Particle composition containing ensifentrin

Abstract

The present invention relates to a particulate composition containing ensifentrin, wherein the particulate composition further contains 1,3-bis(2-(2-(mesitylmino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) in amounts exceeding 0.00 wt% and up to 0.60 wt% relative to the total weight of ensifentrin; and a biuret impurity of formula (A) in amounts from 0.00 wt% to 0.50 wt% relative to the total weight of ensifentrin. A liquid pharmaceutical composition containing the particulate composition and a process for producing the particulate composition are also described. JPEG2026522498000024.jpg55111

Description

Technical Field

[0001] Cross-reference This application claims the priority of GB2309605.0 filed on June 26, 2023, and the entire content of the same application is incorporated herein by reference.

[0002] Technical Field The present invention relates to a particulate composition containing ensifentrine, as well as a pharmaceutical composition and a manufacturing process of the particulate composition.

Background Art

[0003] Background of the Invention Ensifentrine (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl}ethyl)urea, also known as RPL554) is a dual inhibitor of PDE3 / PDE4 and is described in WO00 / 58308A1.

[0004] As a combined PDE3 / PDE4 inhibitor, ensifentrine has both bronchodilator and anti-inflammatory activities and is useful for the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD). The chemical structure of ensifentrine is shown below.

[0005]

Chemical Formula

[0006] Impurities associated with the activator must be controlled, and pharmaceuticals are permitted to contain certain levels of impurities (typically referred to as related substances). Known processes for producing ensifentrin have been found to involve undesirable levels of impurities. For example, the process described in WO00 / 58308A1, which involves adding a urea group using sodium cyanate and an aqueous hydrochloric acid solution, produces an ensifentrin substance containing biuret impurities that are not readily removed. WO2018 / 020249A1 discusses several possible reagents that can be used to add a urea group in the final step of ensifentrin production, but does not provide a detailed discussion of the conditions for the final ureation step.

[0007] It is desirable to develop a synthetic process for producing ensifentrin that yields an active pharmaceutical ingredient (API) with a good impurity profile, particularly one with a low biuret impurity content, without requiring large-scale purification or recrystallization. [Overview of the project]

[0008] It was found that ensifentrin with a good impurity profile, particularly ensifentrin with low levels of biuret impurities, can be produced by reacting an amine intermediate with 4-nitrophenyl chloroformate and ammonia in a solvent containing dichloromethane.

[0009] The present invention provides a particulate composition containing ensifenthrin, the particulate composition further comprising: 1,3-bis(2-(2-(mesitylmino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) in amounts exceeding 0.00 wt% and up to 0.60 wt% relative to the total weight of ensemphentrin; and Formula (A) for 0.00 wt% to 0.50 wt% of the total weight of ensifentrin:

[0010] [ka]

[0011] Biuret impurities.

[0012] The present invention also provides a liquid pharmaceutical composition suitable for administration by inhalation, comprising (a) a particle composition and (b) a diluent.

[0013] The present invention further provides a process for producing a particulate composition, the process comprising reacting a compound of formula (IV) with 4-nitrophenyl chloroformate and ammonia, wherein the compound of formula (IV), 4-nitrophenyl chloroformate and ammonia are reacted in a solvent containing dichloromethane.

[0014] [ka]

[0015] Furthermore, in some embodiments herein, liquid pharmaceutical compositions are provided, which are suspensions comprising: (a) 1.2 mg / mL ensifentrin; (b) 0.5 mg / mL polysorbate 20; (c) 0.05 mg / mL sorbitan monolaurate; (d) 0.744 mg / mL sodium dihydrogen phosphate; (e) 0.853 mg / mL disodium hydrogen phosphate; (f) 8.6 mg / mL sodium chloride; and (g) water, relative to the total weight of the liquid pharmaceutical composition.

[0016] Furthermore, in several embodiments, this specification provides a method for a human subject requiring: (a) a method for treating moderate chronic obstructive pulmonary disease (COPD), (b) a method for treating severe COPD, (c) a method for improving trough lung function, or (d) a method for reducing the frequency of COPD exacerbations, the method comprising administering a particulate composition or liquid pharmaceutical composition provided herein to a human subject by inhalation.

[0017] In some embodiments, kits comprising a particle composition or a liquid pharmaceutical composition provided herein are provided herein.

[0018] Detailed description of the invention particle composition The present invention provides a particulate composition comprising ensifenthrin. The particulate composition is formed from particles comprising ensifenthrin. Typically, the particulate composition is a powder comprising ensifenthrin particles. The particulate composition may exist in combination with another medium. For example, the particulate composition may be in the form of a powder comprising ensifenthrin, the powder being dispersed in a diluent, or the powder being mixed with a second particulate composition (e.g., a second particulate composition comprising a carrier such as lactose).

[0019] In some cases, the particle composition contains other related substances (e.g., substances other than encepholin) of about 0.5 wt% or less (e.g., about 0.45 wt%, 0.4 wt%, 0.36 wt%, 0.3 wt%, 0.25 wt%, 0.2 wt%, 0.15 wt%, or 0.1 wt% or less). In some cases, the particle composition contains other related substances (e.g., substances other than encepholin) of at least about 0.01 wt% (e.g., at least about 0.02 wt%, 0.04 wt%, 0.08 wt%, 0.1 wt%, 0.12 wt%, 0.14 wt%, 0.18 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, or 0.5 wt%). In some embodiments, the particle composition contains other related substances (e.g., substances other than encepholin) from about 0 wt% to about 0.5 wt%, from about 0.01 wt% to about 0.4 wt%, from about 0.01 wt% to about 0.3 wt%, from about 0.05 wt% to about 0.5 wt%, from about 0.1 wt% to about 0.5 wt%, or from about 0.1 wt% to about 0.4 wt%. In some embodiments, the particle composition contains other related substances (e.g., substances other than encepholin) of about 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, or about 0.5 wt%.

[0020] In addition to encepholin, the particle composition further comprises: 1,3-bis(2-(2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (BMIQU) of more than 0.00 wt% and up to 0.60 wt% based on the total weight of encepholin; and biuret impurities of formula (A) of from 0.00 wt% to 0.50 wt% based on the total weight of encepholin:

[0021]

Chemical formula

[0022] including those of the above formula (A).

[0023] In some cases, the particulate composition contains biuret impurities. In some embodiments, the biuret impurities are of formula (A). In some embodiments, the particulate composition contains biuret impurities of formula (A) ranging from about 0 wt% to about 0.5 wt%. In some embodiments, the particulate composition contains at least 0.01 wt% (e.g., at least 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.5 wt%) biuret impurities of formula (A). In some embodiments, the particulate composition contains up to 1 wt% (e.g., up to 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.65 wt%, 0.6 wt%, 0.55 wt%, 0.5 wt%, or 0.4 wt%) of biuret impurities of formula (A). In some embodiments, the particulate composition contains biuret impurities of formula (A) from about 0 wt% to about 1 wt%, from 0 wt% to about 0.04 wt%, from about 0.01 wt% to about 0.5 wt%, from 0.02 wt% to about 0.5 wt%, from 0.05 wt% to about 0.5 wt%, from 0.05 wt% to about 0.5 wt%, from 0.05 wt% to about 0.6 wt%, from 0.05 wt% to about 0.8 wt%, from 0.05 wt% to about 1.0 wt%, or from about 0.1 wt% to about 0.5 wt%. In some embodiments, the particulate composition contains biuret impurities of formula (A) in amounts ranging from about 0.01 wt% to about 0.1 wt%. In some embodiments, the particulate composition contains biuret impurities of formula (A) in amounts ranging from about 0 wt%, 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.07 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, or 1 wt%.

[0024] The weight percentage is relative to the total weight of ensifenthrin in the particle composition. BMIQU and, if present, biuret impurities are present in the ensifenthrin-containing particles in the particle composition. The content of BMIQU, biuret impurities, and other related substances or impurities can be measured by high-performance liquid chromatography (HPLC).

[0025] The particulate composition typically contains biuret impurities ranging from 0.00 wt% to 0.30 wt% relative to the total weight of ensifenthrin. The particulate composition may contain biuret impurities ranging from 0.00 wt% to 0.05 wt% relative to the total weight of ensifenthrin. For example, the particulate composition may contain biuret impurities ranging from 0.00 wt% to 0.03 wt% relative to the total weight of ensifenthrin.

[0026] The particulate composition may contain at least 0.005 wt% of BMIQU relative to the total weight of ensifenthrin. Typically, the particulate composition contains 0.01 wt% to 0.30 wt% of BMIQU relative to the total weight of ensifenthrin. The particulate composition may contain 0.30 wt% to 0.60 wt% of BMIQU relative to the total weight of ensifenthrin. The particulate composition may contain 0.02 wt% to 0.06 wt% of BMIQU relative to the total weight of ensifenthrin. The structure of BMIQU is shown below.

[0027] [ka]

[0028] In some embodiments, the particle composition contains at least 0.01 wt% (e.g., at least 0.02 wt%, 0.04 wt%, 0.06 wt%, 0.1 wt%, 0.12 wt%, 0.15 wt%, 0.17 wt%, 0.2 wt%, 0.25 wt%, or 0.3 wt%) of BMIQU (e.g., relative to the total weight of ensifentrin). In some embodiments, the particle composition contains up to 0.5 wt% (e.g., up to 0.45 wt%, 0.4 wt%, 0.35 wt%, 0.3 wt%, 0.25 wt%, or 0.2 wt%) of BMIQU. In some embodiments, the particle composition contains about 0 wt% to about 1 wt%, 0 wt% to about 0.5 wt%, about 0 wt% to about 0.4 wt%, about 0 wt% to about 0.3 wt%, about 0.01 wt% to about 0.3 wt%, about 0.01 wt% to about 0.2 wt%, 0.02 wt% to about 0.1 wt%, or about 0.01 wt% to about 0.1 wt%. In some embodiments, the particle composition contains about 0 wt%, 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.07 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, 0.25 wt%, or 0.3 wt% of BMIQU. In some cases, wt% is relative to the total weight of ensifentrin.

[0029] The particulate composition optionally further comprises 1-(2-(9-hydroxy-2-(mesitylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (9-des-methyl impurity) and / or 1-(2-(10-hydroxy-2-(mesitylimino)-9-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (10-des-methyl impurity). The structures of these compounds are shown below.

[0030] [ka]

[0031] The particulate composition typically further contains: 9-des-methyl impurities in amounts between 0.00 wt% and up to 0.10 wt% relative to the total weight of ensifenthrin; and / or 10-des-methyl impurities in amounts between 0.00 wt% and up to 0.10 wt%. Furthermore, the particulate composition may contain 9-des-methyl impurities in amounts between 0.01 wt% and 0.10 wt% relative to the total weight of ensifenthrin, and 10-des-methyl impurities in amounts between 0.01 wt% and up to 0.10 wt%.

[0032] In some cases, the particulate composition further contains 9-des-methyl impurities. In some embodiments, the particulate composition contains 9-des-methyl impurities ranging from about 0 to about 0.1 wt%. In some embodiments, the particulate composition contains at least 0.01 wt% (e.g., at least 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.15 wt%, or 0.2 wt%) of 9-des-methyl impurities. In some embodiments, the particulate composition contains up to 0.3 wt% (e.g., up to 0.28 wt%, 0.26 wt%, 0.24 wt%, 0.22 wt%, 0.2 wt%, 0.18 wt%, 0.15 wt%, or 0.1 wt%) of 9-des-methyl impurities. In some embodiments, the particulate composition contains 9-des-methyl impurities ranging from about 0.01 wt% to about 0.3 wt%, 0.01 wt% to about 0.25 wt%, 0.01 wt% to about 0.2 wt%, 0.05 wt% to about 0.2 wt%, 0.01 wt% to about 0.1 wt%, or about 0.1 wt% to about 0.2 wt%. In some embodiments, the particulate composition contains 9-des-methyl impurities ranging from about 0 wt%, 0.01 wt%, 0.04 wt%, 0.06 wt%, 0.1 wt%, 0.12 wt%, 0.14 wt%, 0.16 wt%, 0.18 wt%, 0.2 wt%, 0.24 wt%, 0.28 wt%, or about 0.3 wt%. In some embodiments, the particle composition contains less than 1 wt% of 9-des-methyl impurities.

[0033] In some cases, the particulate composition further contains 10-des-methyl impurities. In some embodiments, the particulate composition contains 10-des-methyl impurities ranging from about 0 to about 0.1 wt%. In some embodiments, the particulate composition contains at least 0.01 wt% (e.g., at least 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.15 wt%, or 0.2 wt%) of 10-des-methyl impurities. In some embodiments, the particulate composition contains up to 0.3 wt% (e.g., up to 0.28 wt%, 0.26 wt%, 0.24 wt%, 0.22 wt%, 0.2 wt%, 0.18 wt%, 0.15 wt%, or 0.1 wt%) of 10-des-methyl impurities. In some embodiments, the particulate composition contains 10-des-methyl impurities ranging from about 0.01 wt% to about 0.3 wt%, 0.01 wt% to about 0.25 wt%, 0.01 wt% to about 0.2 wt%, 0.01 wt% to about 0.1 wt%, 0.05 wt% to about 0.2 wt%, or from about 0.1 wt% to about 0.2 wt%. In some embodiments, the particle composition contains 10-des-methyl impurities in amounts of about 0 wt%, 0.01 wt%, 0.04 wt%, 0.06 wt%, 0.1 wt%, 0.12 wt%, 0.14 wt%, 0.16 wt%, 0.18 wt%, 0.2 wt%, 0.24 wt%, 0.28 wt%, or about 0.3 wt%. In some embodiments, the particle composition contains less than about 1 wt% of 10-des-methyl impurities. For example, the particle composition may contain: 10-des-methyl impurities from 0.01 to 0.04 wt%; 9-des-methyl impurities from 0.05 to 0.09 wt%; biuret impurities from 0.01 to 0.03 wt%; and BMIQU from 0.02 to 0.06 wt% (wherein wt% is relative to the total weight of ensifentrin in the particle composition).

[0034] In some embodiments, the particulate composition may contain: 0.01 to 0.4 wt% of 10-des-methyl impurities; 0.05 to 0.9 wt% of 9-des-methyl impurities; 0.01 to 0.5 wt% of biuret impurities; and 0.02 to 0.6 wt% of BMIQU (wherein wt% is relative to the total weight of ensifentrin in the particulate composition).

[0035] The particulate composition may further contain (E)-2-(mesitylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4-one (compound (I)) and / or (E)-3-(2-aminoethyl)-2-(mesitylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4-one (compound (IV)), whose structures are shown below. Typically, the particulate composition may contain neither compound (I) nor compound (IV), or the particulate composition may contain compound (I) and compound (IV) in a total amount of less than 0.04 wt% relative to the total weight of ensifentrin.

[0036] [ka]

[0037] In some cases, the particulate composition contains compound (I). In some embodiments, the particulate composition contains compound (I) in amounts ranging from about 0 to about 0.1 wt%. In some embodiments, the particulate composition contains at least 0.01 wt% (e.g., at least 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.15 wt%, or 0.2 wt%) of compound (I). In some embodiments, the particulate composition contains up to 0.3 wt% (e.g., up to 0.28 wt%, 0.26 wt%, 0.24 wt%, 0.22 wt%, 0.2 wt%, 0.18 wt%, 0.15 wt%, or 0.1 wt%) of compound (I). In some embodiments, the particle composition contains compound (I) in amounts ranging from about 0.01 wt% to about 0.3 wt%, 0.01 wt% to about 0.25 wt%, 0.01 wt% to about 0.2 wt%, 0.01 wt% to about 0.1 wt%, 0.05 wt% to about 0.2 wt%, or about 0.1 wt% to about 0.2 wt%. In some embodiments, the particle composition contains compound (I) in amounts ranging from about 0 wt%, 0.01 wt%, 0.04 wt%, 0.06 wt%, 0.1 wt%, 0.12 wt%, 0.14 wt%, 0.16 wt%, 0.18 wt%, 0.2 wt%, 0.24 wt%, 0.28 wt%, or about 0.3 wt%. In some embodiments, the particle composition contains compound (I) in amounts less than about 1 wt%.

[0038] In some cases, the particulate composition contains compound (IV). In some embodiments, the particulate composition contains compound (IV) in amounts from about 0 to about 0.1 wt%. In some embodiments, the particulate composition contains at least 0.01 wt% (e.g., at least 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.15 wt%, or 0.2 wt%) of compound (IV). In some embodiments, the particulate composition contains up to 0.3 wt% (e.g., up to 0.28 wt%, 0.26 wt%, 0.24 wt%, 0.22 wt%, 0.2 wt%, 0.18 wt%, 0.15 wt%, or 0.1 wt%) of compound (IV). In some embodiments, the particle composition contains compound (IV) in amounts ranging from about 0.01 wt% to about 0.3 wt%, 0.01 wt% to about 0.25 wt%, 0.01 wt% to about 0.2 wt%, 0.01 wt% to about 0.1 wt%, 0.05 wt% to about 0.2 wt%, or about 0.1 wt% to about 0.2 wt%. In some embodiments, the particle composition contains compound (IV) in amounts ranging from about 0 wt%, 0.01 wt%, 0.04 wt%, 0.06 wt%, 0.1 wt%, 0.12 wt%, 0.14 wt%, 0.16 wt%, 0.18 wt%, 0.2 wt%, 0.24 wt%, 0.28 wt%, or about 0.3 wt%. In some embodiments, the particle composition contains compound (IV) in amounts ranging from less than about 1 wt%.

[0039] One or more compounds, BMIQU, biuret impurity, 9-des-methyl impurity, 10-des-methyl impurity, and compound (I) and compound (IV) if present, may optionally exist in salt form. Typically, BMIQU, biuret impurity, 9-des-methyl impurity, 10-des-methyl impurity, compound (I) and compound (IV) exist in the form of free bases.

[0040] In some embodiments, the particulate composition contains a residual organic solvent of less than 15,000 ppm (e.g., less than 10,000 ppm, 5,000 ppm, or 2,500 ppm). In some embodiments, the particulate composition contains a residual organic solvent of 100 ppm to 15,000 ppm (e.g., 500 ppm to 15,000 ppm, 1,000 ppm to 15,000 ppm, 1,000 ppm to 10,000 ppm, or 5,000 ppm to 15,000 ppm).

[0041] In some embodiments, the residual organic solvent is the organic solvent remaining from the method of preparing ensifentrin. In some embodiments, the residual organic solvent is selected from acetone, acetonitrile, dichloromethane, methanol, toluene, tetrahydrofuran, dimethyl sulfoxide, or a combination thereof. In some embodiments, the residual organic solvent includes, for example, a combination of acetone, acetonitrile, dichloromethane, methanol, toluene, tetrahydrofuran, and dimethyl sulfoxide, in amounts as described herein.

[0042] In some mechanisms, the amount of residual organic solvent is determined by gas chromatography.

[0043] In some embodiments, the residual organic solvent is acetone. In some embodiments, acetone is present in the particulate composition in amounts less than 5000 ppm (e.g., 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or less than 1000 ppm). In some embodiments, acetone is present in the particulate composition in amounts ranging from about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0044] In some embodiments, the residual organic solvent is acetonitrile. In some embodiments, acetonitrile is present in the particulate composition in amounts less than 410 ppm (e.g., 400 ppm, 350 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or less than 100 ppm). In some embodiments, acetonitrile is present in the particulate composition in amounts from 100 ppm to 410 ppm (e.g., 100 ppm to 350 ppm, 200 ppm to 410 ppm, or 300 ppm to 400 ppm).

[0045] In some embodiments, the residual organic solvent is dichloromethane. In some embodiments, dichloromethane is present in the particulate composition in amounts less than 5000 ppm (e.g., 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or less than 1000 ppm). In some embodiments, dichloromethane is present in the particulate composition in amounts ranging from about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0046] In some embodiments, the residual organic solvent is methanol. In some embodiments, methanol is present in the particulate composition in amounts less than 3000 ppm (e.g., 2500 ppm, 2000 ppm, 1500 ppm, 1000 ppm, or less than 500 ppm). In some embodiments, methanol is present in the particulate composition in amounts from 500 ppm to 3000 ppm (e.g., 1000 ppm to 3000 ppm, 1500 ppm to 3000 ppm, or 2000 ppm to 3000 ppm).

[0047] In some embodiments, the residual organic solvent is toluene. In some embodiments, toluene is present in the particulate composition in amounts less than 5000 ppm (e.g., 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or less than 1000 ppm). In some embodiments, toluene is present in the particulate composition in amounts ranging from about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0048] In some embodiments, the residual organic solvent is tetrahydrofuran. In some embodiments, tetrahydrofuran is present in the particulate composition in amounts less than 720 ppm (e.g., 700 ppm, 650 ppm, 600 ppm, 550 ppm, 500 ppm, 450 ppm, or less than 400 ppm). In some embodiments, tetrahydrofuran is present in the particulate composition in amounts ranging from 250 ppm to 720 ppm (e.g., 400 ppm to 720 ppm, 500 ppm to 720 ppm, or 600 ppm to 720 ppm).

[0049] In some embodiments, the residual organic solvent is dimethyl sulfoxide. In some embodiments, dimethyl sulfoxide is present in the particulate composition in amounts less than 5000 ppm (e.g., 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or less than 1000 ppm). In some embodiments, dimethyl sulfoxide is present in the particulate composition in amounts ranging from about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0050] In some embodiments, the particulate composition comprises less than 5000 ppm of acetone, less than 410 ppm of acetonitrile, less than 5000 ppm of dichloromethane, less than 3000 ppm of methanol, less than 5000 ppm of toluene, less than 720 ppm of tetrahydrofuran, and less than 5000 ppm of dimethyl sulfoxide.

[0051] In some embodiments, the particulate composition contains one or more elemental impurities. In some embodiments, the elemental impurities are selected from nickel, arsenic, lead, cadmium, mercury, lithium, or any combination thereof.

[0052] In some embodiments, the elemental impurity is nickel. In some embodiments, nickel is present in the particulate composition at an approximate level of less than 200 ppm (e.g., less than 175 ppm, 150 ppm, 125 ppm, or 100 ppm).

[0053] In some embodiments, the elemental impurity is arsenic. In some embodiments, arsenic is present in the particulate composition in amounts less than 0.2 ppm (e.g., less than 0.17 ppm, 0.15 ppm, 0.13 ppm, less than 0.1 ppm, or less than 0.05 ppm).

[0054] In some embodiments, the elemental impurity is lead. In some embodiments, lead is present in the particulate composition in an amount of less than 0.5 ppm (e.g., less than 0.4 ppm, 0.3 ppm, 0.25 ppm, 0.2 ppm, 0.1 ppm, or 0.05 ppm).

[0055] In some embodiments, the elemental impurity is cadmium. In some embodiments, cadmium is present in the particulate composition in an amount of less than 0.2 ppm (e.g., less than 0.17 ppm, 0.15 ppm, 0.13 ppm, less than 0.1 ppm, or less than 0.05 ppm).

[0056] In some embodiments, the elemental impurity is mercury. In some embodiments, mercury is present in the particulate composition in amounts less than 0.1 ppm (e.g., less than 0.08 ppm, 0.06 ppm, 0.05 ppm, 0.04 ppm, or 0.02 ppm).

[0057] In some embodiments, the elemental impurity is lithium. In some embodiments, lithium is present in the particulate composition at an approximate concentration of less than 200 ppm (e.g., less than 175 ppm, 150 ppm, 125 ppm, or 100 ppm).

[0058] In some embodiments, the particulate composition contains less than 200 ppm of nickel, less than 0.2 ppm of arsenic, less than 0.5 ppm of lead, less than 0.2 ppm of cadmium, less than 0.1 ppm of mercury, and less than 200 ppm of lithium.

[0059] The particulate composition typically contains at least 98.0 wt% ensifenthrin based on the total weight of the particulate composition. The particulate composition may contain at least 99.0 wt% ensifenthrin based on the total weight of the particulate composition, or at least 99.2 wt% ensifenthrin based on the total weight of the particulate composition.

[0060] In some embodiments, the particle composition contains at least 98 wt% (e.g., at least 98.5 wt%, 98.9 wt%, 99 wt%, 99.2 wt%, 99.4 wt%, 99.6 wt%, 99.8 wt%, or 99.9 wt%) of ensifenthrin based on the total weight of the particle composition. In some embodiments, the particle composition contains ensifenthrin ranging from about 95 wt% to about 99.9 wt%, from about 96 wt% to about 99.9 wt%, from about 97 wt% to about 99.5 wt%, from 97 wt% to about 99 wt%, or from about 98 wt% to about 99.9 wt%, based on the total weight of the particle composition.

[0061] In the particle composition, ensifentrin is ensifentrin free base. In another embodiment, the particle composition contains a pharmaceutically acceptable salt of ensifentrin.

[0062] Enciphenthrin is typically in a crystalline form. At least 90 wt% of the ensifentrin present in the particulate composition is typically in the form of ensifentrin free base form I. Enciphenthrin free base form I is a crystalline polymorph of ensifentrin (crystalline polymorph form I) and typically has a powder X-ray diffraction pattern that includes characteristic peaks at 10.1° and 12.9°±0.1° 2θ. As described herein, the value of °2θ is typically measured using the CuKα X-ray wavelength (λ=1.5406 Å). The powder X-ray diffraction pattern of form I further typically includes characteristic peaks at 15.3° and 17.6°±0.1° 2θ. Form I of ensifentrin may have a powder X-ray diffraction pattern containing at least five characteristic peaks selected from 6.4°, 10.1°, 12.6°, 12.9°, 13.6°, 14.2°, 14.7°, 15.3°, 15.4°, 15.8°, 17.0°, 17.6°, 18.9°, 20.9°, 22.4°, 22.8°, and 28.7°±0.1° 2θ. Crystalline polymorph form I typically has a differential scanning calorimetry trace that is maximum at 248°C.

[0063] The particulate composition typically contains at least 98.0 wt% or at least 99.0 wt% of ensifentrin crystalline polymorph form I, based on the total weight of the particulate composition.

[0064] In some embodiments, the particle composition contains at least 98 wt% (e.g., at least 98.5 wt%, 98.9 wt%, 99 wt%, 99.2 wt%, 99.4 wt%, 99.6 wt%, 99.8 wt%, or 99.9 wt%) of ensifentrin crystalline polymorph form I based on the total weight of the particle composition. In some embodiments, the particle composition contains ensifentrin crystalline polymorph form I in amounts ranging from about 95 wt% to about 99.9 wt%, from about 96 wt% to about 99.9 wt%, from about 97 wt% to about 99.5 wt%, from 97 wt% to about 99 wt%, or from about 98 wt% to about 99.9 wt%, based on the total weight of the particle composition.

[0065] Typically, the particle composition is: Encifentrin in 99.4 to 99.9 wt% amounts; BMIQU from 0.01 wt% to 0.30 wt%; Biuret impurities ranging from 0.00 wt% to 0.10 wt%; 9-des-methyl impurities ranging from 0.01 wt% to 0.20 wt%; and 10-des-methyl impurities ranging from 0.01 wt% to 0.20 wt%, This includes, and wt% is relative to the total weight of the particle composition.

[0066] Particle composition: Encifentrin in a concentration of 99.5 to 99.9 wt%; BMIQU from 0.02 wt% to 0.10 wt%; Biuret impurities ranging from 0.00 wt% to 0.04 wt%; 9-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%; and 10-des-methyl impurities ranging from 0.01 wt% to 0.10 wt% It may contain, and wt% is relative to the total weight of the particle composition.

[0067] For example, a particle composition: Encifentrin in a concentration of 99.6 to 99.9 wt%; BMIQU from 0.02 wt% to 0.10 wt%; Biuret impurities ranging from 0.00 wt% to 0.04 wt%; 9-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%; 10-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%; and Total of other related substances less than 0.36 wt% It can consist of, where wt% is relative to the total weight of the particle composition.

[0068] The particulate composition comprises particles containing ensifentrin and additional impurity compounds as defined above. The particulate composition typically contains particles of inhalable size. The particulate composition typically has a Dv50 ranging from about 0.2 to about 5.0 μm. The particulate composition may have a Dv50 ranging from about 1.0 μm to about 2.2 μm.

[0069] The particle composition may have a Dv50 of at least 0.1 μm (e.g., at least 0.2 μm, 0.3 μm, 0.5 μm, 0.8 μm, 1 μm, 1.3 μm, 1.5 μm, 1.8 μm, 2 μm, 2.2 μm, 2.5 μm, 3 μm, 3.5 μm, or 4 μm). The particle composition may have a Dv50 of up to 6 μm (e.g., up to 5.8 μm, 5.5 μm, 5.3 μm, 5.2 μm, 5.1 μm, 5 μm, or 4.5 μm).

[0070] The particle composition may have a Dv10 ranging from approximately 0.2 μm to approximately 1 μm. The particle composition may have a Dv10 of at least 0.1 μm (e.g., 0.15 μm, 0.18 μm, 0.2 μm, 0.4 μm, 0.6 μm, 0.8 μm, or 1 μm). The particle composition may have a Dv10 of up to 1.3 μm (e.g., up to 1.2 μm, 1.1 μm, 1 μm, 0.95 μm, or 0.9 μm).

[0071] The particle composition may have a Dv90 of at least 1.7 μm (e.g., at least 1.8 μm, 1.9 μm, 2 μm, 2.1 μm, 2.2 μm, 2.3 μm, or 2.4 μm). The particle composition may have a Dv90 of up to 5.5 μm (e.g., up to 5.4 μm, 5.2 μm, 5 μm, 4.8 μm, 4.6 μm, 4.5 μm, or 4.4 μm).

[0072] The particle composition typically has Dv10 from about 0.3 μm to about 0.9 μm and / or Dv90 from about 2.3 μm to about 4.5 μm. The particle composition may typically have Dv50 from about 1.0 μm to about 2.2 μm, Dv10 from about 0.3 μm to about 0.9 μm, and Dv90 from about 2.3 μm to about 4.5 μm.

[0073] The technique used to measure the Dv50 (and Dv10 and Dv90) values ​​referred to herein is typically laser diffraction. The particle size distribution of a particulate composition may also be measured by laser diffraction using a wet powder dispersion system. For example, the particle size distribution can be measured by laser diffraction using a Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters for a Malvern Spraytec are as follows: • Particles - standard opaque particles; • Refractive index particle -1.50; • Refractive index (imaginary): -0.50; Particle density -1.00; • Refractive index of the dispersant: -1.33; • Control unit - 1000 RPM; • Measurement type - time specified; • Initial sampling time -30s; • Damping rate: -20% to -30%; • Dispersant - 1% polysorbate 20 in deionized water.

[0074] The particle composition may be produced by any pharmaceutically acceptable size reduction process or particle size control manufacturing process. For example, particles may be produced by size reduction of the solid form of ensifenthrin, for example by air jet pulverization, mechanical micronization or media pulverization, or by precipitation from a solution of ensifenthrin. The present invention also provides a solid form of ensifenthrin having the composition described above for the particle composition (i.e., comprising ensifenthrin and one or more of the impurity compounds described above). This solid form may take the form of a filter cake, pellets, blocks, layers, or crystals.

[0075] Pharmaceutical composition The present invention also provides a pharmaceutical composition comprising a particle composition. The pharmaceutical composition may be a dry powder suitable for administration, comprising the particle composition and a carrier. The carrier may be, for example, lactose powder.

[0076] Typically, the pharmaceutical composition is a liquid pharmaceutical composition suitable for administration by inhalation, comprising (a) a particulate composition and (b) a diluent. The particulate composition is typically suspended in the diluent.

[0077] The pharmaceutical composition may contain any of the relevant substances described in the above specification (for example, substances other than ensifentrin) in the amounts described in the above specification. In some embodiments, the relevant substances include BMIQU, a biuret impurity of formula (A), a 9-des-methyl impurity, and a 10-des-methyl impurity.

[0078] The pharmaceutical composition typically contains 1.00 wt% or less of BMIQU relative to the total weight of ensifentrin in the pharmaceutical composition. For example, a liquid pharmaceutical composition may contain 0.50 wt% or less, or 0.20 wt% or less of BMIQU, relative to the total weight of ensifentrin.

[0079] The pharmaceutical composition may contain biuret impurities in an amount of 0.10 wt% or less, or 0.05 wt% or less, relative to the total weight of ensifentrin in the pharmaceutical composition.

[0080] In some embodiments, the pharmaceutical composition provided herein further comprises one or more osmotic regulators, one or more buffers, and one or more surfactants. In some embodiments, the pharmaceutical composition further comprises one or more osmotic regulators. In some embodiments, the pharmaceutical composition further comprises one or more buffers. In some embodiments, the pharmaceutical composition further comprises one or more surfactants.

[0081] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more osmotic regulators. In some embodiments, the osmotic regulator comprises sodium chloride. In some embodiments, the osmotic regulator (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of at least 1 mg / mL (e.g., 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL). In some embodiments, the osmotic regulator (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of up to 15 mg / mL (e.g., 14 mg / mL, 13 mg / mL, 12 mg / mL, 11 mg / mL, 10 mg / mL, 9 mg / mL). In some embodiments, the osmotic regulator (e.g., sodium chloride) is present in the pharmaceutical composition at concentrations ranging from about 1 mg / mL to about 15 mg / mL, about 3 mg / mL to about 10 mg / mL, about 4 mg / mL to about 10 mg / mL, about 5 mg / mL to about 11 mg / mL, about 5 mg / mL to about 9 mg / mL, or about 6 mg / mL to about 9 mg / mL. In some embodiments, the osmotic regulator (e.g., sodium chloride) is present in the pharmaceutical composition at concentrations ranging from about 7 mg / mL to about 10 mg / mL. In some embodiments, the osmotic regulator (e.g., sodium chloride) is present in the pharmaceutical composition at concentrations ranging from 8 mg / mL to 9 mg / mL. In a particular embodiment, the osmotic regulator (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of (e.g., about) 8.6 mg / mL.

[0082] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more buffers. In some embodiments, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the pharmaceutical composition at a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.8 mg / mL, 1 mg / mL, or 1.4 mg / mL). In some embodiments, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the pharmaceutical composition at a concentration of 4 mg / mL (e.g., 3.8 mg / mL, 3.3 mg / mL, 2.8 mg / mL, 2.5 mg / mL, or 2 mg / mL). In some embodiments, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the pharmaceutical composition at concentrations ranging from about 1 mg / mL to about 2 mg / mL, about 1.2 mg / mL to about 1.8 mg / mL, or about 1.4 mg / mL to about 1.7 mg / mL. In some embodiments, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the pharmaceutical composition at concentrations ranging from about 1.5 mg / mL to about 1.7 mg / mL.

[0083] In some embodiments, the pharmaceutical composition contains sodium dihydrogen phosphate dihydrate at a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL). In some embodiments, the pharmaceutical composition contains sodium dihydrogen phosphate dihydrate at a concentration of up to 1.2 mg / mL (e.g., 1.1 mg / mL, 1.0 mg / mL, 0.9 mg / mL, 0.8 mg / mL). In some embodiments, the pharmaceutical composition contains sodium dihydrogen phosphate dihydrate at a concentration ranging from about 0.5 mg / mL to about 0.9 mg / mL. In some embodiments, the pharmaceutical composition contains sodium dihydrogen phosphate dihydrate at a concentration ranging from about 0.7 mg / mL to about 0.8 mg / mL. In some embodiments, the pharmaceutical composition contains sodium dihydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL. In certain embodiments, the pharmaceutical composition contains sodium dihydrogen phosphate dihydrate at a concentration of (for example) about 0.744 mg / mL.

[0084] In some embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL). In some embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration of up to 1.2 mg / mL (e.g., 1.1 mg / mL, 1.0 mg / mL, 0.9 mg / mL). In some embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration ranging from about 0.7 mg / mL to about 1 mg / mL. In some embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration ranging from about 0.8 mg / mL to about 0.9 mg / mL. In some embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration of about 0.8 mg / mL. In some embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration of about 0.9 mg / mL. In certain embodiments, the pharmaceutical composition contains disodium hydrogen phosphate dihydrate at a concentration of (for example) about 0.853 mg / mL.

[0085] In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of at least 0.05 mg / mL (e.g., 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL). In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of up to 1 mg / mL (e.g., 0.9 mg / mL, 0.8 mg / mL, 0.7 mg / mL, 0.6 mg / mL). In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration ranging from about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration ranging from about 0.01 mg / mL to 2 mg / mL. In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration ranging from about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.5 mg / mL. In some embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.6 mg / mL. In certain embodiments, the pharmaceutical composition contains one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of (e.g., about) 0.55 mg / mL.

[0086] In some embodiments, the pharmaceutical composition contains polysorbate 20 (e.g., Tween 20) at a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL). In some embodiments, the pharmaceutical composition contains polysorbate 20 (e.g., Tween 20) at a concentration of up to 1 mg / mL (e.g., 0.9 mg / mL, 0.8 mg / mL, 0.7 mg / mL, 0.6 mg / mL). In some embodiments, the pharmaceutical composition contains polysorbate 20 (e.g., Tween 20) at a concentration ranging from about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the pharmaceutical composition contains polysorbate 20 (e.g., Tween 20) at a concentration ranging from about 0.4 mg / mL to about 0.6 mg / mL. In certain embodiments, the pharmaceutical composition contains polysorbate 20 (e.g., Tween 20) at a concentration of about 0.5 mg / mL.

[0087] In some embodiments, the pharmaceutical composition contains sorbitan monolaurate (Span 20) at a concentration of at least 0.01 mg / mL (e.g., 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL). In some embodiments, the pharmaceutical composition contains sorbitan monolaurate (Span 20) at a concentration of up to 0.1 mg / mL (e.g., 0.09 mg / mL, 0.08 mg / mL, 0.07 mg / mL, 0.06 mg / mL). In some embodiments, the pharmaceutical composition contains sorbitan monolaurate (Span 20) at a concentration ranging from about 0.03 mg / mL to about 0.07 mg / mL. In some embodiments, the pharmaceutical composition contains sorbitan monolaurate (Span 20) at a concentration ranging from about 0.04 mg / mL to about 0.06 mg / mL. In certain embodiments, the pharmaceutical composition contains sorbitan monolaurate (Span 20) at a concentration of (for example, about) 0.05 mg / mL.

[0088] The liquid pharmaceutical composition typically comprises, relative to the total weight of the liquid pharmaceutical composition: (i) a particulate composition with a concentration of 0.8 to 1.6 mg / mL; (ii) one or more surfactants with a total concentration of 0.1 to 1.0 mg / mL; (iii) one or more buffers with a total concentration of 1.0 to 2.0 mg / mL; and (iv) water. The liquid pharmaceutical composition optionally further comprises an osmotic pressure regulator, the concentration of which may be from 1.0 to 20.0 mg / mL or from 7.0 to 10.0 mg / mL. The osmotic pressure regulator may be sodium chloride.

[0089] The liquid pharmaceutical composition may contain, in relation to the total weight of the liquid pharmaceutical composition: (i) a particulate composition with a concentration of 1.0 to 1.4 mg / mL, the particulate composition having Dv50 from about 1.0 to about 2.2 μm and optionally Dv10 from about 0.3 μm to about 0.9 μm and Dv90 from about 2.3 μm to about 4.5 μm; (ii) one or more surfactants with a total concentration of 0.4 to 0.7 mg / mL; (iii) one or more buffers with a total concentration of 1.4 to 1.8 mg / mL; (iv) water; and (v) an osmotic pressure regulator with a concentration of 7.0 to 10.0 mg / mL.

[0090] The liquid pharmaceutical composition may contain at least 95 wt% or at least 99 wt% of (i), (ii), (iii), (iv), and optionally (v) based on the total weight of the liquid pharmaceutical composition.

[0091] Examples of buffers include citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer. Preferably, one or more buffers include phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0092] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG300, PEG600, PEG1000, Brij30, Brij35, Brij56, Brij76 and Brij97), polypropylene glycol (e.g., PPG2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, and polyoxyethylene glycol sorbitan alkyl esters (polysorbate, e.g., polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate). Examples include β-80), sorbitan alkyl esters (e.g., sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 85)), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamer), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactants), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, and polyethoxylated beef tallowamine (POEA).

[0093] Preferably, one or more surfactants include polysorbate and / or sorbitan alkyl esters. The one or more surfactants may include, for example, polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may also include, for example, sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), or sorbitan trioleate (Span 85). Preferably, one or more buffers include polysorbate 20 (Tween 20) and / or sorbitan monolaurate (Span 20).

[0094] The liquid pharmaceutical composition may contain, in relation to the total weight of the liquid pharmaceutical composition: (i) a particulate composition with a concentration of 1.0 to 1.4 mg / mL, wherein the particulate composition has Dv50 from about 1.0 μm to about 2.2 μm and optionally Dv10 from about 0.3 μm to about 0.9 μm and Dv90 from about 2.3 μm to about 4.5 μm; (ii) one or more surfactants with a total concentration of 0.4 to 0.7 mg / mL, wherein one or more surfactants are selected from polysorbates and / or sorbitan alkyl esters; (iii) one or more buffers with a total concentration of 1.4 to 1.8 mg / mL, wherein one or more buffers are selected from phosphate buffers; (iv) water; and (v) sodium chloride with a concentration of 7.0 to 10.0 mg / mL.

[0095] For example, with respect to the total weight of the liquid pharmaceutical composition: - Particle compositions with concentrations ranging from 1.0 to 1.4 mg / mL; - Polysorbate 20 (Tween 20) with concentrations ranging from 0.3 to 0.7 mg / mL; - Sorbitan monolaurate with a concentration of 0.0 to 0.1 mg / mL (Span 20); - Sodium dihydrogen phosphate dihydrate with a concentration of 0.5 to 1.0 mg / mL; - Disodium hydrogen phosphate dihydrate in concentrations of 0.5 to 1.0 mg / mL; - Sodium chloride with a concentration of 5 to 10 mg / mL; and - water It may include.

[0096] The liquid pharmaceutical composition typically contains a particulate composition ranging from about 2.0 mg to about 4.0 mg. Therefore, the liquid pharmaceutical composition typically contains ensifentrin ranging from about 2.0 mg to about 4.0 mg.

[0097] In some embodiments, the liquid pharmaceutical composition is sterile. In specific embodiments, the liquid pharmaceutical composition is USP <71> It is sterile according to [the relevant standard].

[0098] The liquid pharmaceutical composition has a sterility assurance level (SAL) of 10 -3 The following 10 -6 The following, or 10 -9 The following is possible. For example, if SAL is 10 -6 In that case, the probability that the final product is not sterile is 1 / 10. 6 This means that the sterile liquid pharmaceutical composition may have a total bioburden limit of 10 CFU / mL or less, or 1 CFU / mL or less. "CFU" is a colony-forming unit. Bioburden is defined in USP31. <61> It can be measured using the plate counting method described, for example, the pour-plate method.

[0099] Typically, the sterility of liquid pharmaceutical compositions is determined by the USP <71> Alternatively, it is measured according to Ph Eur 2.6.1. Liquid pharmaceutical compositions are typically measured according to USP <71> Alternatively, it satisfies the criteria defined in Ph Eur 2.6.1. In some embodiments, the liquid pharmaceutical composition is stored in an ampoule.

[0100] In some embodiments, the liquid pharmaceutical composition stored in ampoules is evaluated for leachate after 18 months at 25°C / 60%RH (relative humidity), 6 months at 40°C / 75%RH, or 33 months at 25°C / 60%RH. In some embodiments, the liquid pharmaceutical composition contains elemental impurities below the ICH Q3D daily exposure threshold and does not increase during storage.

[0101] In some embodiments, the liquid pharmaceutical composition contains 3,3-dimethyl-1,5-dioxacycloundecane-6,11-dione and 1,4,7-trioxacyclotridecane-8,13-dione in amounts below the threshold of toxicological concern according to the ICH M7 guidelines.

[0102] Nebulizers containing liquid pharmaceutical compositions are also provided. The nebulizer may be a soft mist nebulizer, a vibrating mesh nebulizer, a jet nebulizer, or an ultrasonic nebulizer. Typically, the nebulizer is a jet nebulizer.

[0103] In some embodiments, a kit comprising a particle composition provided herein is provided herein. In other embodiments, the kit comprises a liquid pharmaceutical composition provided herein.

[0104] In some embodiments, the kit includes instructions for using either the particle composition or the liquid pharmaceutical composition provided herein.

[0105] Treatment method Liquid pharmaceutical compositions are typically used to treat or prevent diseases or conditions selected from chronic obstructive pulmonary disease (COPD), asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, pulmonary fibrosis, interstitial lung disease, skin diseases, atopic dermatitis, psoriasis, ocular inflammation, cerebral ischemia, inflammatory diseases, and autoimmune diseases. The disease or condition may be COPD or asthma. In many cases, the disease or condition is chronic obstructive pulmonary disease (COPD).

[0106] COPD In some cases, (for example, liquid) pharmaceutical compositions may be used in methods of treating COPD. In some cases, the COPD is moderate COPD; in other cases, the COPD is severe COPD.

[0107] The above COPD stages can be classified as follows: FEV1 is the forced expiratory volume per second, and FVC is the forced vital capacity. - Mild COPD: FEV1 / FVC < 0.7 and FEV1 ≥ 80% predicted. - Moderate COPD: FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% forecast - Severe COPD: FEV1 / FVC < 0.7 and 30% ≤ EV1 < 50% prediction - Extremely severe COPD: FEV1 / FVC < 0.7 and FEV1 < 30% predicted.

[0108] In either case, the actual FEV1 of a human subject is compared to a predicted FEV1 value based on factors such as the subject's age and height. These predicted values ​​are readily available to those skilled in the art, for example, from the National Health and Nutrition Examination Survey III (Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values ​​from a sample of general US Population. Am J Respir Crit Care. 1999;159:179-187). An example of a formula for calculating the predicted FEV1 (in L units) of a human subject is as follows, where H is height (cm) and A is age (years): - Male: 0.0430H-0.0290A-2.490 - Female: 0.0395H-0.025A-2.600

[0109] FEV1 and FVC used for assessing COPD severity in humans are measured by spirometry immediately after administering an appropriate dose of at least one short-acting inhaled bronchodilator. In some embodiments, FEV1 and FVC measurements for COPD severity assessment are performed between 15 and 30 minutes after administration of salbutamol (albuterol).

[0110] In some embodiments, FEV1 and FVC used herein are determined as presented in the article Standardisation of spirometry, Eur J 2005;26;319-338.

[0111] Human subjects may be judged to have moderate COPD by measuring a predicted FEV1 value when FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80%. Here, FEV1 is the forced expiratory volume in one second, FVC is the forced vital capacity measured between 15 and 30 minutes after administration of a bronchodilator, and the bronchodilator is optionally salbutamol. Human subjects may be judged to have severe COPD by measuring a predicted FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50%. Here, FEV1 is the forced expiratory volume in one second, FVC is the forced vital capacity measured between 15 and 30 minutes after administration of a bronchodilator, and the bronchodilator is optionally salbutamol. The severity of COPD in human subjects can be determined at least one day before the first administration of the composition. In some embodiments, treatment with the compositions disclosed herein results in an increase of at least about 75, 90, or 100 mL in average FEV1 after 12 weeks post-administration.

[0112] Trough lung function In some cases, (e.g., liquid) pharmaceutical compositions may be used in methods to improve trough lung function. Improvement in trough lung function in patients with COPD is sometimes determined by measuring the increase in trough FEV1, i.e., the increase in the patient's FEV1 immediately before administration of the composition as part of maintenance therapy. In some embodiments, trough lung function increases by at least 30 mL (e.g., at least 35 mL, 40 mL, 45 mL, 50 mL, or 55 mL). In some cases, the increase is measured after a certain period of time has elapsed since the previous administration of the liquid pharmaceutical composition, compared to the FEV1 of a human subject before the first administration of the liquid pharmaceutical composition. In some embodiments, the certain period is about 11.5 hours to about 12 hours.

[0113] In some cases, pharmaceutical compositions (e.g., liquids) may be used to improve morning trough lung function. Morning trough lung function can be measured by determining the patient's FEV1 immediately before administering the composition in the morning as part of maintenance therapy. For example, FEV1 may be measured less than one hour before administering the composition in the morning. Morning trough FEV1 may be FEV1 measured between 11.5 and 12 hours after the previous evening dose.

[0114] COPD exacerbation In some cases, pharmaceutical compositions (e.g., liquids) may be used as a method to reduce the frequency and / or severity of COPD exacerbations. In some embodiments, COPD exacerbations are reduced by at least 30% (e.g., at least 32%, 34%, 36%, 40%, 45%, or 50%) compared to the frequency of COPD exacerbations in untreated subjects and subjects not administered with the pharmaceutical compositions disclosed herein.

[0115] In some embodiments, the method includes extending the time to the first COPD exacerbation in a human subject. Therefore, the subject may not yet have experienced a COPD exacerbation, and the pharmaceutical compositions disclosed herein may extend the time to the subject experiencing the first COPD exacerbation (delay the first COPD exacerbation). Thus, the pharmaceutical compositions may reduce the risk of COPD exacerbation in COPD patients. A COPD exacerbation may include one or more of the following: dyspnea (shortness of breath), increased cough, increased sputum production, purulent sputum, wheezing, sore throat, common cold, and fever. Purulent sputum is a change in the color of a voluntarily coughed sample from colorless to yellowish-green. A COPD exacerbation may last for at least one day, or at least two days.

[0116] An exacerbation of COPD may include (A) worsening of two or more of the following major symptoms for at least two consecutive days: dyspnea, increased sputum, or purulent sputum, or (B) worsening of one of the major symptoms, plus worsening of one of the following minor symptoms for at least two consecutive days: sore throat, cold (runny nose and / or nasal congestion), fever of no other cause (oral temperature > 37.5°C), or increased cough. For example, an exacerbation of COPD may include worsening of two or more of the major symptoms (dyspnea, increased sputum, and purulent sputum) for at least two consecutive days.

[0117] COPD exacerbations can be either moderate or severe. A moderate exacerbation is defined as an worsening of COPD symptoms (as defined above) requiring treatment with oral / systemic corticosteroids and / or antibiotics for at least three days. A severe exacerbation is defined as an worsening of COPD symptoms (as defined above) requiring hospitalization. The composition may reduce the severity of COPD exacerbations in patients and may therefore be used to prevent severe COPD exacerbations in patients. For example, a patient may not experience a severe COPD exacerbation for one year after the first dose of the composition.

[0118] regimen The liquid pharmaceutical composition may be administered once, twice, or three times a day, or two, three, four, or five times a week. For example, the pharmaceutical composition may be administered twice a day.

[0119] The method may include administering a pharmaceutical composition (e.g., liquid) containing approximately 3 mg of ensifentrin free base to a human subject by inhalation twice daily. The method may also include administering approximately 3 mg of the pharmaceutical composition to a human subject by inhalation twice daily (3 mg BID). In some cases, the method may include administering approximately 3 mg of the pharmaceutical composition to a human subject by nebulizer twice daily. Each dose may be 3.0 mg of ensifentrin free base administered by nebulizer.

[0120] In some embodiments, the human subject may be male. In some embodiments, the human subject may be female. The age of the human subject may be 65 years or older. The age of the human subject may be under 65 years. The human subject may be taking background medication selected from one or more of the following: long-acting muscarinic antagonists (LAMAs), long-acting β-agonists (LABAs), and inhaled corticosteroids (ICS). In some embodiments, the human subject is taking a LAMA. In some embodiments, the human subject is taking a LABA. In some embodiments, the human subject is taking an ICS.

[0121] In some cases, human subjects are not taking background medications. For example, human subjects may not be taking background medications, which may be long-acting muscarinic antagonists (LAMAs), long-acting β-agonists (LABAs), or inhaled corticosteroids (ICSs). In some embodiments, human subjects are not taking LAMAs. In some embodiments, human subjects are not taking LABAs. In some embodiments, human subjects are not taking ICSs.

[0122] A pharmaceutical composition (for example, a liquid) may be used as maintenance therapy. In some embodiments, the method includes administering the pharmaceutical composition to a human subject at least once daily for at least eight weeks. The pharmaceutical composition may be administered to a human subject at least once daily for at least sixteen weeks, or at least twenty-four weeks. The method may include administering the pharmaceutical composition to a human subject for at least one year. The method may include administering the composition to a human subject once every 24 hours, twice every 24 hours, for at least eight weeks, at least sixteen weeks, or at least twenty-four weeks.

[0123] Preparation method This specification provides a method for producing the particle composition described herein.

[0124] A process for producing a particulate composition may include reacting the compound of formula (IV) with 4-nitrophenyl chloroformate and ammonia. The compound of formula (IV), 4-nitrophenyl chloroformate and ammonia are reacted in a solvent containing dichloromethane.

[0125] [ka]

[0126] The solvents typically include dichloromethane and water.

[0127] In some embodiments, the solvent includes dichloromethane. In some embodiments, the solvent includes water.

[0128] For example, the solvent may contain 30 to 60 vol% dichloromethane and 30 to 60 vol% water relative to the total volume of the solvent.

[0129] The solvent may contain approximately 30 vol%, approximately 35 vol%, approximately 40 vol%, approximately 45 vol%, approximately 50 vol%, approximately 55 vol%, or approximately 60 vol% of dichloromethane. The solvent may also contain approximately 30 vol%, approximately 35 vol%, approximately 40 vol%, approximately 45 vol%, approximately 50 vol%, approximately 55 vol%, or approximately 60 vol% of water.

[0130] The solvent may contain 40 to 55 vol% dichloromethane and 40 to 55 vol% water relative to the total volume of the solvent. The total content of dichloromethane and water in the solvent is typically at least 90 vol% or at least 95 vol% based on the total volume of the solvent.

[0131] One eqv of the compound of formula (IV) typically reacts with 0.8 to 1.5 eqv of 4-nitrophenyl chloroformate.

[0132] In some embodiments, the compound of formula (IV) is reacted with about 0.8 eqv, about 0.85 eqv, about 0.9 eqv, about 0.95 eqv, about 1 eqv, about 1.05 eqv, about 1.1 eqv, about 1.15 eqv, about 1.2 eqv, about 1.25 eqv, about 1.3 eqv, about 1.35 eqv, about 1.4 eqv, about 1.45 eqv, or about 1.5 eqv of 4-nitrophenyl chloroformate.

[0133] The compound of formula (IV) can be reacted with 4-nitrophenyl chloroformate in concentrations from 1.0 to 1.2 eqv.

[0134] The compound of formula (IV) can be reacted with 4-nitrophenyl chloroformate and ammonia at a temperature of 20 to 40°C for at least 1 hour.

[0135] The process may include: (i) mixing the compound of formula (IV) with dichloromethane in a reactor; (ii) then adding an aqueous solution of a base to the reactor; (iii) then adding a solution of 4-nitrophenyl chloroformate in dichloromethane to the reactor; and (iv) then adding an ammonia solution to the reactor. The ammonia solution is typically an aqueous solution of ammonia, such as 25% aqueous ammonia. The base in step (ii) is typically potassium bicarbonate.

[0136] In some cases, the process includes mixing the compound of formula (IV) with dichloromethane in the reactor. In some cases, the process includes adding an aqueous solution of a base to the reactor. In some cases, the process includes adding a solution of 4-nitrophenyl chloroformate in dichloromethane to the reactor. In some cases, the process includes adding an ammonia solution to the reactor.

[0137] The organic phase products from steps (i) to (iv) are typically isolated, concentrated, and then mixed with methanol to produce a suspension of the particle composition. The process may further include drying, recrystallization, and optionally reduction of particle size of the particle composition.

[0138] The present invention will be described in more detail by the following embodiments. [Examples]

[0139] method Ultra-high-performance liquid chromatography (UPLC) - Column: Acquity UPLC BEH Phenyl 100 mm x 2.1 mm, 1.7 μm - Detector wavelength: 254nm - Retractive index detector sensitivity: N / AP - Retractive index detector temperature: N / AP - Column temperature: 35℃ - Autosampler temperature: N / AP - Flow rate: 0.53mL / min - Injection volume: 1μL - Runtime: 11.10 min - Gradient Program:

[0140] JPEG2026522498000010.jpg5564

[0141] - Mobile phase, washing solution, and dissolving mixture - Mobile phase A: Water / trifluoroacetic acid (100 / 0.1, v / v) (Transfer 1000 mL of water and 1 mL of trifluoroacetic acid accurately into a suitable flask, mix well, and degas before use.) - Mobile phase B: Acetonitrile / trifluoroacetic acid (100 / 0.1, v / v) (Transfer 1000 mL of acetonitrile and 1 mL of trifluoroacetic acid accurately into a suitable flask, mix well, and degas before use.) - Dissolving mixture (diluent): Acetonitrile / water (50 / 50, v / v) (Transfer 500 mL of acetonitrile to a suitable flask and add 500 mL of water. Mix well until homogenized, and degas before use.) - Needle washing: Acetonitrile / water (50 / 50, v / v) (Transfer 500 mL of acetonitrile to a suitable flask and add 500 mL of water. Mix well until uniform, and degas before use.) - Sealing and column washing: Acetonitrile / water (10 / 90, v / v) (Transfer 900 mL of water to a suitable flask and add 100 mL of acetonitrile. Mix well until homogenized, and degas before use.) - Equipment cleaning (column storage): Acetonitrile / water (90 / 10, v / v) (Transfer 900 mL of acetonitrile to a suitable flask and add 100 mL of water. Mix homogenously and degas before use.)

[0142] Example 1 - Preparation of ensifentrin Preparation of (E)-3-(2-aminoethyl)-2-(mesitylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4one

[0143] [ka]

[0144] A mixture of 10 g of compound (I), 3.21 g of lithium carbonate, 155 mL of acetonitrile, and 4.29 g of bromoacetonitrile was refluxed until the reaction was complete. The solid was removed by filtration, and the filtrate was concentrated by vacuum distillation while adding tetrahydrofuran. The resulting solid product was isolated by filtration.

[0145] NMR and single-crystal X-ray diffraction analysis revealed that the product is a cyclic ammonium bromide salt (II) with the following structure.

[0146] [ka]

[0147] Under hydrogenation conditions using Raney Ni and 7N methanol ammonia, the cyclic ammonium bromide salt (II) undergoes ring opening to form (E)-2-(2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)acetonitrile (compound (III))

[0148] [ka]

[0149] A compound (E) was generated, which was then reduced in situ to produce (E)-3-(2-aminoethyl)-2-(mesitylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4-one (compound (IV)).

[0150] [ka]

[0151] Production of ensifentrin from compound (IV) using sodium cyanate

[0152] [ka]

[0153] Compound (IV) was converted to ensifentrin (compound (V)) with sodium cyanate using the following procedure.

[0154] 8.0 g of compound (IV) was added to 70.4 mL of methanol. A solution of 1.80 g of sodium cyanate (1.5 eq) in 18.4 mL of deionized water (2.3 vol) was added over 30 minutes. The mixture was heated between 55 and 65°C. A solution of 1.68 mL of hydrochloric acid (1.1 eq) and 24.0 mL of deionized water (3 vol) was added over 15 minutes, and the temperature was maintained between 55 and 65°C. The suspension was refluxed and stirred for at least 2 hours. The suspension was cooled between 0 and 5°C and stirred for 1 hour. The suspension was filtered, and the filtered cake was washed with deionized water. The cake was then vacuum-dried to prepare the product.

[0155] The obtained product was analyzed by UPLC. The composition of the product is shown in Table 1 below.

[0156] [Table 1]

[0157] Biuret impurities (RRT 0.98) could not be easily removed by recrystallization. The structure of the impurities is shown below.

[0158] [ka]

[0159] [ka]

[0160] Preparation of ensifentrin from compound (IV) using nitrophenyl chloroformate and ammonia Compound (IV) was converted to ensefentrin using nitrophenyl chloroformate and ammonia according to the following procedure.

[0161] 132.0 g of compound (IV) was added to a reactor, to which 660.0 mL of dichloromethane (5 vol) was added. 153.12 g of potassium bicarbonate solution in 1320.0 mL of deionized water (10 vol) was added to the reactor, and the mixture was adjusted to a temperature between 0 and 5°C. Next, 660.0 mL of dichloromethane (5 vol) and a solution of 73.47 g of 4-nitrophenyl chloroformate (1.2 eq) were added, and the temperature was maintained between 0 and 10°C. The mixture was then stirred at a temperature between 5 and 10°C for at least 2 hours, after which 1320.0 mL of 25% aqueous ammonia (10 vol) was added. The mixture was then stirred overnight at a temperature between 25 and 35°C. Stirring was stopped, and each phase was separated for at least 15 minutes. The organic phase contained the product. The aqueous phase was extracted with 660 mL of dichloromethane, and the combined organic phase was washed with 660 mL of deionized water. The organic phase was filtered, and the reactor and filter were washed with 132.0 mL of dichloromethane. After concentrating the filtrate, methanol was added. The resulting suspension was heated and stirred. The suspension was cooled to a temperature of 15 to 25°C, and the suspension was filtered. The filtered cake was washed with methanol and then vacuum-dried to obtain the product.

[0162] The obtained products were analyzed by UPLC. The composition of the products is shown in Table 2 below.

[0163] [Table 2]

[0164] Only trace amounts of biuret impurities (RRT 0.98) were generated.

[0165] Example 2 - Preparation of a large batch of encifentrin Large batches of ensifentrin were prepared using 4-nitrophenyl chloroformate and ammonia. The obtained active pharmaceutical ingredient (API) was analyzed by UPLC. The main impurities present in the API are shown in Table 3 below.

[0166] [Table 3]

[0167] Example 3 - Preparation of aqueous suspension formulation The active pharmaceutical ingredient obtained from Example 2 was pulverized and subjected to dry heat treatment at 160°C for at least 120 minutes to produce sterile ensifentrin particles. The sterile ensifentrin particles obtained by dry heat treatment were mixed with a suspension vehicle under sterile conditions to obtain a sterile suspension formulation containing ensifentrin having the composition shown in Table 4.

[0168] [Table 4]

[0169] The suspension formulation was evaluated by HPLC, and it was found that the content of the impurity bis(mesitylisoquinolinone)urea (BMIQU) was 0.6 wt% or less relative to the total amount of ensemfentrin in the suspension formulation.

Claims

1. A particulate composition containing ensifenthrin, further comprising: 1,3-bis(2-(2-(mesitylmino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) in amounts exceeding 0.00 wt% and up to 0.60 wt% relative to the total weight of ensemphentrin; and Formula (A) for 0.00 wt% to 0.50 wt% of the total weight of ensifentrin: 【Chemistry 1】 Biuret impurities A particle composition containing the following:

2. The particle composition according to claim 1, comprising 0.00 wt% to 0.30 wt% of biuret impurities based on the total weight of ensifentrin.

3. The particle composition according to claim 1 or claim 2, comprising 0.00 wt% to 0.05 wt% of biuret impurities based on the total weight of ensifentrin.

4. A particle composition according to any one of the preceding claims, comprising 0.01 wt% to 0.30 wt% of BMIQU based on the total weight of ensifentrin.

5. A particle composition according to any one of the preceding claims, comprising 0.02 wt% to 0.06 wt% of BMIQU based on the total weight of ensifentrin.

6. 1-(2-(9-hydroxy-2-(mesitylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (9-des-methyl impurity) in amounts greater than 0.00 wt% and up to 0.10 wt%, and / or 1-(2-(10-hydroxy-2-(mesitylimino)-9-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (10-des-methyl impurity) A particle composition according to any one of the prior claims, further comprising:

7. A particle composition according to any one of the preceding claims, comprising at least 98.0 wt% of ensifentrin based on the total weight of the particle composition.

8. The particle composition according to any one of the preceding claims, comprising at least 99.0 wt% of ensifenthrin based on the total weight of the particle composition, and optionally comprising at least 99.2 wt% of ensifenthrin based on the total weight of the particle composition.

9. Encifentrin in amounts ranging from 99.4% to 99.9% wt%; BMIQU from 0.01 wt% to 0.30 wt%; Biuret impurities ranging from 0.00 wt% to 0.10 wt%; 9-des-methyl impurities ranging from 0.01 wt% to 0.20 wt%; and 10-des-methyl impurities ranging from 0.01 wt% to 0.20 wt%: The particle composition according to any one of the preceding claims, wherein the wt% is relative to the total weight of the particle composition.

10. Encifentrin in amounts ranging from 99.5 to 99.9 wt%; BMIQU from 0.02 wt% to 0.10 wt%; Biuret impurities ranging from 0.00 wt% to 0.04 wt%; 9-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%; and 10-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%: The particle composition according to any one of the preceding claims, wherein the wt% is relative to the total weight of the particle composition.

11. Encifentrin in amounts ranging from 99.6 to 99.9 wt%; BMIQU from 0.02 wt% to 0.10 wt%; Biuret impurities ranging from 0.00 wt% to 0.04 wt%; 9-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%; 10-des-methyl impurities ranging from 0.01 wt% to 0.10 wt%; and Total of other related substances less than 0.36 wt% The particle composition according to any one of the preceding claims, wherein wt% is relative to the total weight of the particle composition.

12. A particle composition according to any one of the preceding claims, having a Dv50 ranging from approximately 0.2 to approximately 5.0 μm.

13. The particle composition according to claim 12, having a Dv50 ranging from approximately 1.0 μm to approximately 2.2 μm.

14. A particle composition according to any one of the preceding claims, having a Dv10 ranging from about 0.3 μm to about 0.9 μm and / or a Dv90 ranging from about 2.3 μm to about 4.5 μm.

15. A liquid pharmaceutical composition suitable for administration by inhalation, comprising (a) a particle composition as defined in any one of the preceding claims and (b) a diluent.

16. The liquid pharmaceutical product according to claim 15, suspended in a diluent.

17. The liquid pharmaceutical composition according to claim 15 or claim 16, comprising 1.00 wt% or less of BMIQU based on the total weight of ensifentrin.

18. The liquid pharmaceutical composition according to claim 17, comprising 0.50 wt% or less of BMIQU based on the total weight of ensifentrin.

19. For the total weight of the liquid pharmaceutical composition: a) Particle compositions with concentrations ranging from 0.8 to 1.6 mg / mL; b) One or more surfactants with a total concentration of 0.1 to 1.0 mg / mL; c) One or more buffers with a total concentration of 1.0 to 2.0 mg / mL; and d) water A liquid pharmaceutical composition according to any one of claims 15 to 18, comprising:

20. For the total weight of the liquid pharmaceutical composition: a) Particle compositions with concentrations ranging from 1.0 to 1.4 mg / mL; b) Polysorbate 20 (Tween 20) with a concentration of 0.3 to 0.7 mg / mL; c) Sorbitan monolaurate (Span 20) with a concentration of 0.0 to 0.1 mg / mL; d) Sodium dihydrogen phosphate dihydrate in a concentration of 0.5 to 1.0 mg / mL; e) Disodium hydrogen phosphate dihydrate in concentrations of 0.5 to 1.0 mg / mL; f) Sodium chloride with a concentration of 5 to 10 mg / mL; and g) water A liquid pharmaceutical composition according to any one of claims 15 to 19, comprising:

21. A liquid pharmaceutical composition according to any one of claims 15 to 20, comprising a particle composition ranging from approximately 2.0 mg to approximately 4.0 mg.

22. The liquid pharmaceutical composition is a suspension, and with respect to the total weight of the liquid pharmaceutical composition: a) 1.2 mg / mL of ensifentrin; b) Polysorbate 20 at 0.5 mg / ml; c) 0.05 mg / ml sorbitan monolaurate; d) 0.744 mg / ml sodium dihydrogen phosphate; e) 0.853 mg / ml disodium hydrogen phosphate; f) 8.6 mg / ml sodium chloride; and g) water A liquid pharmaceutical composition according to any one of claims 15 to 21, comprising:

23. For human subjects requiring the following: a) Treatment of moderate chronic obstructive pulmonary disease (COPD), b) Treatment of severe COPD, c) Improvement of trough lung function, or d) Reduction in the frequency of COPD exacerbations; A method comprising administering to a human subject by inhalation a particle composition according to any one of claims 1 to 14, or a liquid formulation composition according to any one of claims 15 to 22.

24. A process for producing a particle composition as defined in any one of claims 1 to 14, wherein formula (IV): 【Chemistry 2】 A step of reacting the compound with 4-nitrophenyl chloroformate and ammonia, wherein the compound of formula (IV), 4-nitrophenyl chloroformate and ammonia are reacted in a solvent containing dichloromethane.

25. The process according to claim 24, comprising reacting a compound of formula (IV) at 1 eqv with 4-nitrophenyl chloroformate at 0.8 to 1.5 eqv, and optionally with 4-nitrophenyl chloroformate at 1.0 to 1.2 eqv.

26. (i) Mixing the compound of formula (IV) with dichloromethane in the reactor; (ii) Adding an aqueous solution of a base to the reactor; (iii) Adding a 4-nitrophenyl chloroformate solution in dichloromethane to the reactor; and (iv) Add ammonia solution to the reactor. The process according to claim 24 or claim 25, including the process described in claim 24 or 25.

27. The process according to claim 26, wherein the base in step (ii) is potassium bicarbonate.

28. A kit comprising a particle composition according to any one of claims 1 to 14, or a liquid pharmaceutical composition according to any one of claims 15 to 22.

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