Particulate composition comprising ensefinine

Abstract

The present invention relates to a particulate composition comprising ensafetine wherein the particulate composition further comprises: from more than 0.00% to 0.60% by weight of 1, 3-bis (2-(2-(mesitylene imino)-9, 10-dimethoxy-4-oxo-6, 7-dihydro-2H-pyrimido [6, 1-a] isoquinolin-3 (4H)-yl) ethyl) urea (BMIQU), relative to the total weight of ensafetine, and a particulate composition comprising: from more than 0.00% to 0.60% by weight of 1, 3-bis (2-(2-(mesitylene imino)-9, 10-dimethoxy-4-oxo-6, 7-dihydro-2H-pyrimido [6, 1-a] isoquinolin-3 (4H)-yl) ethyl) urea And 0.00% to 0.50% by weight of a biuret impurity of formula (A) with respect to the total weight of ensefin. Also described are liquid pharmaceutical compositions comprising the particulate compositions, as well as methods for producing the particulate compositions.

Description

[0001] Quote

[0002] This application claims the benefit of GB 2309605.0, filed on June 26, 2023, which is incorporated herein by reference in its entirety. Invention Field

[0003] This invention relates to a granular composition comprising encefentin, as well as a pharmaceutical composition and a method for preparing the granular composition. Background of the Invention

[0005] Encefentin (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl}ethyl)urea; also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO00 / 58308A1.

[0006] As a combination PDE3 / PDE4 inhibitor, enstatin possesses bronchodilatory and anti-inflammatory activities and can be used to treat respiratory diseases, including chronic obstructive pulmonary disease (COPD). The chemical structure of enstatin is shown below.

[0007]

[0008] Impurities associated with the active agent need to be controlled, with certain levels of specific impurities (often referred to as related substances) permitted only in pharmaceutical products. Known methods for the production of encefentin have been found to be associated with undesirable impurity levels. For example, the method described in WO00 / 58308A1, which involves adding a urea group using an aqueous solution of sodium cyanate and hydrochloric acid, produces an encefentin product containing a biuret impurity that cannot be easily removed. WO 2018 / 020249 A1 discusses several possible reagents that can be used to add a urea group in the final step of the production of encefentin, but does not provide a detailed discussion of the conditions for the final ureation step.

[0009] The aim is to develop a synthetic method for producing encefentin that produces a drug substance with a favorable impurity distribution without requiring extensive purification and recrystallization, especially when the drug substance contains low levels of biuret impurities. Invention Overview

[0011] It has been found that encefentin with a favorable impurity distribution, particularly encefentin with low levels of biuret impurities, can be prepared by a reaction involving reacting an amine intermediate with 4-nitrophenyl chloroformate and ammonia in a solvent containing dichloromethane.

[0012] This invention provides a particulate composition comprising encefenidine, wherein the particulate composition further comprises:

[0013] 1,3-bis(2-(2-(trimethylmethylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) at a weight ratio greater than 0.00% to 0.60% relative to the total weight of encefentin; and

[0014] Biuret impurities of formula (A) at a weight ratio of 0.00% to 0.50% relative to the total weight of encefentin:

[0015]

[0016] The present invention also provides a liquid pharmaceutical composition suitable for administration by inhalation, comprising (a) a particulate composition and (b) a diluent.

[0017] The present invention also provides a method for preparing the particulate composition, the method 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.

[0018]

[0019] In some embodiments, a liquid pharmaceutical composition is also provided herein, wherein the liquid pharmaceutical composition is a suspension comprising, relative to the total weight of the liquid pharmaceutical composition: (a) 1.2 mg / mL encefentin; (b) 0.5 mg / mL polysorbate 20; (c) 0.05 mg / mL sorbitol 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.

[0020] In some embodiments, this document also provides methods for (a) treating moderate chronic obstructive pulmonary disease (COPD); (b) treating severe COPD; (c) increasing trough lung function; or (d) reducing the frequency of COPD exacerbations in human individuals in need of such methods; said methods comprising administering the particulate or liquid pharmaceutical composition provided herein to the human individual by inhalation.

[0021] In some embodiments, this document provides kits comprising the particulate compositions or liquid pharmaceutical compositions provided herein. Invention Details

[0023] Particulate composition

[0024] This invention provides a particulate composition comprising encefentin. The particulate composition is formed from particles comprising encefentin. The particulate composition is typically a powder comprising encefentin particles. The particulate composition may be present in combination with a separate medium. For example, the particulate composition may be in the form of a powder comprising encefentin dispersed in a diluent or the powder may be combined with a second particulate composition (e.g., a second particulate composition comprising a carrier such as lactose).

[0025] In some cases, the particulate composition contains no more than about 0.5% by weight (e.g., no more than about 0.45%, 0.4%, 0.36%, 0.3%, 0.25%, 0.2%, 0.15%, or 0.1% by weight) of other related substances (e.g., substances other than enstatin). In some cases, the particulate composition contains at least about 0.01% by weight (e.g., at least about 0.02%, 0.04%, 0.08%, 0.1%, 0.12%, 0.14%, 0.18%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% by weight) of other related substances (e.g., substances other than enstatin). In some embodiments, the particulate composition comprises about 0% by weight to about 0.5% by weight, about 0.01% by weight to about 0.4% by weight, about 0.01% by weight to about 0.3% by weight, about 0.05% by weight to about 0.5% by weight, about 0.1% by weight to about 0.5% by weight, or about 0.1% by weight to about 0.4% by weight of other related substances (e.g., substances other than enstatin). In some embodiments, the particulate composition comprises about 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.15% by weight, 0.2% by weight, 0.25% by weight, 0.3% by weight, 0.35% by weight, 0.4% by weight, 0.45% by weight, or about 0.5% by weight of other related substances (e.g., substances other than enstatin).

[0026] In addition to encefentin, the particulate composition further comprises: 1,3-bis(2-(2-(trimethylmethylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) in a weight ratio greater than 0.00% to 0.60% relative to the total weight of encefentin; and a biuret impurity of formula (A) in a weight ratio of 0.00% to 0.50% relative to the total weight of encefentin.

[0027]

[0028] In some cases, the particulate composition contains a biuret impurity. In some embodiments, the biuret impurity comprises formula (A). In some embodiments, the particulate composition contains a biuret impurity of formula (A) at about 0% by weight to about 0.5% by weight. In some embodiments, the particulate composition contains a biuret impurity of formula (A) at least 0.01% by weight (e.g., at least 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, or 0.5% by weight). In some embodiments, the particulate composition contains up to 1% by weight (e.g., up to 0.9%, 0.8%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, or 0.4% by weight) of a biuret impurity of formula (A). In some embodiments, the particulate composition contains about 0% by weight to about 1% by weight, 0% by weight to about 0.04% by weight, about 0.01% by weight to about 0.5% by weight, 0.02% by weight to about 0.5% by weight, 0.05% by weight to about 0.5% by weight, 0.05% by weight to about 0.6% by weight, 0.05% by weight to about 0.8% by weight, 0.05% by weight to about 1.0% by weight, or about 0.1% by weight to about 0.5% by weight of a biuret impurity of formula (A). In some embodiments, the particulate composition comprises a biuret impurity of formula (A) at about 0.01% by weight to about 0.1% by weight. In some embodiments, the particulate composition comprises a biuret impurity of formula (A) at about 0% by weight, 0.01% by weight, 0.02% by weight, 0.03% by weight, 0.04% by weight, 0.05% by weight, 0.07% by weight, 0.1% by weight, 0.15% by weight, 0.2% by weight, 0.25% by weight, 0.3% by weight, 0.35% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, or 1% by weight.

[0029] The weight percentage is relative to the total weight of encefentin in the particulate composition. BMIQU and, if present, biuret impurities are present in the particulate composition containing encefentin. The content of BMIQU, biuret impurities, and other related substances or impurities can be measured by high performance liquid chromatography (HPLC).

[0030] The particulate composition typically contains biuret impurities at a weight ratio of 0.00% to 0.30% relative to the total weight of encefentin. The particulate composition may contain biuret impurities at a weight ratio of 0.00% to 0.05% relative to the total weight of encefentin. The particulate composition may, for example, contain biuret impurities at a weight ratio of 0.00% to 0.03% relative to the total weight of encefentin.

[0031] The granular composition may contain at least 0.005% BMIQU relative to the total weight of encefentanil. The granular composition typically contains 0.01% to 0.30% BMIQU relative to the total weight of encefentanil. The granular composition may contain 0.30% to 0.60% BMIQU relative to the total weight of encefentanil. The granular composition may contain 0.02% to 0.06% BMIQU relative to the total weight of encefentanil. The structure of the BMIQU is shown below.

[0032]

[0033] In some embodiments, the particulate composition comprises at least 0.01% by weight (e.g., at least 0.02%, 0.04%, 0.06%, 0.1%, 0.12%, 0.15%, 0.17%, 0.2%, 0.25%, or 0.3%) of BMIQU (e.g., relative to the total weight of encefentanyl). In some embodiments, the particulate composition comprises at most 0.5% by weight (e.g., at most 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, or 0.2%) of BMIQU. In some embodiments, the particulate composition comprises about 0% by weight to about 1% by weight, 0% by weight to about 0.5% by weight, about 0% by weight to about 0.4% by weight, about 0% by weight to about 0.3% by weight, about 0.01% by weight to about 0.3% by weight, about 0.01% by weight to about 0.2% by weight, 0.02% by weight to about 0.1% by weight, or about 0.01% by weight to about 0.1% by weight. In some embodiments, the particulate composition comprises about 0% by weight, 0.01% by weight, 0.02% by weight, 0.05% by weight, 0.07% by weight, 0.1% by weight, 0.15% by weight, 0.2% by weight, 0.25% by weight, or 0.3% by weight of BMIQU. In some cases, the percentage by weight is relative to the total weight of encefentanyl.

[0034] The particulate composition optionally further comprises 1-(2-(9-hydroxy-2-(trimethylylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (9-demethyl impurity) and / or 1-(2-(10-hydroxy-2-(trimethylylimino)-9-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (10-demethyl impurity). The structures of these compounds are shown below.

[0035]

[0036] The particulate composition typically also comprises: a 9-demethyl impurity at a weight ratio greater than 0.00% to 0.10% relative to the total weight of encefentin; and / or a 10-demethyl impurity at a weight ratio greater than 0.00% to 0.10%. The particulate composition may further comprise a 9-demethyl impurity at a weight ratio of 0.01% to 0.10% relative to the total weight of encefentin and a 10-demethyl impurity at a weight ratio greater than 0.01% to 0.10%.

[0037] In some cases, the particulate composition also contains a 9-demethyl impurity. In some embodiments, the particulate composition contains about 0 to about 0.1% by weight of a 9-demethyl impurity. In some embodiments, the particulate composition contains at least 0.01% by weight (e.g., at least 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, or 0.2%) of a 9-demethyl impurity. In some embodiments, the particulate composition contains at most 0.3% by weight (e.g., at most 0.28%, 0.26%, 0.24%, 0.22%, 0.2%, 0.18%, 0.15%, or 0.1%) of a 9-demethyl impurity. In some embodiments, the particulate composition comprises about 0.01% by weight to about 0.3% by weight, 0.01% by weight to about 0.25% by weight, 0.01% by weight to about 0.2% by weight, 0.05% by weight to about 0.2% by weight, 0.01% by weight to about 0.1% by weight, or about 0.1% by weight to about 0.2% by weight of a 9-demethyl impurity. In some embodiments, the particulate composition comprises about 0% by weight, 0.01% by weight, 0.04% by weight, 0.06% by weight, 0.1% by weight, 0.12% by weight, 0.14% by weight, 0.16% by weight, 0.18% by weight, 0.2% by weight, 0.24% by weight, 0.28% by weight, or about 0.3% by weight of a 9-demethyl impurity. In some embodiments, the particulate composition comprises less than about 1% by weight of a 9-demethyl impurity.

[0038] In some cases, the particulate composition also contains a 10-demethyl impurity. In some embodiments, the particulate composition contains about 0 to about 0.1% by weight of a 10-demethyl impurity. In some embodiments, the particulate composition contains at least 0.01% by weight (e.g., at least 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, or 0.2%) of a 10-demethyl impurity. In some embodiments, the particulate composition contains at most 0.3% by weight (e.g., at most 0.28%, 0.26%, 0.24%, 0.22%, 0.2%, 0.18%, 0.15%, or 0.1%) of a 10-demethyl impurity. In some embodiments, the particulate composition comprises about 0.01% by weight to about 0.3% by weight, 0.01% by weight to about 0.25% by weight, 0.01% by weight to about 0.2% by weight, 0.01% by weight to about 0.1% by weight, 0.05% by weight to about 0.2% by weight, or about 0.1% by weight to about 0.2% by weight of a 10-demethyl impurity. In some embodiments, the particulate composition comprises about 0% by weight, 0.01% by weight, 0.04% by weight, 0.06% by weight, 0.1% by weight, 0.12% by weight, 0.14% by weight, 0.16% by weight, 0.18% by weight, 0.2% by weight, 0.24% by weight, 0.28% by weight, or about 0.3% by weight of a 10-demethyl impurity. In some embodiments, the particulate composition comprises less than about 1% by weight of a 10-demethyl impurity. For example, the particulate composition may contain: 0.01 to 0.04% by weight of 10-demethyl impurity; 0.05 to 0.09% by weight of 9-demethyl impurity; 0.01 to 0.03% by weight of biuret impurity; and 0.02 to 0.06% by weight of BMIQU, wherein the percentage by weight is relative to the total weight of encefentin in the particulate composition.

[0039] In some embodiments, the particulate composition may comprise: 0.01 to 0.4% by weight of 10-demethyl impurity; 0.05 to 0.9% by weight of 9-demethyl impurity; 0.01 to 0.5% by weight of biuret impurity; and 0.02 to 0.6% by weight of BMIQU, wherein the percentage by weight is relative to the total weight of encefentin in the particulate composition.

[0040] The particulate composition may also comprise (E)-2-(trimethylmethylimino)-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-(trimethylmethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4-one (compound (IV)), the structure of which is shown below. The particulate composition typically contains neither compound (I) nor compound (IV), or the particulate composition contains less than 0.04% by weight of compound (I) and compound (IV) relative to the total weight of encefentin.

[0041]

[0042] In some embodiments, the particulate composition comprises compound (I). In some embodiments, the particulate composition comprises about 0 to about 0.1% by weight of compound (I). In some embodiments, the particulate composition comprises at least 0.01% by weight (e.g., at least 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, or 0.2%) of compound (I). In some embodiments, the particulate composition comprises at most 0.3% by weight (e.g., at most 0.28%, 0.26%, 0.24%, 0.22%, 0.2%, 0.18%, 0.15%, or 0.1%) of compound (I). In some embodiments, the particulate composition comprises about 0.01% by weight to about 0.3% by weight, 0.01% by weight to about 0.25% by weight, 0.01% by weight to about 0.2% by weight, 0.01% by weight to about 0.1% by weight, 0.05% by weight to about 0.2% by weight, or about 0.1% by weight to about 0.2% by weight. In some embodiments, the particulate composition comprises about 0% by weight, 0.01% by weight, 0.04% by weight, 0.06% by weight, 0.1% by weight, 0.12% by weight, 0.14% by weight, 0.16% by weight, 0.18% by weight, 0.2% by weight, 0.24% by weight, 0.28% by weight, or about 0.3% by weight. In some embodiments, the particulate composition comprises less than about 1% by weight of compound (I).

[0043] In some embodiments, the particulate composition comprises compound (IV). In some embodiments, the particulate composition comprises about 0 to about 0.1% by weight of compound (IV). In some embodiments, the particulate composition comprises at least 0.01% by weight (e.g., at least 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, or 0.2%) of compound (IV). In some embodiments, the particulate composition comprises at most 0.3% by weight (e.g., at most 0.28%, 0.26%, 0.24%, 0.22%, 0.2%, 0.18%, 0.15%, or 0.1%) of compound (IV). In some embodiments, the particulate composition comprises about 0.01% by weight to about 0.3% by weight, 0.01% by weight to about 0.25% by weight, 0.01% by weight to about 0.2% by weight, 0.01% by weight to about 0.1% by weight, 0.05% by weight to about 0.2% by weight, or about 0.1% by weight to about 0.2% by weight. In some embodiments, the particulate composition comprises about 0% by weight, 0.01% by weight, 0.04% by weight, 0.06% by weight, 0.1% by weight, 0.12% by weight, 0.14% by weight, 0.16% by weight, 0.18% by weight, 0.2% by weight, 0.24% by weight, 0.28% by weight, or about 0.3% by weight. In some embodiments, the particulate composition comprises less than about 1% by weight of the compound (IV).

[0044] One or more of the following compounds: BMIQU, biuret impurity, 9-demethyl impurity, 10-demethyl impurity, compound (I), and compound (IV), if present, may optionally be present in the form of a salt. Typically, BMIQU, biuret impurity, 9-demethyl impurity, 10-demethyl impurity, compound (I), and compound (IV) are present as free bases.

[0045] In some embodiments, the particulate composition contains less than 15,000 ppm (e.g., less than 10,000 ppm, 5,000 ppm, or 2,500 ppm) of residual organic solvent. In some embodiments, the particulate composition contains 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).

[0046] In some embodiments, the residual organic solvent is an organic solvent remaining from the process of preparing encefentin. In some embodiments, the residual organic solvent is selected from acetone, acetonitrile, dichloromethane, methanol, toluene, tetrahydrofuran, dimethyl sulfoxide, or combinations thereof. In some embodiments, the residual organic solvent comprises, for example, a combination of acetone, acetonitrile, dichloromethane, methanol, toluene, tetrahydrofuran, and dimethyl sulfoxide in amounts described herein.

[0047] In some implementations, the amount of residual organic solvent is determined by gas chromatography.

[0048] In some embodiments, the residual organic solvent is acetone. In some embodiments, acetone is present in the particulate composition in an amount of less than 5000 ppm (e.g., less than 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or 1000 ppm). In some embodiments, acetone is present in the particulate composition in an amount of about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0049] In some embodiments, the residual organic solvent is acetonitrile. In some embodiments, acetonitrile is present in the particulate composition in an amount of less than 410 ppm (e.g., less than 400 ppm, 350 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm). In some embodiments, acetonitrile is present in the particulate composition in an amount of 100 ppm to 410 ppm (e.g., 100 ppm to 350 ppm, 200 ppm to 410 ppm, or 300 ppm to 400 ppm).

[0050] In some embodiments, the residual organic solvent is dichloromethane. In some embodiments, dichloromethane is present in the particulate composition in an amount of less than 5000 ppm (e.g., less than 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or 1000 ppm). In some embodiments, dichloromethane is present in the particulate composition in an amount of about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0051] In some embodiments, the residual organic solvent is methanol. In some embodiments, methanol is present in the particulate composition in an amount of less than 3000 ppm (e.g., less than 2500 ppm, 2000 ppm, 1500 ppm, 1000 ppm, or 500 ppm). In some embodiments, methanol is present in the particulate composition in an amount of 500 ppm to 3000 ppm (e.g., 1000 ppm to 3000 ppm, 1500 ppm to 3000 ppm, or 2000 ppm to 3000 ppm).

[0052] In some embodiments, the residual organic solvent is toluene. In some embodiments, toluene is present in the particulate composition in an amount of less than 5000 ppm (e.g., less than 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or 1000 ppm). In some embodiments, toluene is present in the particulate composition in an amount of about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0053] In some embodiments, the residual organic solvent is tetrahydrofuran. In some embodiments, tetrahydrofuran is present in the particulate composition in an amount of less than 720 ppm (e.g., less than 700 ppm, 650 ppm, 600 ppm, 550 ppm, 500 ppm, 450 ppm, or 400 ppm). In some embodiments, tetrahydrofuran is present in the particulate composition in an amount of 250 ppm to 720 ppm (e.g., 400 ppm to 720 ppm, 500 ppm to 720 ppm, or 600 ppm to 720 ppm).

[0054] In some embodiments, the residual organic solvent is dimethyl sulfoxide (DMSO). In some embodiments, DMSO is present in the particulate composition in an amount of less than 5000 ppm (e.g., less than 3500 ppm, 3000 ppm, 2500 ppm, 2000 ppm, 1500 ppm, or 1000 ppm). In some embodiments, DMSO is present in the particulate composition in an amount of about 100 ppm to 5000 ppm (e.g., 500 ppm to 5000 ppm, 1000 ppm to 5000 ppm, or 500 ppm to 4000 ppm).

[0055] 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.

[0056] 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.

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

[0058] In some embodiments, the elemental impurity is arsenic. In some embodiments, arsenic 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, 0.1 ppm, or less than 0.05 ppm).

[0059] 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).

[0060] 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, 0.1 ppm, or less than 0.05 ppm).

[0061] In some embodiments, the elemental impurity is mercury. In some embodiments, mercury is present in the particulate composition in an amount of 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).

[0062] In some embodiments, the elemental impurity is lithium. In some embodiments, lithium is present in the particulate composition in an amount of less than 200 ppm (e.g., less than 175 ppm, 150 ppm, 125 ppm, or 100 ppm).

[0063] 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.

[0064] The granular composition typically contains at least 98.0% by weight of encefentin relative to the total weight of the granular composition. The granular composition may contain at least 99.0% by weight of encefentin relative to the total weight of the granular composition, or at least 99.2% by weight of encefentin relative to the total weight of the granular composition.

[0065] In some embodiments, the particulate composition comprises at least 98% by weight (e.g., at least 98.5%, 98.9%, 99%, 99.2%, 99.4%, 99.6%, 99.8%, or 99.9% by weight) of encefentin relative to the total weight of the particulate composition. In some embodiments, the particulate composition comprises about 95% to about 99.9%, about 96% to about 99.9%, about 97% to about 99.5%, 97% to about 99% by weight, or about 98% to about 99.9% by weight relative to the total weight of the particulate composition.

[0066] The encefentin in the granule composition is the free base of encefentin. In other embodiments, the granule composition comprises a pharmaceutically acceptable salt of encefentin.

[0067] Encerfentin is typically found in crystalline form. In particulate compositions, at least 90% by weight of encerfentin is typically in the form of free base form I. Encerfentin free base form I is the crystalline polymorph of encerfentin (crystalline polymorph form I), which typically has a powder X-ray diffraction pattern containing characteristic peaks at 10.1° and 12.9° ± 0.1°2θ. As described herein, X-ray wavelengths typically using CuKα radiation are used. The value of 2θ is measured. The powder X-ray diffraction pattern of Form I typically also includes characteristic peaks at 15.3° and 17.6° ± 0.1°2θ. Form I of Encerfentin can 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. The crystalline polymorph Form I typically has a differential scanning calorimetry trace that shows a maximum value at 248°C.

[0068] The particulate composition typically contains at least 98.0% or at least 99.0% by weight of encefenstein crystalline polymorph I relative to the total weight of the particulate composition.

[0069] In some embodiments, the particulate composition comprises at least 98% by weight (e.g., at least 98.5%, 98.9%, 99%, 99.2%, 99.4%, 99.6%, 99.8%, or 99.9% by weight) of encefenstein crystalline polymorph I relative to the total weight of the particulate composition. In some embodiments, the particulate composition comprises about 95% to about 99.9%, about 96% to about 99.9%, about 97% to about 99.5%, 97% to about 99%, or about 98% to about 99.9% by weight relative to the total weight of the particulate composition.

[0070] Typically, the particulate composition comprises:

[0071] Encerfentin at a weight ratio of 99.4% to 99.9%;

[0072] BMIQU from 0.01% to 0.30% by weight;

[0073] Biuret impurities ranging from 0.00% to 0.10% by weight;

[0074] 9-Demethylated impurities ranging from 0.01% to 0.20% by weight; and

[0075] 10-Demethyl impurities ranging from 0.01% to 0.20% by weight.

[0076] The % weight ratio is relative to the total weight of the particulate composition.

[0077] The particulate composition may contain:

[0078] Encerfentin at a weight ratio of 99.5% to 99.9%;

[0079] BMIQU from 0.02% to 0.10% by weight;

[0080] Biuret impurities ranging from 0.00% to 0.04% by weight;

[0081] 9-Demethylated impurities ranging from 0.01% to 0.10% by weight; and

[0082] 10-Demethyl impurities ranging from 0.01% to 0.10% by weight.

[0083] The % weight ratio is relative to the total weight of the particulate composition.

[0084] For example, the particulate composition may consist of the following:

[0085] Encerfentin at a weight ratio of 99.6% to 99.9%;

[0086] BMIQU at 0.02% - 0.10% by weight;

[0087] Biuret impurities ranging from 0.00% to 0.04% by weight;

[0088] 9-Demethylated impurities, ranging from 0.01% to 0.10% by weight;

[0089] 10-Demethyl impurities ranging from 0.01% to 0.10% by weight; and

[0090] Other related substances not exceeding 0.36% by weight.

[0091] The % weight ratio is relative to the total weight of the particulate composition.

[0092] The particulate composition comprises particles containing encefentin and other impurity compounds as defined above. The particulate composition typically comprises particles of an inhalable size. The particulate composition typically has a Dv50 of about 0.2 to about 5.0 μm. The particulate composition may have a Dv50 of about 1.0 μm to about 2.2 μm.

[0093] The particulate 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 particulate 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).

[0094] The particulate composition may have a Dv10 of about 0.2 μm to about 1 μm. The particulate 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 particulate 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).

[0095] The particulate 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 particulate 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).

[0096] The particulate composition typically has a Dv10 of about 0.3 to 0.9 μm and / or a Dv90 of about 2.3 to 4.5 μm. The particulate composition may typically have a Dv50 of about 1.0 μm to about 2.2 μm, a Dv10 of about 0.3 μm to about 0.9 μm, and a Dv90 of about 2.3 μm to about 4.5 μm.

[0097] The techniques used to measure Dv50 (as well as Dv10 and Dv90) values, as described herein, are typically laser diffraction. The particle size distribution of a particulate composition can be measured using laser diffraction with a wet powder dispersion system. For example, particle size distribution can be measured by laser diffraction using a MalvernSpraytec in conjunction with a wet dispersion cell. Typically, the instrument parameters for a MalvernSpraytec are as follows:

[0098] • Granules - Standard opaque granules;

[0099] • Refractive index particles -1.50;

[0100] • Refractive index (imaginary part) -0.50;

[0101] • Particle density -1.00;

[0102] • The refractive index of the dispersant is -1.33;

[0103] • Controller unit - 1000 RPM;

[0104] • Measurement type - Timed;

[0105] • Initial sampling time -30s;

[0106] • Light blocking -20% to 30%;

[0107] • Dispersant - 1% deionized aqueous solution of polysorbate 20.

[0108] The particulate composition can be produced by any pharmaceutically acceptable particle size reduction method or particle size control manufacturing method. For example, particles can be produced by reducing the size of the solid form of encefentin, such as by air jet milling, mechanical micronization, or media milling, or by precipitation from a solution of encefentin. The present invention also provides a solid form of encefentin having the composition of the above-described particulate composition (i.e., comprising encefentin and one or more of the said impurity compounds), wherein the solid form is in the form of filter cake, pellets, blocks, layers, or crystals.

[0109] Pharmaceutical Composition

[0110] The present invention also provides pharmaceutical compositions comprising the said particulate composition. The pharmaceutical composition may be a dry powder suitable for administration, comprising the particulate composition and a carrier. The carrier may, for example, be lactose powder.

[0111] Typically, a 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.

[0112] The pharmaceutical composition may comprise any of the relevant substances described above (e.g., substances other than encefentin), and in the amounts described above. In some embodiments, the relevant substances include BMIQU, biuret impurities of formula (A), 9-demethyl impurities, and 10-demethyl impurities.

[0113] Pharmaceutical compositions typically contain a BMIQU of no more than 1.00% by weight relative to the total weight of encefentanil in the pharmaceutical composition. For example, a liquid pharmaceutical composition may contain a BMIQU of no more than 0.50% or no more than 0.20% by weight relative to the total weight of encefentanil.

[0114] The pharmaceutical composition may contain a biuret impurity in a weight ratio of not more than 0.10% or not more than 0.05% relative to the total weight of encefentin in the pharmaceutical composition.

[0115] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more tension modifiers, one or more buffers, and one or more surfactants. In some embodiments, the pharmaceutical compositions further comprise one or more tension modifiers. In some embodiments, the pharmaceutical compositions further comprise one or more buffers. In some embodiments, the pharmaceutical compositions further comprise one or more surfactants.

[0116] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more tension modifiers. In some embodiments, the tension modifier comprises sodium chloride. In some embodiments, the tension modifier (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 tension modifier (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 tension modifier (e.g., sodium chloride) is present in the pharmaceutical composition at concentrations of 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 tension modifier (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of about 7 mg / mL to about 10 mg / mL. In some embodiments, the tension modifier (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of 8 mg / mL to 9 mg / mL. In some embodiments, the tension modifier (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of (e.g., about) 8.6 mg / mL.

[0117] 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 a concentration of 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, a buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the pharmaceutical composition at a concentration of about 1.5 mg / mL to about 1.7 mg / mL.

[0118] In some embodiments, the pharmaceutical composition comprises 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 comprises 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 comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 0.9 mg / mL. In some embodiments, the pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL to about 0.8 mg / mL. In some embodiments, the pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL. In some embodiments, the pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration (e.g., about) 0.744 mg / mL.

[0119] In some embodiments, the pharmaceutical composition comprises 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 comprises 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 comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL to about 1 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.8 mg / mL to about 0.9 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.8 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.9 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration (e.g., about) of 0.853 mg / mL.

[0120] In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol 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 comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol 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 comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol monolaurate) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol monolaurate) at a concentration of about 0.01 mg / mL to 2 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol monolaurate) at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol monolaurate) at a concentration of about 0.5 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol monolaurate) at a concentration of about 0.6 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitol monolaurate) at a concentration (e.g., about) 0.55 mg / mL.

[0121] In some embodiments, the pharmaceutical composition comprises 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 comprises 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 comprises polysorbate 20 (e.g., Tween 20) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration of about 0.5 mg / mL.

[0122] In some embodiments, the pharmaceutical composition comprises sorbitol 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 comprises sorbitol 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 comprises sorbitol monolaurate (Span 20) at a concentration of about 0.03 mg / mL to about 0.07 mg / mL. In some embodiments, the pharmaceutical composition comprises sorbitol monolaurate (Span 20) at a concentration of about 0.04 mg / mL to about 0.06 mg / mL. In some embodiments, the pharmaceutical composition comprises sorbitol monolaurate (Span 20) at a concentration (e.g., about) of 0.05 mg / mL.

[0123] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition typically comprises: (i) a particulate composition at a concentration of 0.8 to 1.6 mg / mL; (ii) one or more surfactants at a total concentration of 0.1 to 1.0 mg / mL; (iii) one or more buffer solutions at a total concentration of 1.0 to 2.0 mg / mL; and (iv) water. The liquid pharmaceutical composition optionally also comprises a tension modifier, which may have a concentration of 1.0 to 20.0 mg / mL or 7.0 to 10.0 mg / mL. The tension modifier may be sodium chloride.

[0124] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise: (i) a particulate composition having a concentration of 1.0 to 1.4 mg / mL, the particulate composition having a Dv50 of about 1.0 μm to about 2.2 μm, and optionally having a Dv10 of about 0.3 μm to about 0.9 μm and a Dv90 of about 2.3 μm to about 4.5 μm; (ii) one or more surfactants having a total concentration of 0.4 to 0.7 mg / mL; (iii) one or more buffers having a total concentration of 1.4 to 1.8 mg / mL; (iv) water; and (v) a tension modifier having a concentration of 7.0 to 10.0 mg / mL.

[0125] The liquid pharmaceutical composition may contain at least 95% by weight or at least 99% by weight of (i), (ii), (iii), (iv), and optionally (v) relative to the total weight of the liquid pharmaceutical composition.

[0126] Examples of buffer solutions include citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer. Preferably, one or more of the buffer solutions comprise a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0127] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76 and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ether, polyoxyethylene glycol alkylphenol ether, glyceryl alkyl esters, polyoxyethylene glycol dehydrated sorbitan alkyl esters (polysorbates, e.g., polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80), dehydrated sorbitan alkyl esters (e.g., dehydrated sorbitan monolaurate (Span 20), dehydrated sorbitan monooleate (Span 20)). Span 80 and Sorbitol Trioleate (Span 85), Cocamide MEA, Cocamide DEA, Dodecyl Dimethylamine Oxide, Block Copolymers of Polyethylene Glycol and Polypropylene Glycol (Poloxamer), Block Copolymers of Polyethylene Glycol and Polypropylene Oxide (e.g., Pluronic Surfactant), Polyvinylpyrrolidone K25, Polyvinyl Alcohol, Polylactic Acid, Sodium Dioctyl Sulfosuccinate, and Polyethoxylated Tallow Acid (POEA).

[0128] Preferably, the one or more surfactants comprise polysorbate and / or sorbitol alkyl esters. One or more surfactants may, for example, comprise polysorbate 20 (polyoxyethylene (20) sorbitol monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitol monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitol monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitol monooleate). One or more surfactants may, for example, comprise sorbitol monolaurate (Span 20), sorbitol monooleate (Span 80), or sorbitol trioleate (Span 85). Preferably, one or more buffers comprise polysorbate 20 (Tween 20) and / or sorbitol monolaurate (Span 20).

[0129] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise: (i) a particulate composition having a concentration of 1.0 to 1.4 mg / mL, the particulate composition having a Dv50 of about 1.0 μm to about 2.2 μm, and optionally having a Dv10 of about 0.3 μm to about 0.9 μm and a Dv90 of about 2.3 μm to about 4.5 μm; (ii) one or more surfactants having a total concentration of 0.4 to 0.7 mg / mL, said one or more surfactants being selected from polysorbate and / or dehydrated sorbitol alkyl esters; (iii) one or more buffers having a total concentration of 1.4 to 1.8 mg / mL, said one or more buffers being selected from phosphate buffers; (iv) water; and (v) sodium chloride having a concentration of 7.0 to 10.0 mg / mL.

[0130] The liquid pharmaceutical composition may, for example, comprise, relative to the total weight of the liquid pharmaceutical composition:

[0131] - A particulate composition with a concentration of 1.0 to 1.4 mg / mL;

[0132] - Polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL;

[0133] - Anhydrous sorbitol monolaurate (Span 20) at a concentration of 0.0 to 0.1 mg / mL;

[0134] - Sodium dihydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL;

[0135] - Disodium hydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL;

[0136] - Sodium chloride at a concentration of 5 to 10 mg / mL; and

[0137] -water.

[0138] Liquid pharmaceutical compositions typically contain about 2.0 mg to about 4.0 mg of granular composition. Therefore, liquid pharmaceutical compositions typically contain about 2.0 mg to about 4.0 mg of encefentin.

[0139] In some embodiments, the liquid pharmaceutical composition is sterile. In specific embodiments, the liquid pharmaceutical composition is formulated according to USP. <71> It is sterile.

[0140] Liquid pharmaceutical compositions may have a concentration of less than or equal to 10. -3 Less than or equal to 10 -6 or less than or equal to 10 -9 The sterility assurance level (SAL). For example, an SAL of 10. -6 This means the probability that the final product is non-sterile is 1 / 10.6 Sterile liquid pharmaceutical compositions may have a total bioload limit of less than or equal to 10 CFU / mL, or less than or equal to 1 CFU / mL. “CFU” stands for colony-forming unit. Bioload can be measured using standards such as USP 31. <61> The plate counting method described in the text, such as the tilting plate method.

[0141] Typically, the sterility of liquid pharmaceutical compositions is determined according to USP. <71> Or as determined by Ph Eur 2.6.1. Liquid pharmaceutical compositions generally meet USP standards. <71> Or the acceptance criteria defined in Ph Eur 2.6.1. In some embodiments, the liquid pharmaceutical composition is stored in ampoules.

[0142] In some embodiments, exudates from the liquid pharmaceutical composition stored in the ampoule are evaluated 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 daily exposure ICH Q3D threshold and does not increase during storage.

[0143] In some embodiments, the liquid pharmaceutical composition comprises 3,3-dimethyl-1,5-dioxane-6,11-dione and 1,4,7-trioxane-8,13-dione in amounts less than the ICH M7 guideline threshold of toxicological concern. In some embodiments, the liquid pharmaceutical composition comprises 1,4,7-trioxane-8,13-dione in amounts less than the ICH M7 guideline threshold of toxicological concern.

[0144] A sprayer comprising the liquid pharmaceutical composition is also provided. The sprayer may be a soft mist sprayer, a vibrating mesh sprayer, a jet sprayer, or an ultrasonic sprayer. Typically, the sprayer is a jet sprayer.

[0145] In some embodiments, this document provides a kit comprising the particulate composition provided herein. In other embodiments, the kit comprises the liquid pharmaceutical composition provided herein.

[0146] In some implementations, the kit includes instructions for use of any of the particulate or liquid pharmaceutical compositions provided herein.

[0147] Treatment

[0148] Liquid pharmaceutical compositions are commonly used to treat or prevent diseases or disease states selected from the following: 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 disease state may be COPD or asthma. Typically, the disease or disease state is chronic obstructive pulmonary disease (COPD).

[0149] COPD

[0150] In some cases, (e.g., liquid) pharmaceutical compositions may be used in methods of treating COPD. In some cases, COPD is moderate. In some cases, COPD is severe.

[0151] The aforementioned stages of COPD can be classified as follows, where FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity.

[0152] Mild COPD: FEV1 / FVC < 0.7 and FEV1 ≥ 80% of predicted values.

[0153] • Moderate COPD: FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% of predicted COPD.

[0154] • Severe COPD: FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50% of predicted COPD.

[0155] • Very severe COPD: FEV1 / FVC < 0.7 and FEV1 < 30% of predicted levels

[0156] In each case, the patient's actual FEV1 is compared to a predicted FEV1 value based on factors such as the patient'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 the general US Population. AM J Respir Crit Care 1999; 159:179-187). An example of an equation used to calculate a patient's predicted FEV1 (in L) is as follows, where H is height (cm) and A is age (years):

[0157] ·Male: 0.0430H-0.0290A-2.490

[0158] ·Female: 0.0395H-0.025A-2.600

[0159] FEV1 and FVC, used to determine the severity of a patient's COPD, are measured by vital capacity determination shortly after administration of an adequate dose of at least one short-acting inhaled bronchodilator. In some embodiments, FEV1 and FVC measurements for determining COPD severity are performed 15 to 30 minutes after administration of salbutamol.

[0160] In some implementations, FEV1 and FVC as used herein are measured as described in Standardisation of Spirometry (Eur J 2005; 26; 319-338).

[0161] Moderate COPD has been identified in human individuals by measuring FEV1 values ​​predicted by FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80%, where FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity measured 15 to 30 minutes after administration of a bronchodilator, optionally salbutamol. Severe COPD has been identified in human individuals by measuring FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50%, where FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity measured 15 to 30 minutes after administration of a bronchodilator, optionally salbutamol. The determination of COPD severity in human individuals can be performed at least one day before the first administration of the composition. In some embodiments, treatment with the compositions disclosed herein increases mean FEV1 by at least about 75, 90, or 100 mL within 12 weeks after administration.

[0162] Valley value lung function

[0163] In some cases, (e.g., liquid) pharmaceutical compositions can be used in methods to increase trough lung function. In some cases, the increase in trough lung function in patients with COPD is determined by measuring an increase in trough FEV1, which is the patient's FEV1 shortly before administration of the composition as part of maintenance therapy. In some embodiments, the increase in trough lung function is 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 period of time following prior administration of the liquid pharmaceutical composition, compared to the individual's FEV1 before the first administration of the liquid pharmaceutical composition. In some embodiments, this period is about 11.5 to about 12 hours.

[0164] In some cases, (e.g., liquid) pharmaceutical compositions can be used to increase morning trough lung function. Morning trough lung function can be measured by measuring the patient's FEV1 shortly before administering the composition in the morning as part of maintenance therapy. For example, FEV1 can be measured less than 1 hour before administering the composition in the morning. Morning trough FEV1 can be FEV1 measured between 11.5 and 12 hours after the previous evening administration.

[0165] COPD worsening

[0166] In certain circumstances, (e.g., liquid) pharmaceutical compositions may be used in methods for reducing the frequency and / or severity of COPD exacerbations, in some embodiments of which 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 individuals who are not given the pharmaceutical compositions disclosed herein.

[0167] In some embodiments, the method includes increasing the time to the first COPD exacerbation in a human individual. Therefore, an individual may not have yet experienced a COPD exacerbation, and the pharmaceutical compositions disclosed herein can increase the time to the individual experiencing their first COPD exacerbation (the first COPD exacerbation is delayed). Therefore, the pharmaceutical compositions can reduce the risk of COPD exacerbations in patients with COPD. COPD exacerbations can include one or more of the following: dyspnea (breathing difficulty), worsening cough, increased sputum volume, purulent sputum, wheezing, sore throat, cold, and fever. Purulent sputum is a spontaneously expelled sample that changes color from unstained to yellowish-green. COPD exacerbations can last for at least one day or at least two days.

[0168] COPD exacerbations may include (A) worsening of two or more of the following primary symptoms over at least two consecutive days: dyspnea, sputum volume, and purulent sputum; or (B) worsening of any one primary symptom along with any of the following secondary symptoms over at least two consecutive days: sore throat, cold (nasal runny nose and / or nasal congestion), fever without other cause (oral temperature >37.5°C), and worsening cough. For example, a COPD exacerbation may include a worsening of two or more primary symptoms (dyspnea, sputum volume, and purulent sputum) over at least two consecutive days.

[0169] COPD exacerbations can be moderate or severe. A moderate exacerbation is defined as a worsening of COPD symptoms (as defined above) requiring at least three days of treatment with oral / systemic corticosteroids and / or antibiotics. A severe exacerbation is defined as a worsening of COPD symptoms (as defined above) requiring hospitalization. This compound can reduce the severity of COPD exacerbations in patients, and therefore can be used to prevent severe COPD exacerbations in patients. For example, a patient may not experience a severe COPD exacerbation within one year after the first administration of the compound.

[0170] Treatment plan

[0171] Liquid pharmaceutical compositions can be administered once, twice, or three times a day, or twice, three times, four times, or five times a week. For example, a pharmaceutical composition can be administered twice a day.

[0172] The method may include administering a two-dose (e.g., liquid) pharmaceutical composition to a human individual daily via inhalation, the pharmaceutical composition comprising approximately 3 mg of encefentin free base. The method may include administering a dose of approximately 3 mg of the pharmaceutical composition twice daily (3 mg BID) to a human individual via inhalation. In some cases, the method includes administering a dose of approximately 3 mg of the pharmaceutical composition twice daily to a human individual via a nebulizer. Each dose may be 3.0 mg of the free base encefentin administered via a nebulizer.

[0173] In some embodiments, the human individual may be male. In some embodiments, the human individual may be female. The human individual may be 65 years of age or older. The human individual may be under 65 years of age. The human individual may be taking one or more background medications selected from long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS). In some embodiments, the human individual is taking LAMA. In some embodiments, the human individual is taking LABA. In some embodiments, the human individual is taking ICS.

[0174] In some cases, the human individual is not receiving a background medication. For example, the human individual may not be taking a background medication that is a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), or an inhaled corticosteroid (ICS). In some embodiments, the human individual is not taking a LAMA. In some embodiments, the human individual is not taking a LABA. In some embodiments, the human individual is not taking an ICS.

[0175] The (e.g., liquid) pharmaceutical composition can be used as maintenance therapy. In some embodiments, the method includes administering the pharmaceutical composition to a human individual at least once daily for at least 8 weeks. The pharmaceutical composition may be administered to a human individual at least once daily for at least 16 weeks or at least 24 weeks. The method may include administering the pharmaceutical composition to a human individual for at least 1 year. The method may include administering the composition to a human individual at least once every 24 hours, at least twice every 24 hours, for at least 8 weeks, at least 16 weeks, or at least 24 weeks.

[0176] Preparation method

[0177] This article provides a method for preparing the particulate composition described herein.

[0178] A method for preparing a particulate composition may include 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.

[0179]

[0180] The solvent typically contains dichloromethane and water.

[0181] In some embodiments, the solvent comprises dichloromethane. In some embodiments, the solvent comprises water.

[0182] For example, the solvent may contain 30 to 60% by volume of dichloromethane and 30 to 60% by volume of water relative to the total volume of the solvent.

[0183] The solvent may contain about 30% by volume, about 35% by volume, about 40% by volume, about 45% by volume, about 50% by volume, about 55% by volume, or about 60% by volume of dichloromethane. The solvent may contain about 30% by volume, about 35% by volume, about 40% by volume, about 45% by volume, about 50% by volume, about 55% by volume, or about 60% by volume of water.

[0184] The solvent may contain 40 to 55% by volume of dichloromethane and 40 to 55% by volume of water relative to the total volume of the solvent. Based on the total volume of the solvent, the total content of dichloromethane and water in the solvent is typically at least 90% by volume or at least 95% by volume.

[0185] One equivalent of the compound of formula (IV) is typically reacted with 0.8 to 1.5 equivalents of 4-nitrophenyl chloroformate.

[0186] In some embodiments, the compound of formula (IV) is reacted with about 0.8 equivalents, about 0.85 equivalents, about 0.9 equivalents, about 0.95 equivalents, about 1 equivalent, about 1.05 equivalents, about 1.1 equivalents, about 1.15 equivalents, about 1.2 equivalents, about 1.25 equivalents, about 1.3 equivalents, about 1.35 equivalents, about 1.4 equivalents, about 1.45 equivalents, or about 1.5 equivalents of chloroformate.

[0187] The compound of formula (IV) can react with 1.0 to 1.2 equivalents of 4-nitrophenyl chloroformate.

[0188] 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.

[0189] The method 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 dichloromethane solution of 4-nitrophenyl chloroformate 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% ammonia water. The base in step (ii) is typically potassium bicarbonate.

[0190] In some cases, the method involves mixing a compound of formula (IV) with dichloromethane in a reactor. In some cases, the method involves adding an aqueous solution of a base to the reactor. In some cases, the method involves adding a dichloromethane solution of 4-nitrophenyl chloroformate to the reactor. In some cases, the method involves adding an ammonia solution to the reactor.

[0191] The organic phase products from steps (i) to (iv) are typically separated, concentrated, and then mixed with methanol to produce a suspension of the particulate composition. The method may further include drying, recrystallization, and optionally, particle size reduction of the particulate composition.

[0192] The invention is described in more detail through the following embodiments. Example

[0193] method

[0194] Ultra-high performance liquid chromatography (UPLC)

[0195] • Column: Acquity UPLC BEH phenyl 100mm × 2.1mm, 1.7μm

[0196] • Detector wavelength: 254nm

[0197] • Refractometer sensitivity: N / AP

[0198] • Refractometer temperature: N / AP

[0199] Column temperature: 35℃

[0200] • Autosampler temperature: N / AP

[0201] • Flow rate: 0.53 mL / min

[0202] Injection volume: 1 μL

[0203] Runtime: 11.10 min

[0204] Gradient procedure:

[0205] Time (minutes) % Mobile phase A % Mobile phase B 0 97 3 2.27 70 30 4.86 55 45 6.48 5 95 7.45 5 95 8.1 97 3 11.1 97 3

[0206] • Mobile phase, washing solution and dissolving mixture

[0207] ○Mobile phase A: Water / trifluoroacetic acid (100 / 0.1, v / v) (Accurately transfer 1000 mL of water and 1 mL of trifluoroacetic acid to a suitable flask, mix thoroughly and degas before use.)

[0208] ○Mobile phase B: Acetonitrile / trifluoroacetic acid (100 / 0.1, v / v) (Accurately transfer 1000 mL of acetonitrile and 1 mL of trifluoroacetic acid to a suitable flask, mix thoroughly and degas before use.)

[0209] ○ Dissolving the mixture (diluent): Acetonitrile / water (50 / 50, v / v) (Transfer 500 mL of acetonitrile to a suitable flask and add 500 mL of water. Mix thoroughly and degas before use.)

[0210] ○ Needle wash: Acetonitrile / water (50 / 50, v / v) (Transfer 500 mL of acetonitrile to a suitable flask and add 500 mL of water. Mix thoroughly and degas before use.)

[0211] ○ 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 thoroughly and degas before use.)

[0212] ○ Equipment washing (column storage): Acetonitrile / water (90 / 10, v / v) (Transfer 900 mL of acetonitrile to a suitable flask and add 100 mL of water. Homogenize and degas before use.)

[0213] Example 1 - Preparation of Encerfentin

[0214] Preparation of (E)-3-(2-aminoethyl)-2-(trimethylmethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one

[0215]

[0216] 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 distillation under reduced pressure. Tetrahydrofuran was added. The resulting solid product was separated by filtration.

[0217] NMR and single-crystal X-ray diffraction analyses showed that the product was a cyclic ammonium bromide salt (II) with the following structure.

[0218]

[0219] Under hydrogenation conditions using Raney nickel and 7N methanol ammonia, the cyclic ammonium bromide salt (II) undergoes ring-opening to produce (E)-2-(2-(trimethylmethylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)acetonitrile (compound (III)).

[0220]

[0221] It was reduced in situ to produce (E)-3-(2-aminoethyl)-2-(trimethylmethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (compound (IV)).

[0222]

[0223] Encerfentin is produced from compound (IV) using sodium cyanate.

[0224]

[0225] Use sodium cyanate to convert compound (IV) to encefentin (compound (V)).

[0226] Add 70.4 mL of methanol to 8.0 g of compound (IV). Over 30 minutes, add a solution of 1.80 g sodium cyanate (1.5 equivalents) in 18.4 mL of deionized water (2.3 volumes). Heat the mixture to 55–65 °C. Over 15 minutes, add a solution of 1.68 mL hydrochloric acid (1.1 equivalents) and 24.0 mL of deionized water (3 volumes), while maintaining the temperature at 55–65 °C. Stir the suspension under reflux for at least 2 hours. Cool the suspension to 0–5 °C and stir for 1 hour. Filter the suspension and wash the filter cake with deionized water. Then dry the filter cake under vacuum to produce the product.

[0227] The products were obtained by UPLC analysis. The composition of the products is listed in Table 1 below.

[0228]

[0229] Table 1

[0230] Biuret impurities (RRT 0.98) are not easily removed by recrystallization.

[0231] The structure of the impurity is shown below.

[0232]

[0233]

[0234] Encerfentin was produced from compound (IV) using nitrophenyl chloroformate and ammonia.

[0235] The following procedure is used to convert compound (IV) to encefentin using nitrobenzene chloroformate and ammonia.

[0236] Add 660.0 mL of dichloromethane (5 volumes) to a reactor containing 132.0 g of compound (IV). Add a solution of 153.12 g of potassium bicarbonate in 1320.0 mL of deionized water (10 volumes) to the reactor and adjust the mixture to a temperature of 0 to 5 °C. Then add a solution of 660.0 mL of dichloromethane (5 volumes) and 73.47 g of 4-nitrophenyl chloroformate (1.2 equivalents), maintaining the temperature at 0 to 10 °C. Then stir the mixture at 5 to 10 °C for at least 2 hours, and then add 1320.0 mL of 25% ammonia water (10 volumes). Then stir the mixture overnight at 25 to 35 °C. Stop stirring and allow the phases to separate for at least 15 minutes. The organic phase contains the product. Extract the aqueous phase with 660 mL of dichloromethane, and wash the combined organic phases with 660 mL of deionized water. The organic phase was filtered, and the reactor and filter were washed with 132.0 mL of dichloromethane. The filtrate was then concentrated, and methanol was added. The resulting suspension was heated and stirred. The suspension was cooled to 15–25 °C and filtered. The filter cake was washed with methanol and then dried under vacuum to obtain the product.

[0237] The products were obtained by UPLC analysis. The composition of the products is listed in Table 2 below.

[0238]

[0239] Table 2

[0240] Only a very small amount of biuret impurities are produced (RRT 0.98).

[0241] Example 2 - Preparation of a larger batch of encefentin

[0242] Larger quantities of encefentin were prepared using 4-nitrophenyl chloroformate and ammonia. The obtained drug substance was analyzed by UPLC. The major impurities present in the drug substance are shown in Table 3 below.

[0243]

[0244]

[0245] Table 3

[0246] Example 3 - Preparation of Aqueous Suspension Formulation

[0247] The pharmaceutical material obtained from Example 2 was micronized and subjected to dry heat treatment at 160°C for at least 120 minutes to produce sterile encefentin particles. The sterile encefentin particles obtained by dry heat treatment were mixed with a suspension carrier under aseptic conditions to obtain a sterile suspension formulation containing encefentin, having the composition shown in Table 4.

[0248] Components Concentration (mg / mL) Sterilized Encerfentin granules (RPL554) 1.2 Polysorbate 20 (Tween 20) 0.50 Sorbitol monolaurate (Span 20) 0.05 Sodium dihydrogen phosphate dihydrate 0.744 Disodium hydrogen phosphate dihydrate 0.853 Sodium chloride solution 8.60 water Add appropriate amount to 1mL

[0249] Table 4

[0250] HPLC evaluation of the suspension formulation revealed that the content of the impurity bis-(trimethylisoquinolone)urea (BMIQU) was no more than 0.6% by weight relative to the total amount of encefentin in the suspension formulation.

Claims

1. A granular composition comprising encainide, wherein the granular composition further comprises: from greater than 0.00% to 0.60% by weight of 1,3-bis(2-(2-(mesityl imino)-9,10- dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1 -a]isoquinolin-3(4H)-yl)ethyl)urea (BMIQU) relative to the total weight of encainide; and from 0.00% to 0.50% by weight of a biuret impurity of Formula (A) relative to the total weight of encainide:

2. The granular composition of claim 1, wherein the granular composition comprises from 0.00% to 0.30% by weight of biuret impurity relative to the total weight of encainide.

3. The granular composition of claim 1 or 2, wherein the granular composition comprises from 0.00% to 0.05% by weight of biuret impurity relative to the total weight of encainide.

4. The granular composition of any preceding claim, wherein the granular composition comprises from 0.01 % to 0.30% by weight of BMIQU relative to the total weight of encainide.

5. The granular composition of any preceding claim, wherein the granular composition comprises from 0.02% to 0.06% by weight of BMIQU relative to the total weight of encainide.

6. The granular composition of any preceding claim, wherein the granular composition further comprises: from greater than 0.00% to 0.10% by weight of 1 -(2-(9-hydroxy-2-(mesityl imino)-10- methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1 -a]isoquinolin-3(4H)-yl)ethyl)urea (9- desmethyl impurity); and / or from greater than 0.00% to 0.10% by weight of 1 -(2-(10-hydroxy-2-(mesityl imino)-9- methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1 -a]isoquinolin-3(4H)-yl)ethyl)urea (10- desmethyl impurity).

7. The granular composition of any preceding claim, wherein the granular composition comprises at least 98.0% by weight of encainide relative to the total weight of the granular composition.

8. The granular composition of any preceding claim, wherein the granular composition comprises at least 99.0% by weight of encainide relative to the total weight of the granular composition, optionally at least 99.2% by weight of encainide relative to the total weight of the granular composition.

9. The granular composition of any preceding claim, wherein the granular composition comprises: 99.4 to 99.9% by weight of encainide; 0.01 % to 0.30% by weight of BMIQU; 0.00% to 0.10% by weight of biuret impurity; 0.01 % to 0.20% by weight of 9-desmethyl impurity; and 0.00% to 0.10% by weight of 10-desmethyl impurity. 0.01 to 0.20% w / w of 10-desmethyl impurity, wherein the % w / w is relative to the total weight of the granular composition.

10. The granular composition of any one of the preceding claims, wherein the granular composition comprises: 99.5 to 99.9% w / w of ambrisentan; 0.02 to 0.10% w / w of BMIQU; 0.00 to 0.04% w / w of biuret impurity; 0.01 to 0.10% w / w of 9-desmethyl impurity; and 0.01 to 0.10% w / w of 10-desmethyl impurity, wherein the % w / w is relative to the total weight of the granular composition.

11. The granular composition of any one of the preceding claims, wherein the granular composition consists of: 99.6 to 99.9% w / w of ambrisentan; 0.02 to 0.10% w / w of BMIQU; 0.00 to 0.04% w / w of biuret impurity; 0.01 to 0.10% w / w of 9-desmethyl impurity; 0.01 to 0.10% w / w of 10-desmethyl impurity; and not more than 0.36% w / w of total other related substances, wherein the % w / w is relative to the total weight of the granular composition.

12. The granular composition of any one of the preceding claims, wherein the granular composition has a Dv50 of about 0.2 to about 5.0 pm.

13. The granular composition of claim 12, wherein the granular composition has a Dv50 of about 1.0 pm to about 2.2 pm.

14. The granular composition of any one of the preceding claims, wherein the granular composition has a Dv10 of about 0.3 pm to about 0.9 pm and / or a Dv90 of about 2.3 pm to about 4.5 pm.

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

16. The liquid pharmaceutical of claim 15, wherein the granular composition is suspended in the diluent.

17. The liquid pharmaceutical composition of claim 15 or 16, wherein the liquid pharmaceutical composition comprises no more than 1.00% w / w of BMIQU relative to the total weight of ambrisentan.

18. The liquid pharmaceutical composition of claim 17, wherein the liquid pharmaceutical composition comprises no more than 0.50% w / w of BMIQU relative to the total weight of ambrisentan.

19. The liquid pharmaceutical composition of any one of claims 15 to 18, wherein the liquid pharmaceutical composition comprises, relative to the total weight of the liquid pharmaceutical composition: a) the granular composition at a concentration of 0.8 to 1.6 mg / mL; b) one or more surfactants at a total concentration of 0.1 to 1.0 mg / mL; c) one or more buffers at a total concentration of 1.0 to 2.0 mg / ml; and d) water.

20. The liquid pharmaceutical composition of any one of claims 15 to 19, wherein the liquid pharmaceutical composition comprises, relative to the total weight of the liquid pharmaceutical composition: a) the particulate composition at a concentration of 1.0 to 1.4 mg / mL; b) polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL; c) sorbitan monolaurate (Span 20) at a concentration of 0.0 to 0.1 mg / mL; d) sodium phosphate dibasic dihydrate at a concentration of 0.5 to 1.0 mg / mL; e) sodium phosphate monobasic dihydrate at a concentration of 0.5-1.0 mg / mL; f) sodium chloride at a concentration of 5 to 10 mg / mL; and g) water.

21. The liquid pharmaceutical composition of any one of claims 15 to 20, wherein the liquid pharmaceutical composition comprises about 2.0 mg to about 4.0 mg of the particulate composition.

22. The liquid pharmaceutical composition of any one of claims 15 to 21, wherein the liquid pharmaceutical composition is a suspension comprising, relative to the total weight of the liquid pharmaceutical composition: a) 1.2 mg / mL of ertugliflozin; b) 0.5 mg / ml of polysorbate 20; c) 0.05 mg / ml of sorbitan monolaurate; d) 0.744 mg / ml of sodium phosphate dibasic; e) 0.853 mg / ml of sodium phosphate monobasic; f) 8.6 mg / ml of sodium chloride; and g) water.

23. A method of: a) treating moderate chronic obstructive pulmonary disease (COPD), b) treating severe COPD, c) increasing trough lung function, or d) reducing the frequency of COPD exacerbations; in a human individual in need thereof; the method comprising administering to the human individual by inhalation the particulate composition of any one of claims 1 to 14 or the liquid pharmaceutical composition of any one of claims 15 to 22.

24. A method for producing the particulate composition as defined in any one of claims 1 to 14, the method comprising: reacting a compound of formula (IV) with 4-nitrophenyl chloroformate and ammonia, wherein the compound of formula (IV), the 4-nitrophenyl chloroformate and the ammonia are reacted in a solvent comprising dichloromethane, 25. The method of claim 24, wherein 1 equivalent of the compound of formula (IV) is reacted with 0.8 to 1.5 equivalents of 4-nitrophenyl chloroformate, optionally with 1.0 to 1.2 equivalents of 4-nitrophenyl chloroformate.

26. The method of claim 24 or 25, wherein the method comprises: (i) mixing the compound of formula (IV) with dichloromethane in a reactor; (ii) adding an aqueous solution of a base to the reactor; (iii) adding a dichloromethane solution of 4-nitrophenyl chloroformate to the reactor; and (iv) adding an ammonia solution to the reactor.

27. The method of claim 26, wherein the base in step (ii) is potassium bicarbonate.

28. A kit comprising the granular composition of any one of claims 1 to 14 or the liquid pharmaceutical composition of any one of claims 15 to 22.

Images