2 / g, 10m 2 / g ~ approx. 30m 2 / g, 10m 2 / g ~ approx. 28m 2 / g, 10m 2 / g ~ approx. 25m 2 / g, 10m 2 / g ~ approx. 23m 2 / g, 10m 2 / g~about 20m 2 / g, 10m 2 / g ~ approx. 18m 2 / g, or 10m 2 / g ~ approx. 15m 2 It has an SSA of / g.

[0033] In one embodiment, niclosamide particles have an average particle diameter with a volume distribution of approximately 0.1 microns to approximately 10.5 microns. In another embodiment, niclosamide particles have an average particle diameter with a volume distribution of approximately 0.1 microns to approximately 8 microns. In some embodiments, niclosamide particles have an average particle diameter with a volume distribution of approximately 0.3 μm to approximately 7 μm, or approximately 0.5 μm to approximately 6 μm. The size range of niclosamide particles is such that they are unlikely to be transported from the administration site by systemic circulation or phagocytosis, but benefit from a high specific surface area that provides enhanced drug solubilization and release.

[0034] In one embodiment, the particles are (i) 0.40 g / cm³ 3 Average bulk density less than (without tapping), (ii) 0.55 g / cm³ 3 Less than average tap density, and (iii) at least 3.6m 2 Specific surface area (SSA) of / g It holds.

[0035] In another embodiment, the particles are (i) 0.40 g / cm³ 3 Average bulk density less than (without tapping), (ii) 0.55 g / cm³ 3 Less than average tap density, and (iii) at least 5m 2 Specific surface area (SSA) of / g It holds.

[0036] In various further embodiments, the particles are (i) 0.30 g / cm³ 3 Average bulk density less than 0.30 g / cm³ (without tapping), 3 Less than average tap density, and at least 3.6m 2 / g, 4.0m 2 / g, 4.5m 2 / g, 5m 2 / g, 5.5m 2 / g, 6m 2 / g, 6.5m 2 / g, 7m 2 / g, 7.5m 2 / g, 8m 2 / g, 8.5m 2 / g, 9m 2 / g, 9.5m 2 / g, 10m 2 / g, 10.5m 2 / g, 11m 2 / g, 11.5m 2 / g, 12m 2 / g, 12.5m 2 / g, 13m 2 / g, or 13.5m 2 Specific surface area (SSA) of / g, (ii) 0.10 g / cm³ 3 Average bulk density less than 0.10 g / cm³ (without tapping), 0.10 g / cm³ 3 Less than average tap density, and at least 3.6m 2 / g, 4.0m 2 / g, 4.5m 2 / g, 5m 2 / g, 5.5m 2 / g, 6m 2 / g, 6.5m 2 / g, 7m 2 / g, 7.5m 2 / g, 8m 2 / g, 8.5m 2 / g, 9m 2 / g, 9.5m 2 / g, 10m 2 / g, 10.5m 2 / g, 11m 2 / g, 11.5m 2 / g, 12m 2 / g, 12.5m 2 / g, 13m 2 / g, or 13.5m 2 Specific surface area (SSA) of / g, (iii) 0.02 g / cm³ 3 Average bulk density less than 0.02 g / cm³ (without tapping), 0.02 g / cm³ 3 Less than average tap density, and at least 3.6m 2 / g, 4.0m 2 / g, 4.5m 2 / g, 5m 2 / g, 5.5m 2 / g, 6m 2 / g, 6.5m 2 / g, 7m 2 / g, 7.5m 2 / g, 8m 2 / g, 8.5m 2 / g, 9m 2 / g, 9.5m 2 / g, 10m 2 / g, 10.5m 2 / g, 11m 2 / g, 11.5m 2 / g, 12m 2 / g, 12.5m 2 / g, 13m 2 / g, or 13.5m 2 Specific surface area (SSA) of / g, (iv) 0.30 g / cm³ 3 Average bulk density less than 0.30 g / cm³ (without tapping), 3 Less than average tap density, and 3.6m 2 / g~about 50m 2 / g, 4m 2 / g~about 50m 2 / g, 4.5m 2 / g~about 50m 2 / g, 5m 2 / g~about 50m 2 / g, 5m 2 / g ~ approx. 45m 2 / g, 5m 2 / g~about 40m 2 / g, 5m 2 / g ~ approx. 35m 2 / g, 5m 2 / g ~ approx. 33m 2 / g, 5m 2 / g ~ approx. 30m 2 / g, 5m 2 / g ~ approx. 28m 2 / g, 5m 2 / g ~ approx. 25m 2 / g, 5m 2 / g ~ approx. 23m 2 / g, 5m 2 / g~about 20m 2 / g, 5m 2 / g ~ approx. 18m 2 / g, 5m 2 / g ~ approx. 15m 2 / g, 6m 2 / g~about 50m 2 / g, 6m 2 / g ~ approx. 45m 2 / g, 6m 2 / g~about 40m 2 / g, 6m 2 / g ~ approx. 35m 2 / g, 6m 2 / g ~ approx. 33m 2 / g, 6m 2 / g ~ approx. 30m 2 / g, 6m 2 / g ~ approx. 28m 2 / g, 6m 2 / g ~ approx. 25m2 / g、6m 2 / g~approximately 23m 2 / g、6m 2 / g~approximately 20m 2 / g、6m 2 / g~approximately 18m 2 / g、6m 2 / g~approximately 15m 2 / g、7m 2 / g~approximately 50m 2 / g、7m 2 / g~approximately 45m 2 / g、7m 2 / g~approximately 40m 2 / g、7m 2 / g~approximately 35m 2 / g、7m 2 / g~approximately 33m 2 / g、7m 2 / g~approximately 30m 2 / g、7m 2 / g~approximately 28m 2 / g、7m 2 / g~approximately 25m 2 / g、7m 2 / g~approximately 23m 2 / g、7m 2 / g~approximately 20m 2 / g、7m 2 / g~approximately 18m 2 / g、7m 2 / g~approximately 15m 2 / g、8m 2 / g~approximately 50m 2 / g、8m 2 / g~approximately 45m 2 / g、8m 2 / g~approximately 40m 2 / g、8m 2 / g~approximately 35m 2 / g、8m 2 / g~approximately 33m 2 / g、8m 2 / g~approximately 30m 2 / g、8m 2 / g~approximately 28m 2 / g、8m 2 / g~approximately 25m 2 / g、8m 2 / g~approximately 23m 2 / g、8m 2 / g~approximately 20m 2 / g、8m 2 / g~approximately 18m 2 / g、8m 2 / g~approximately 15m 2 / g、9m 2 / g~approximately 50m 2 / g、9m 2 / g~approximately 45m 2 / g、9m 2 / g~approximately 40m 2 / g、9m 2 / g~approximately 35m 2 / g、9m 2 / g~approximately 33m 2 / g、9m 2 / g~approximately 30m 2 / g、9m 2 / g~approximately 28m 2 / g、9m 2 / g~approximately 25m 2 / g、9m 2 / g~approximately 23m 2 / g、9m 2 / g~approximately 20m 2 / g、9m 2 / g~approximately 18m 2 / g、9m 2 / g~approximately 15m 2 / g, 10m 2 / g~approximately 50m 2 / g, 10m 2 / g~approximately 45m 2 / g, 10m 2 / g~approximately 40m 2 / g, 10m 2 / g~approximately 35m 2 / g, 10m 2 / g~approximately 33m 2 / g, 10m 2 / g~approximately 30m 2 / g, 10m 2 / g~approximately 28m 2 / g, 10m 2 / g~approximately 25m 2 / g, 10m 2 / g~approximately 23m 2 / g, 10m 2 / g~approximately 20m 2 / g, 10m 2 / g~approximately 18m 2 / g、もしくは10m 2 / g~approximately 15m2 Specific surface area (SSA) of / g, (v) 0.10 g / cm³ 3 Average bulk density less than 0.10 g / cm³ (without tapping), 0.10 g / cm³ 3 Less than average tap density, and 3.6m 2 / g~about 50m 2 / g, 4m 2 / g~about 50m 2 / g, 4.5m 2 / g~about 50m 2 / g, 5m 2 / g~about 50m 2 / g, 5m 2 / g ~ approx. 45m 2 / g, 5m 2 / g~about 40m 2 / g, 5m 2 / g ~ approx. 35m 2 / g, 5m 2 / g ~ approx. 33m 2 / g, 5m 2 / g ~ approx. 30m 2 / g, 5m 2 / g ~ approx. 28m 2 / g, 5m 2 / g ~ approx. 25m 2 / g, 5m 2 / g ~ approx. 23m 2 / g, 5m 2 / g~about 20m 2 / g, 5m 2 / g ~ approx. 18m 2 / g, 5m 2 / g ~ approx. 15m 2 / g, 6m 2 / g~about 50m 2 / g, 6m 2 / g ~ approx. 45m 2 / g, 6m 2 / g~about 40m 2 / g, 6m 2 / g ~ approx. 35m 2 / g, 6m 2 / g ~ approx. 33m 2 / g, 6m 2 / g ~ approx. 30m 2 / g, 6m 2 / g ~ approx. 28m 2 / g, 6m 2 / g ~ approx. 25m 2 / g, 6m2 / g~approximately 23m 2 / g、6m 2 / g~approximately 20m 2 / g、6m 2 / g~approximately 18m 2 / g、6m 2 / g~approximately 15m 2 / g、7m 2 / g~approximately 50m 2 / g、7m 2 / g~approximately 45m 2 / g、7m 2 / g~approximately 40m 2 / g、7m 2 / g~approximately 35m 2 / g、7m 2 / g~approximately 33m 2 / g、7m 2 / g~approximately 30m 2 / g、7m 2 / g~approximately 28m 2 / g、7m 2 / g~approximately 25m 2 / g、7m 2 / g~approximately 23m 2 / g、7m 2 / g~approximately 20m 2 / g、7m 2 / g~approximately 18m 2 / g、7m 2 / g~approximately 15m 2 / g、8m 2 / g~approximately 50m 2 / g、8m 2 / g~approximately 45m 2 / g、8m 2 / g~approximately 40m 2 / g、8m 2 / g~approximately 35m 2 / g、8m 2 / g~approximately 33m 2 / g、8m 2 / g~approximately 30m 2 / g、8m 2 / g~approximately 28m 2 / g、8m 2 / g~approximately 25m 2 / g、8m 2 / g~approximately 23m 2 / g、8m 2 / g~approximately 20m 2 / g、8m 2 / g~approximately 18m 2 / g、8m 2 / g~approximately 15m 2 / g、9m 2 / g~approximately 50m 2 / g、9m 2 / g~approximately 45m 2 / g、9m 2 / g~approximately 40m 2 / g、9m 2 / g~approximately 35m 2 / g、9m 2 / g~approximately 33m 2 / g、9m 2 / g~approximately 30m 2 / g、9m 2 / g~approximately 28m 2 / g、9m 2 / g~approximately 25m 2 / g、9m 2 / g~approximately 23m 2 / g、9m 2 / g~approximately 20m 2 / g、9m 2 / g~approximately 18m 2 / g、9m 2 / g~approximately 15m 2 / g, 10m 2 / g~approximately 50m 2 / g, 10m 2 / g~approximately 45m 2 / g, 10m 2 / g~approximately 40m 2 / g, 10m 2 / g~approximately 35m 2 / g, 10m 2 / g~approximately 33m 2 / g, 10m 2 / g~approximately 30m 2 / g, 10m 2 / g~approximately 28m 2 / g, 10m 2 / g~approximately 25m 2 / g, 10m 2 / g~approximately 23m 2 / g, 10m 2 / g~approximately 20m 2 / g, 10m 2 / g~approximately 18m 2 / g、もしくは10m 2 / g~approximately 15m 2The specific surface area (SSA) per g, or (vi) less than 0.05 g / cm 3 average bulk density (without tapping), less than 0.05 g / cm 3 average tapped density, and 3.6 m 2 / g to about 50 m 2 / g, 4 m 2 / g to about 50 m 2 / g, 4.5 m 2 / g to about 50 m 2 / g, 5 m 2 / g to about 50 m 2 / g, 5 m 2 / g to about 45 m 2 / g, 5 m 2 / g to about 40 m 2 / g, 5 m 2 / g to about 35 m 2 / g, 5 m 2 / g to about 33 m 2 / g, 5 m 2 / g to about 30 m 2 / g, 5 m 2 / g to about 28 m 2 / g, 5 m 2 / g to about 25 m 2 / g, 5 m 2 / g to about 23 m 2 / g, 5 m 2 / g to about 20 m 2 / g, 5 m 2 / g to about 18 m 2 / g, 5 m 2 / g to about 15 m 2 / g, 6 m 2 / g to about 50 m 2 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ / g~approximately 23m 2 / g、6m 2 / g~approximately 20m 2 / g、6m 2 / g~approximately 18m 2 / g、6m 2 / g~approximately 15m 2 / g、7m 2 / g~approximately 50m 2 / g、7m 2 / g~approximately 45m 2 / g、7m 2 / g~approximately 40m 2 / g、7m 2 / g~approximately 35m 2 / g、7m 2 / g~approximately 33m 2 / g、7m 2 / g~approximately 30m 2 / g、7m 2 / g~approximately 28m 2 / g、7m 2 / g~approximately 25m 2 / g、7m 2 / g~approximately 23m 2 / g、7m 2 / g~approximately 20m 2 / g、7m 2 / g~approximately 18m 2 / g、7m 2 / g~approximately 15m 2 / g、8m 2 / g~approximately 50m 2 / g、8m 2 / g~approximately 45m 2 / g、8m 2 / g~approximately 40m 2 / g、8m 2 / g~approximately 35m 2 / g、8m 2 / g~approximately 33m 2 / g、8m 2 / g~approximately 30m 2 / g、8m 2 / g~approximately 28m 2 / g、8m 2 / g~approximately 25m 2 / g、8m 2 / g~approximately 23m 2 / g、8m 2 / g~approximately 20m 2 / g、8m 2 / g~approximately 18m2 / g、8m 2 / g~approximately 15m 2 / g、9m 2 / g~approximately 50m 2 / g、9m 2 / g~approximately 45m 2 / g、9m 2 / g~approximately 40m 2 / g、9m 2 / g~approximately 35m 2 / g、9m 2 / g~approximately 33m 2 / g、9m 2 / g~approximately 30m 2 / g、9m 2 / g~approximately 28m 2 / g、9m 2 / g~approximately 25m 2 / g、9m 2 / g~approximately 23m 2 / g、9m 2 / g~approximately 20m 2 / g、9m 2 / g~approximately 18m 2 / g、9m 2 / g~approximately 15m 2 / g, 10m 2 / g~approximately 50m 2 / g, 10m 2 / g~approximately 45m 2 / g, 10m 2 / g~approximately 40m 2 / g, 10m 2 / g~approximately 35m 2 / g, 10m 2 / g~approximately 33m 2 / g, 10m 2 / g~approximately 30m 2 / g, 10m 2 / g~approximately 28m 2 / g, 10m 2 / g~approximately 25m 2 / g, 10m 2 / g~approximately 23m 2 / g, 10m 2 / g~approximately 20m 2 / g, 10m 2 / g~approximately 18m 2 / g、もしくは10m 2 / g~approximately 15m 2 / g specific surface area (SSA) It holds.

[0037] In any of these various embodiments, the niclosamide particles are, for example, at least 5 × 10¹⁶ particles per niclosamide particle. -15 Grams of niclosamide or its pharmaceutically acceptable salts, hydrates, solvates, or cocrystals, or approximately 1 × 10⁻¹⁶ particles per niclosamide particle. -8 ~Approx. 5×10 -15 It may contain grams of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0038] In one embodiment, the particles are uncoated. In further embodiments, the composition comprises a suspension further comprising a pharmaceutically acceptable aqueous carrier. The suspension of the present disclosure comprises nicrosamide particles and a liquid carrier. The liquid carrier may be aqueous. The nicrosamide particles do not contain added excipients, but the liquid carrier of the suspension may contain water and, optionally, one or more excipients selected from the group consisting of buffers, osmotic regulators, preservatives, lubricants, viscosity modifiers, osmotic agents, surfactants, antioxidants, alkalizing agents, acidifying agents, defoaming agents, and colorants. For example, the suspension may comprise nicrosamide particles, water, a buffer, and a salt. This may optionally further comprise a surfactant. In some embodiments, the suspension comprises or comprises water, nicrosamide particles suspended in water, and a buffer. The suspension may further comprise an osmotic salt.

[0039] In one embodiment, the composition further comprises one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol, and hydroxypropylmethylcellulose.

[0040] The suspension may contain one or more surfactants. Suitable surfactants include, but are not limited to, polysorbates, lauryl sulfates, acetylated monoglycerides, diacetylated monoglycerides, and poloxamers.

[0041] The suspension may contain one or more osmoregulators. Suitable osmoregulators include, but are not limited to, one or more inorganic salts, electrolytes, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium sulfate, potassium sulfate, sodium bicarbonate and potassium bicarbonate, as well as alkaline earth metal inorganic salts, such as calcium salts and magnesium salts, mannitol, glucose, glycerin, propylene glycol, and mixtures thereof.

[0042] The suspension may contain one or more buffers. Suitable buffers include, but are not limited to, dibasic sodium phosphate, monobasic sodium phosphate, citric acid, sodium citrate hydrochloride, sodium hydroxide, tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)iminotris-(hydroxymethyl)methane, and sodium bicarbonate, and others known to those skilled in the art. Buffers are commonly used to adjust the pH to a range desirable for intraperitoneal use. Typically, a pH of approximately 5–9, 5–8, 6–7.4, 6.5–7.5, or 6.9–7.4 is preferred.

[0043] The suspension may contain one or more lubricants. Lubricants are agents that form an analgesic film on mucous membranes, such as the membrane covering the peritoneum and the organs within it. Lubricants can relieve minor pain and inflammation and are often called mucosal protectants. Suitable lubricants include cellulose derivatives ranging from about 0.2% to about 2.5%, such as sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and methylcellulose; about 0.01% gelatin; about 0.05% to about 1% glycerin; about 0.05% to about 1% polyols, including polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, and propylene glycol; about 0.1% to about 4% polyvinyl alcohol; about 0.1% to about 2% povidone; and about 0.1% dextran 70 when used with other polymer lubricants described herein.

[0044] The suspension may contain one or more alkalizing agents for adjusting the pH. As used herein, the term “alkalizing agent” is intended to mean a compound used to provide an alkaline medium. Examples of such compounds include, but are not limited to, ammonia solution, ammonium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, and others known to those skilled in the art.

[0045] The suspension may contain one or more acidifying agents for adjusting the pH. As used herein, the term “acidifying agent” is intended to mean a compound used to provide an acidic medium. Examples of such compounds include, but are not limited to, acetic acid, amino acids, citric acid, nitric acid, fumaric acid, and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, and nitric acid, and others known to those skilled in the art.

[0046] The suspension may contain one or more defoaming agents. As used herein, the term “defoaming agent” is intended to mean one or more compounds that prevent or reduce the amount of foaming that occurs on the surface of the filling composition. Suitable defoaming agents include, but are not limited to, dimethicone, SIMETHICONE®, octoxynol, and others known to those skilled in the art.

[0047] The suspension may contain one or more viscosity modifiers that increase or decrease the viscosity of the suspension. Suitable viscosity modifiers include methylcellulose, hydroxypropylmethylcellulose, mannitol, and polyvinylpyrrolidone.

[0048] The suspension may contain one or more osmotic agents, such as those used in peritoneal dialysis. Suitable osmotic agents include icodextrin (glucose polymer), sodium chloride, potassium chloride, and salts, which are also used as buffers.

[0049] As used herein, “pharmaceutically acceptable salts, hydrates, or solvates” of niclosamide are, within the bounds of sound medical judgment, suitable for use in contact with patient tissue without excessive toxicity, irritation, or allergic reactions, commensurate with a reasonable benefit-risk ratio, effective for their intended use, and, if possible, in the zwitterionic form of niclosamide. The term “salt” refers to relatively non-toxic inorganic and organic acid addition salts of niclosamide. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. These may include, but are not limited to, cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. (See, for example, Berge SM et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.) In one embodiment, a pharmaceutically acceptable salt of niclosamide includes niclosamide malate.

[0050] In one embodiment, the composition comprises a dosage form of suspended niclosamide (i.e., a pharmaceutically acceptable carrier and any other components) in a dose deemed suitable for the intended use by the attending physician. Any suitable dosage form may be used, and in various non-limiting embodiments, the dosage form is sufficient to provide approximately 0.01 mg / kg body weight / day to approximately 50 mg / kg body weight / day. In various further embodiments, the dosage forms are sufficient to provide approximately 0.01 mg / kg body weight / day to approximately 45 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 40 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 35 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 30 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 25 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 20 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 15 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 10 mg / kg body weight / day, approximately 0.01 mg / kg body weight / day to approximately 5 mg / kg body weight / day, or approximately 0.01 mg / kg body weight / day to approximately 1 mg / kg body weight / day. The suspension may be administered as is, or it may be diluted before administration with a diluent, such as an injectable saline solution optionally containing a buffer and one or more other excipients. For example, the volume ratio of suspension to diluent may be in the range of 1:1 to 1:100 (v / v), or other preferred ratios.

[0051] In another embodiment, niclosamide particles or suspensions thereof are formulated for administration via the pulmonary, intramuscular, subcutaneous, or intraperitoneal route. In one embodiment in which niclosamide particles or suspensions thereof are formulated for administration via the pulmonary route, the niclosamide particles may be formulated as a dry powder. In another embodiment in which niclosamide particles or suspensions thereof are formulated for administration via the pulmonary route, the niclosamide particles may be formulated as an aerosol (i.e., droplets of a stable dispersion or suspension of niclosamide particles in a gaseous medium). Niclosamide particles delivered by aerosol may be deposited in the airways by gravity settling, inertial impaction, and / or diffusion. Any suitable device for generating the aerosol may be used, including but not limited to pressurized metered-dose inhalers (pMDIs), nebulizers, dry powder inhalers (DPIs), and soft mist inhalers.

[0052] In one embodiment in which niclosamide particles or a suspension thereof are formulated for administration via a pulmonary route, the niclosamide particles or a suspension thereof may be suspended in a suitable propellant system (including, but not limited to, hydrofluoroalkanes (HFAs)) containing at least one liquefied gas in a pressurized vessel sealed with a throttle valve. The operation of the valve results in the delivery of a quantitative aerosol spray of the niclosamide particles or a suspension thereof.

[0053] In another aspect, the Disclosure may include, but is not limited to, parasitic infections, viral infections (coronaviruses (SARS, MERS, SARS-CoV-2), influenza, Ebola virus, Lassa virus, Zika virus, dengue virus), West Nile and Japanese encephalitis viruses, Chikungunya virus, Sindbis virus, Ross River virus, Semryki Forest virus), yellow fever virus, rabies virus, herpes simplex virus, hepatitis C virus, rhinovirus, and coxsackievirus, bacterial infections (drug-resistant Mycobacterium tuberculosis, Mycobacterium abscesses, methicillin-resistant Staphylococcus aureus and biofilms, Pseudomonas aeruginosa and biofilms, vancomycin-resistant enterococci, multidrug-resistant Gram-negative bacteria, and Bacillus anthrax). The present invention provides a method for treating or limiting the manifestation of disorders, including, but not limited to, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, pulmonary and renal fibrosis, pulmonary hypertension, idiopathic pulmonary arterial hypertension (IPAH), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), eosinophilic esophagitis, stroke, ischemia / reperfusion injury, pain, psoriasis and atopic dermatitis, rheumatoid arthritis, graft-versus-host disease and systemic sclerosis, secretory diarrhea, diabetes mellitus, renal disease (including ADPKD), endometriosis, and suppression of uterine contractions in spontaneous early labor, comprising administering to a subject in need an amount of a composition or suspension of any embodiment or combination of embodiments herein that is effective in treating or limiting the manifestation of the disorder.

[0054] Niclosamide possesses general anti-inflammatory activity and is therefore useful in treating a wide variety of inflammatory disorders by inhibiting several key pathways that contribute to inflammation, including Akt, MEK / ERK, mTORC1, STAT3, NF-κB, Wnt / β-catenin, and Notch signaling pathways, as discussed in the scientific literature (see attached bibliography). Niclosamide has also been identified as a potent inhibitor of the calcium-activated chloride channel TMEM16A (anoctamin 1, Ano1), which is expressed in epithelial cells, smooth muscle cells, and sensory nerves and affects their physiology (Miner et al., 2019). The activity of niclosamide in inhibiting this target may explain its efficacy in treating many of the aforementioned disorders, and this disclosure provides a method for treating disorders resulting from hyperactivation of TMEM16A.

[0055] However, niclosamide is poorly absorbed from the gastrointestinal tract and is substantially toxic when administered intravenously (Andrews et al., 1982; Schweizer et al., 2018). This disclosure provides unique low bulk density, high surface area niclosamide particles, either alone or in cocrystal form, that can be administered via, for example, transpulmonary, intramuscular, subcutaneous, and intraperitoneal routes, and are considered suitable for treating a given disease, as they offer significantly improved solubility, significantly enhanced residence time, and much higher concentrations at the target body site. Thus, this disclosure provides niclosamide particles and suspensions thereof with significantly improved therapeutic properties compared to previous niclosamide therapies. Furthermore, in some embodiments, the methods of this disclosure can reduce the frequency of niclosamide administration and side effects.

[0056] The particles may be administered via any preferred route of administration deemed optimal by the attending physician, taking into account all factors of the given subject, including but not limited to transpulmonary, intramuscular, subcutaneous, or intraperitoneal routes.

[0057] The subjects include, but are not limited to, humans, primates, dogs, cats, horses, and cattle, and may be any suitable subject having a tumor. In one embodiment, the subject is a human subject.

[0058] As used herein, “to treat” or “to treat” means to achieve one or more of the following: (a) reducing the severity of a disorder; (b) limiting or preventing the occurrence of symptoms specific to the treated disorder(s); (c) preventing the worsening of symptoms specific to the treated disorder(s); (d) limiting or preventing recurrence of the disorder(s) in a patient who previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in a patient who previously exhibited symptoms of the disorder(s).

[0059] As used herein, “limiting the manifestation” of a disorder or “limiting” a disorder means a precautionary use to prevent or reduce the occurrence of a disorder, such as a precautionary measure to avoid infection with a virus (e.g., vaccination).

[0060] The effective amount for these uses depends on factors including, but are not limited to, the properties of the composition (such as the amount of niclosamide in the particles), the route of administration, the stage and severity of the disorder, the subject's body weight and overall health, and the judgment of the prescribing physician. It will be understood that the amount of the suspension composition of this disclosure actually administered will be determined by the physician taking into account the relevant circumstances described above. In one non-limiting embodiment, the effective amount is an amount that provides 0.01 mg / kg body weight / day to about 50 mg / kg body weight / day.

[0061] In one embodiment, the disorder includes a viral infection, which includes a betacoronavirus infection selected from the group consisting of infections caused by human coronavirus HKU1, SARS-CoV (including but not limited to SARS-CoV-2), and MERS-CoV. In a particular embodiment, the betacoronavirus infection includes SARS-CoV-2 infection. In one embodiment, the method treats the viral infection. In another embodiment, the method limits the manifestation of the viral infection. In other particular embodiments, the disorder includes asthma, COPD, and / or cystic fibrosis.

[0062] In one particular embodiment, the composition is administered via a transpulmonary route. In one particular embodiment of the present invention, transpulmonary administration includes inhalation of a single dose of niclosamide particles, for example, by nasal inhalation, oral inhalation, or both. Niclosamide particles may be administered in two or more separate doses.

[0063] In this embodiment, niclosamide particles may be formulated as a dry powder from a dry powder inhaler (alone, as a mixture, or in a dry blend with, for example, lactose), or as an aerosol spray (i.e., droplets of a stable dispersion or suspension of niclosamide particles in a gaseous medium). Niclosamide particles delivered by aerosol may be deposited in the airways by gravity settling, inertial impaction, and / or diffusion. Any suitable device for generating the aerosol may be used, including but not limited to pressurized metered-dose inhalers (pMDIs), nebulizers, dry powder inhalers (DPIs), and soft mist inhalers.

[0064] In one particular embodiment, the method involves inhalation of aerosolized niclosamide particles via spraying. A nebulizer typically uses compressed air or ultrasonic power to produce inhalable aerosol droplets of niclosamide particles or a suspension thereof. In this embodiment, spraying results in transpulmonary delivery of aerosol droplets of niclosamide particles or a suspension thereof to a subject.

[0065] In another embodiment, the method comprises inhalation of aerosolized niclosamide particles via a pMDI, wherein the niclosamide particles or a suspension thereof are suspended in a suitable propellant system (including, but not limited to, hydrofluoroalkanes (HFAs)) containing at least one liquefied gas in a pressurized vessel sealed with a throttle valve. The operation of the valve results in the delivery of a quantitative aerosol spray of the niclosamide particles or a suspension thereof.

[0066] In such embodiments, particles or their suspension are aerosolized for administration, and the aerosolization results in aerosol droplets having an aerodynamic median particle diameter (MMAD) of approximately 0.5 μm to 6 μm, or approximately 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 2 μm to 5 μm, 2 μm to 4 μm, or 2 μm to 3 μm.

[0067] In all embodiments, the composition may be administered once or multiple times, as deemed appropriate by the attending physician or healthcare professional, taking into account all factors, particularly the disorder being treated.

[0068] In another aspect, the present disclosure relates to a method for producing compound particles, (a) (i) Introducing a solution comprising at least one solvent selected from the group consisting of acetone, ethanol, methanol, dichloromethane, hexafluoroisopropyl alcohol, trifluoroethanol, dimethyl sulfoxide, tetrahydrofuran (THF), dimethylformamide, or a combination thereof, and at least one solute comprising niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, either alone or in combination with urea, nicotinamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, into the nozzle inlet; (ii) Introducing a compressible fluid into the inlet of a vessel defining a pressurizable chamber; (b) A step of passing a solution through a nozzle opening into a pressurizable chamber to generate an output stream of spray droplets, wherein the nozzle opening is located 2 mm to 20 mm from a sound wave energy source located in the output stream, the sound wave energy source generates sound wave energy with an amplitude of 10% to 100% during passage, and the nozzle opening has a diameter of 20 μm to 125 μm. (c) The step of bringing the spray droplets into contact with a compressed fluid to deplete the solvent from the spray droplets and generate nicrosamide compound particles according to any embodiment or combination of embodiments disclosed herein. Includes, Steps (a), (b), and (c) are performed under the supercritical temperature and supercritical pressure of the compressible fluid. Provide a method.

[0069] The method utilizes a sonic energy source located directly within the output stream of a solute dissolved in a solvent. Any suitable sonic energy source suitable for the method of this disclosure may be used, including but not limited to sonic horns, sonic probes, or sonic plates. In various embodiments, the nozzle opening is approximately 2mm to 20mm, 2mm to 18mm, 2mm to 16mm, 2mm to 14mm, 2mm to 12mm, 2mm to 10mm, 2mm to 8mm, 2mm to 6mm, 2mm to 4mm, 4mm to 20mm, 4mm to 18mm, 4mm to 16mm, 4mm to 14mm, 4mm to 12mm, 4mm to 10mm, 4mm to 8mm, 4mm to 6mm, 6mm to 20mm, 6mm to 18mm, 6mm to 16mm, 6mm to 14mm, 6mm to 12mm, 6mm to 18mm, 6mm to 16mm, 6mm to 14mm, 6mm to 12mm, 6mm to 18mm The nozzles are located at approximately 10mm, 6mm to 8mm, 8mm to 20mm, 8mm to 18mm, 8mm to 16mm, 8mm to 14mm, 8mm to 12mm, 8mm to 10mm, 10mm to 20mm, 10mm to 18mm, 10mm to 16mm, 10mm to 14mm, 10mm to 12mm, 12mm to 20mm, 12mm to 18mm, 12mm to 16mm, 12mm to 14mm, 14mm to 20mm, 14mm to 18mm, 14mm to 16mm, 16mm to 20mm, 16mm to 18mm, and 18mm to 20mm. In further embodiments, nozzle assemblies of any embodiment of WO2016 / 197091 may be used.

[0070] Any suitable source of sonic energy suitable for the method of the present disclosure may be used, including but not limited to sonic horns, sonic probes, or sonic plates. In various further embodiments, the sonic energy source generates sonic energy having an amplitude of about 10% to about 100% of the total power that can be generated using the sonic energy source. Taking into account the teachings herein, those skilled in the art can determine a suitable sonic energy source having a specific total power output to be used. In one embodiment, the sonic energy source has a total power output of about 500 to about 900 watts, and in various further embodiments, about 600 to about 800 watts, about 650 to about 750 watts, or about 700 watts.

[0071] In various further embodiments, the sound wave energy source is used to generate approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, approximately 90% to approximately 100%, and approximately 1% of the total power that can be generated using the sound wave energy source. 0%~approx. 90%, approx. 20%~approx. 90%, approx. 30%~approx. 90%, approx. 40%~approx. 90%, approx. 50%~approx. 90%, approx. 60%~approx. 90%, approx. 70%~approx. 90%, approx. 80%~approx. 90%, approx. 10%~approx. 80%, approx. 20%~approx. 80%, approx. 30%~approx. 80%, approx. 40%~approx. 80%, approx. 50%~approx. 80%, approx. 60%~approx. 80%, approx. 70%~ Approximately 80%, approximately 10% to approximately 70%, approximately 20% to approximately 70%, approximately 30% to approximately 70%, approximately 40% to approximately 70%, approximately 50% to approximately 70%, approximately 60% to approximately 70%, approximately 10% to approximately 60%, approximately 20% to approximately 60%, approximately 30% to approximately 60%, approximately 40% to approximately 60%, approximately 50% to approximately 60%, approximately 10% to approximately 50%, approximately 20% to approximately 50%, approximately 30% to approximately 50% The system generates sound wave energy having power outputs of approximately 10%, 40%–50%, 10%–40%, 20%–40%, 30%–40%, 10%–30%, 20%–30%, 10%–20%, or approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or approximately 100%. Taking into account the teachings herein, those skilled in the art can determine appropriate frequencies to be used in the sound wave energy source. In one embodiment, frequencies of approximately 18–22 kHz are used on the sound wave energy source. In various other embodiments, frequencies of approximately 19–21 kHz, approximately 19.5–20.5 kHz, or approximately 20 kHz are used on the sound wave energy source.

[0072] In various further embodiments, the nozzle opening is approximately 20 μm to 125 μm, approximately 20 μm to 115 μm, approximately 20 μm to 100 μm, approximately 20 μm to 90 μm, approximately 20 μm to 80 μm, approximately 20 μm to 70 μm, approximately 20 μm to 60 μm, approximately 20 μm to 50 μm, approximately 20 μm to 40 μm, approximately 20 μm to 30 μm, approximately 30 μm to 125 μm, approximately 30 μm to 115 μm, approximately 30 μm to 100 μm, approximately 30 μm to 90 μm, Approximately 30μm to approximately 80μm, approximately 30μm to approximately 70μm, approximately 30μm to approximately 60μm, approximately 30μm to approximately 50μm, approximately 30μm to approximately 40μm, approximately 40μm to approximately 125μm, approximately 40μm to approximately 115μm, approximately 40μm to approximately 100μ m, approximately 40 μm to approximately 90 μm, approximately 40 μm to approximately 80 μm, approximately 40 μm to approximately 70 μm, approximately 40 μm to approximately 60 μm, approximately 40 μm to approximately 50 μm, approximately 50 μm to approximately 125 μm, approximately 50 μm to approximately 115 μm, approximately 50 μm to approximately 100 μm, approximately 50 μm to approximately 90 μm, approximately 50 μm to approximately 80 μm, approximately 50 μm to approximately 70 μm, approximately 50 μm to approximately 60 μm, approximately 60 μm to approximately 125 μm, approximately 60 μm to approximately 115 μm, approximately 60 μm to approximately 100 μm, approximately 60 μm to approximately 90μm, about 60μm to about 80μm, about 60μm to about 70μm, about 70μm to about 125μm, about 70μm to about 115μm, about 70μm to about 100μm, about 70μm to about 90μm, about 70μm to about 80μm, about 80μm The nozzles have diameters of approximately 125 μm, 80 μm to 115 μm, 80 μm to 100 μm, 80 μm to 90 μm, 90 μm to 125 μm, 90 μm to 115 μm, 90 μm to 100 μm, 100 μm to 125 μm, 100 μm to 115 μm, 115 μm to 125 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 115 μm, or approximately 120 μm. The nozzles are inert to both the solvent and the compressible fluid used in the method.

[0073] The solvent includes acetone, ethanol, methanol, dichloromethane, hexafluoroisopropyl alcohol, trifluoroethanol, dimethyl sulfoxide, dimethylformamide, or a combination thereof. The solvent should constitute at least about 80%, 85%, or 90% by weight of the total solution. In one embodiment, the solvent includes acetone, ethanol, methanol, or a combination thereof.

[0074] A compressible fluid can form a supercritical fluid under the conditions of use, and the solute that forms the particles is sparingly soluble or insoluble in the compressible fluid. As is known to those skilled in the art, a supercritical fluid is any substance at a temperature and pressure above its critical point where there are no separate liquid and gas phases. Steps (a), (b), and (c) of the method of the present disclosure are carried out under the supercritical temperature and supercritical pressure of the compressible fluid, and therefore the compressible fluid exists as a supercritical fluid during these processing steps.

[0075] The compressible fluid can function as a solvent for the particles and can be used to remove unwanted components from the particles. Any suitable compressible fluid can be used in the methods of the present disclosure, and exemplary such compressible fluids are disclosed in U.S. Patents 5,833,891 and 5,874,029. In one non-limiting embodiment, suitable supercritical fluid-forming compressible fluids and / or poor solvents may include carbon dioxide, ethane, propane, butane, isobutane, nitrous oxide, xenon, sulfur hexafluoride, and trifluoromethane. The poor solvent described in step (d) for further solvent depletion is a compressible fluid as defined above and may be the same as or different from the compressible fluid used in steps (a-c). In one embodiment, the poor solvent used in step (d) is the same as the compressible fluid used in steps (a-c). In a preferred embodiment, both the compressible fluid and the poor solvent are supercritical carbon dioxide.

[0076] In all cases, the compressible fluid and the poor solvent should be substantially miscible with the solvent, while the precipitated compound should be substantially insoluble in the compressible fluid; that is, the compound should be soluble in the compressible fluid or poor solvent at a concentration of less than about 5% by weight, preferably essentially completely insoluble, under conditions of contact with the selected solvent / compressible fluid.

[0077] The supercritical conditions used in the methods of this disclosure are typically in the range of 1X to about 1.4X or 1X to about 1.2X of the critical temperature of the supercritical fluid and 1X to about 7X or 1X to about 2X of the supercritical pressure of the compressible fluid.

[0078] Determining the critical temperature and critical pressure of a given compressible fluid or poor solvent is well within the realm of the art. In one embodiment, both the compressible fluid and the poor solvent are supercritical carbon dioxide, with a critical temperature of at least 31.1°C and a maximum of about 60°C, and a critical pressure of at least 1071 psi and a maximum of about 1800 psi. In another embodiment, both the compressible fluid and the poor solvent are supercritical carbon dioxide, with a critical temperature of at least 35°C and a maximum of about 55°C, and a critical pressure of at least 1070 psi and a maximum of about 1500 psi. Those skilled in the art will understand that specific critical temperatures and critical pressures may differ at different steps in the process.

[0079] Any suitable pressurizable chamber may be used, including but not limited to those disclosed in WO2016 / 197091 or U.S. Patents 5,833,891 and 5,874,029. Similarly, the steps of contacting spray droplets with a compressed fluid to deplete the solvent from the droplets, and contacting the droplets with a poor solvent to further deplete the solvent from the droplets, for generating particles of the compound, may be carried out under any suitable conditions, including but not limited to those disclosed in U.S. Patents 5,833,891 and 5,874,029.

[0080] The flow rate can be adjusted to be as high as possible to optimize output, but below the pressure limit of the equipment including the nozzle opening. In one embodiment, the flow rate of the solution through the nozzle ranges from about 0.5 mL / min to about 30 mL / min. In various further embodiments, the flow rates are approximately 0.5 mL / min to approximately 25 mL / min, 0.5 mL / min to approximately 20 mL / min, 0.5 mL / min to approximately 15 mL / min, 0.5 mL / min to approximately 10 mL / min, 0.5 mL / min to approximately 4 mL / min, approximately 1 mL / min to approximately 30 mL / min, approximately 1 mL / min to approximately 25 mL / min, approximately 1 mL / min to approximately 20 mL / min, 1 mL / min to approximately 15 mL / min, approximately 1 mL / min to approximately 10 mL / min, approximately 2 mL / min to approximately 30 mL / min, approximately 2 mL / min to approximately 25 mL / min, approximately 2 mL / min to approximately 20 mL / min, approximately 2 mL / min to approximately 15 mL / min, or approximately 2 mL / min to approximately 10 mL / min. The drug solution to which the flow rate is imparted may be of any preferred concentration, such as approximately 1 mg / ml to approximately 80 mg / ml.

[0081] In one embodiment, the method further includes the steps of receiving a plurality of particles passing through the outlet of a pressurizable chamber and collecting the plurality of particles into a collection device such as that disclosed in WO2016 / 197091.

[0082] In another aspect, the Disclosure provides compound particles prepared by any embodiment or combination of embodiments of the Disclosure.

[0083] Examples method Niclosamide In one specific exemplary method, a 35 mg / ml solution of niclosamide was dissolved in a 1:1 acetone:ethanol (v:v) solution or other solvent. A nozzle and an ultrasonic probe were placed in a pressurizable chamber approximately 9 mm apart. A sintered stainless steel mesh filter with pores of approximately 20 nm was attached to the pressurizable chamber to collect the precipitated niclosamide nanoparticles. Supercritical carbon dioxide was introduced into the pressurizable chamber of the manufacturing equipment at 35.0–42.6°C and at a flow rate of 4–12 kg / hour to 1085–1320 psi. The ultrasonic probe was adjusted to an amplitude of 20–80% of its maximum output at a frequency of 20 kHz. The 1:1 acetone:ethanol solution containing niclosamide was pumped through the nozzle at a flow rate of 2 mL / min for approximately 10 minutes. The precipitated niclosamide particles were then collected from the supercritical carbon dioxide as the mixture was pumped through the stainless steel mesh filter. A filter containing niclosamide nanoparticles was opened, and the resulting product was collected from the filter.

[0084] Urea: Diclosamide coprecipitation In another specific exemplary method, a 1:1, 2:1, or 3:2 urea:niclosamide (mol:mol) solution at 20–25 mg / ml was dissolved in a 1:1 acetone:ethanol (v:v) solution or other solvent. The nozzle and ultrasonic probe were placed in a pressurizable chamber approximately 9 mm apart. A sintered stainless steel mesh filter with pores of approximately 20 nm was attached to the pressurizable chamber to collect the precipitated niclosamide nanoparticles. Supercritical carbon dioxide was introduced into the pressurizable chamber of the manufacturing equipment and heated to 1090–1311 psi at 35.5–42.3°C and a flow rate of 4–12 kg / hour. The ultrasonic probe was adjusted to an amplitude of 20–80% of the maximum output at a frequency of 20 kHz. The 1:1 acetone:ethanol solution containing urea:niclosamide was pumped through the nozzle at a flow rate of 2 mL / min for approximately 15 minutes. Next, the precipitated urea:niclosamide particles were collected from supercritical carbon dioxide as the mixture was pumped through a stainless steel mesh filter. The filter containing the urea:niclosamide nanoparticles was opened, and the resulting product was collected from the filter.

[0085] Nicotinamide:niclosamide coprecipitation In another specific exemplary method, a 4 mg / ml 1:1 nicotinamide:niclosamide (mol:mol) solution was dissolved in a 1:1 acetone:ethanol (v:v) solution or other solvent. The nozzle and ultrasonic probe were placed in a pressurizable chamber approximately 9 mm apart. A sintered stainless steel mesh filter with pores of approximately 20 nm was attached to the pressurizable chamber to collect the precipitated nicotinamide:niclosamide nanoparticles. Supercritical carbon dioxide was introduced into the pressurizable chamber of the manufacturing equipment and pressurized to 1190-1210 psi at 37.2-37.8°C and a flow rate of 4-12 kg / hour. The ultrasonic probe was adjusted to an amplitude of 60% of its maximum output at a frequency of 20 kHz. The 1:1 acetone:ethanol solution containing nicotinamide:niclosamide was pumped through the nozzle at a flow rate of 2 mL / min for approximately 100 minutes. Next, the precipitated nicotinamide:niclosamide particles were collected from supercritical carbon dioxide as the mixture was pumped through a stainless steel mesh filter. The filter containing the nicotinamide:niclosamide nanoparticles was opened, and the resulting product was collected from the filter.

[0086] Niclosamide ethanolamine In another specific exemplary method, a 12.5 mg / ml solution of niclosamide ethanolamine was dissolved in a 1:1 acetone:ethanol (v:v) solution. A nozzle and an ultrasonic probe were placed in a pressurizable chamber approximately 9 mm apart. A sintered stainless steel mesh filter with pores of approximately 20 nm was attached to the pressurizable chamber to collect the precipitated niclosamide nanoparticles. Supercritical carbon dioxide was introduced into the pressurizable chamber of the manufacturing equipment and heated to 1195–1210 psi at 37.5–38.2°C and a flow rate of 4–12 kg / hour. The ultrasonic probe was adjusted to an amplitude of 60% of its maximum output at a frequency of 20 kHz. The 1:1 acetone:ethanol solution containing niclosamide ethanolamine was pumped through the nozzle at a flow rate of 2 mL / min for approximately 50 minutes. The precipitated niclosamide ethanolamine particles were then collected from the supercritical carbon dioxide as the mixture was pumped through the stainless steel mesh filter. A filter containing nanoparticles of nicrosamide ethanolamine was opened, and the resulting product was collected from the filter.

[0087] Micronized niclosamide (supplied by Olon SpA, Italy) was prepared and used for comparison. Micronization is typically performed by milling, such as air jet milling or pin milling.

[0088] The solubility of niclosamide in supercritical fluid carbon dioxide (scCO2) and various organic solvents was evaluated. Approximately 63 precipitation runs (approximately 500 mg to 10 g) were performed in an RC612B precipitation unit according to the examples provided above. The variables changed between each precipitation are detailed in Tables 1-3 below. The precipitates were analyzed by laser diffraction to determine PSD, BET sorptometry to determine SSA, and SEM to determine crystal habit and support the PSD and SSA data.

[0089] PSD analysis was performed on a Malvern Mastersizer® 3000 using an Aero S® dispersion unit, according to the manufacturer's instructions.

[0090] SSA determination analysis was performed using an Automated BET Sorptometer BET-202A from Porous Materials, Inc., according to the manufacturer's instructions.

[0091] SEM was performed using a Hitachi 8130 SEM. Exemplary SEM images can be seen in Figures 1-6.

[0092] Initial data is provided in Tables 1-7. The tables provide general information about the processing conditions, where "low pressure" is 1190-1210 psi, "low temperature" is 20°C-25°C, "high pressure" is 1300-1350 psi, "high temperature" is 40°C-45°C, and "X" represents the average condition of "high" and "low".

[0093] These data demonstrate that the generated niclosamide particles have significantly lower bulk density (with and without tapping) and specific surface area compared to micronized niclosamide (see "Micronized Materials" in Table 2 for details on micronized niclosamide).

[0094] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0095] Exemplary treated products were also used for dissolution for comparison with untreated materials / raw materials. Dissolution tests were performed in 40% isopropanol at 37°C while rotating a paddle at 50 rpm. The data are provided in Table 8 and show a significant improvement in dissolution properties compared to raw material nicrosamide and micronized nicrosamide.

[0096] The aerodynamic median particle size (MMAD) characteristics of exemplary aerosol droplets of the processed product were also determined using a rotating brush generator and a TSI Aerodymanic Particle Sizer, Model 3321. The data are provided in Table 8.

[0097] [Table 8]

[0098] Pharmacokinetic studies will be conducted in adult Sprague-Dawley rats, comparing the raw material or micronized niclosamide suspension administered orally via a tube with the exemplary niclosamide particles / composition of this disclosure ("SCP Niclosamide") administered by inhalation using only nasal inhalation. SCP Niclosamide will be aerosolized using a rotating brush generator, and the airflow will be adjusted to provide a constant and consistent amount of niclosamide in the inhaled air. Samples of the inhaled air will be periodically evaluated to ensure a consistent dose.

[0099] Each group of 24 rats plus an additional rat was administered a single dose of the test substance at time zero. At each of the eight time points, three rats were sacrificed from each dose group, and blood and lung tissue samples were collected. Exemplary time points past time zero are 1, 2, 4, 8, 24, 48, 72, and 96 hours post-administration. Blood samples were stored in an ice bath until they could be centrifuged to separate and collect the plasma. Lung tissue and plasma samples were frozen at -20°C until thawed before assay. Samples were evaluated using a validated LC-MS-MS assay. Data from plasma and lung tissue were evaluated using non-compartmental analysis to determine the Cmax, Tmax, AUC, and apparent terminal phase half-life of niclosamide.

[0100] [Table 9] TIFF0007885204000011.tif242162TIFF0007885204000012.tif242162TIFF0007885204000013.tif242162TIFF0007885204000014.tif109162

Claims

1. A composition comprising particles containing at least 90% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the particles are (i) 0.40g / cm ３ Less than average bulk density (without tapping), and (ii) 0.55g / cm ３ Less than average tap density A composition having the following characteristics.

2. The aforementioned particles are 0.30 g / cm³ ３ The composition according to claim 1, having an average bulk density (without tapping) of less than 1.

3. The aforementioned particles are 0.40 g / cm³ ３ The composition according to claim 1 or claim 2, having an average tap density of less than 1.

4. The particles are at least 0.05 g / cm³ ３ The average bulk density (without tapping) and at least 0.05 g / cm³ ３ The composition according to any one of claims 1 to 3, having an average tap density.

5. The aforementioned particles, 5m ２ / g to 15m ２ The composition according to any one of claims 1 to 4, having a specific surface area (SSA) of 1 / g.

6. The composition according to any one of claims 1 to 5, wherein the particles have an average particle diameter with a volume distribution of 0.1 μm to 8 μm.

7. The composition according to any one of claims 1 to 5, wherein the particles have an average particle diameter with a volume distribution of 0.5 μm to 6 μm.

8. The composition according to any one of claims 1 to 7, wherein the particles comprise at least 95% by weight of niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

9. The composition according to any one of claims 1 to 7, wherein the particles comprise at least 95% by weight of niclosamide.

10. The composition according to any one of claims 1 to 9, wherein the composition comprises a suspension further comprising a pharmaceutically acceptable aqueous carrier.

11. The composition according to any one of claims 1 to 10, formulated for intrapulmonary, intramuscular, subcutaneous, or intraperitoneal administration.

12. The composition according to any one of claims 1 to 11, wherein niclosamide particles or a suspension thereof are formulated as a dry powder inhalation aerosol or a spray suspension, or niclosamide particles or a suspension thereof are suspended in a propellant system containing at least one liquefied gas in a pressurized container sealed with a throttle valve.

13. A composition according to any one of claims 1 to 12, for use in a method for treating or limiting the manifestation of a disorder selected from among parasitic infections, viral infections, bacterial infections, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, pulmonary and renal fibrosis, pulmonary hypertension, idiopathic pulmonary arterial hypertension (IPAH), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), eosinophilic esophagitis, stroke, ischemia / reperfusion injury, pain, psoriasis and atopic dermatitis, rheumatoid arthritis, graft-versus-host disease and systemic sclerosis, secretory diarrhea, diabetes mellitus, kidney disease, endometriosis, and suppression of uterine contractions in spontaneous early labor, comprising administering an amount of the composition effective in treating or limiting the manifestation of the disorder to a subject in need thereof.

14. The composition according to claim 13, wherein the disorder includes a viral infection, and the viral infection includes a betacoronavirus infection selected from the group consisting of infections caused by human coronavirus HKU1, SARS-CoV, and MERS-CoV.

15. The composition according to claim 14, wherein the beta-coronavirus infection includes SARS-CoV-2 infection.

16. The composition according to claim 13, wherein the disorder includes asthma.

17. The composition according to claim 13, wherein the disorder includes COPD.

18. The composition according to claim 13, wherein the disorder includes cystic fibrosis.

19. The composition according to any one of claims 13 to 18, wherein the composition is administered via the lung, intramuscular, or subcutaneous route.

20. The composition according to any one of claims 13 to 19, wherein the composition is administered via the pulmonary route.

21. The composition according to claim 19 or 20, wherein the transpulmonary administration includes inhalation of a dry powder using a dry powder inhalation device.

22. The composition according to claim 19 or 20, wherein the transpulmonary administration comprises a spray, and the spray results in transpulmonary delivery of aerosol droplets of the particles or suspension thereof to a subject.

23. The composition according to any one of claims 20 to 22, wherein the particles or a suspension thereof are aerosolized for administration, and the aerosolization results in aerosol droplets having an aerodynamic median particle diameter (MMAD) of 0.5 μm to 6 μm in diameter.

24. The composition according to any one of claims 13 to 23, wherein the subject is a human subject.

25. The compound is a method for producing particles, (a) (i) introducing a solution comprising at least one solvent selected from the group consisting of acetone, ethanol, methanol, dichloromethane, hexafluoroisopropyl alcohol, trifluoroethanol, dimethyl sulfoxide, tetrahydrofuran (THF), dimethylformamide, or combinations thereof, and at least one solute comprising niclosamide or a pharmaceutically acceptable salt, hydrate, or solvate thereof, into the nozzle inlet; and (ii) introducing a compressible fluid into the inlet of a vessel defining a pressurizable chamber. (b) A step of passing the solution through a nozzle opening into the pressurizable chamber to generate an output stream of spray droplets, wherein the nozzle opening is located 2 mm to 20 mm from a sound wave energy source located in the output stream, the sound wave energy source generates sound wave energy having an amplitude of 10% to 100% during passage, and the nozzle opening has a diameter of 20 μm to 125 μm. (c) The step of bringing the spray droplets into contact with the compressed fluid to deplete the solvent from the spray droplets and generate compound particles according to any one of claims 1 to 24. Includes, Steps (a), (b), and (c) are performed under the supercritical temperature and supercritical pressure of the compressed fluid. method.

26. (d) A step of bringing the compound particles generated in step (c) into contact with a poor solvent to further deplete the solvent from the compound particles, wherein step (d) is performed under the supercritical temperature and supercritical pressure of the poor solvent. The method according to claim 25, further comprising:

27. The method according to any one of claims 25 to 26, wherein the flow rate of the solution passing through the nozzle is in the range of 0.5 mL / min to 30 mL / min.

28. The method according to any one of claims 25 to 27, wherein the sound wave energy source includes one of a sound wave horn, a sound wave probe, or a sound wave plate.

29. The method according to any one of claims 25 to 28, wherein the sound wave energy source has a frequency of 18 kHz to 22 kHz.

30. (e) the step of receiving the plurality of particles passing through the outlet of the pressurizable chamber, (f) The step of collecting the plurality of particles into a collection device The method according to any one of claims 25 to 29, further comprising:

31. The method according to any one of claims 25 to 30, wherein the compressed fluid is supercritical carbon dioxide.

32. The method according to any one of claims 25 to 31, wherein the poor solvent is supercritical carbon dioxide.

33. The method according to any one of claims 25 to 32, wherein the method is carried out at 31.1°C to 60°C and 1071 psi to 1800 psi.

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