PARTICULATE COMPOSITION

1 . A method of treating chronic obstructive pulmonary disease, comprising administering by inhalation to a patient in need thereof an effective amount of a particulate composition comprising ensifentrine, wherein the particulate composition further comprises from about 0.01 wt % to about 1.0 wt % of 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) relative to the total weight of ensifentrine.

2 . The method of claim 1 , wherein the particulate composition further comprises a biuret impurity of formula (A):

3 . The method of claim 1 , wherein the particulate composition has no detectable biuret impurity of formula (A):

based on HPLC measurement.

4 . The method of claim 2 , wherein the particulate composition has from 0.01 wt % to 1.0 wt % of the biuret impurity of formula (A) relative to the total weight of ensifentrine.

5 . The method of claim 4 , wherein the particulate composition has an amount of biuret impurity (A) from 0.01 wt % to 0.30 wt % relative to the total weight of ensifentrine.

6 . The method of claim 5 , wherein the particulate composition has an amount of biuret impurity (A) from 0.01 wt % to 0.10 wt % relative to the total weight of ensifentrine.

7 . The method of claim 6 , wherein the particulate composition has an amount of biuret impurity (A) from 0.01 wt % to 0.05 wt % relative to the total weight of ensifentrine.

8 . The method of claim 1 , wherein the particulate composition comprises from 0.01 wt % to 0.30 wt % of BMIQU relative to the total weight of ensifentrine.

9 . The method of claim 8 , wherein the particulate composition comprises from 0.02 wt % to 0.10 wt % of BMIQU relative to the total weight of ensifentrine.

10 . The method of claim 1 , wherein the particulate composition further comprises:

from greater than 0.00 wt % to 0.10 wt % of 1-(2-(9-hydroxy-2-(mesitylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (9-des-methyl impurity); or

from greater than 0.00 wt % to 0.10 wt % of 1-(2-(10-hydroxy-2-(mesitylimino)-9-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (10-des-methyl impurity).

11 . The method of claim 1 , wherein the particulate composition comprises at least 98.0 wt % of ensifentrine relative to the total weight of the particulate composition.

12 . The method of claim 10 , wherein the particulate composition comprises at least 99.0 wt % of ensifentrine relative to the total weight of the particulate composition, optionally at least 99.2 wt % of ensifentrine relative to the total weight of the particulate composition.

13 . The method of claim 1 , wherein the particulate composition comprises:

from 99.4 to 99.9 wt % of ensifentrine;

from 0.01 wt % to 0.30 wt % of BMIQU;

from 0.01 wt % to 0.10 wt % of the biuret impurity;

from 0.01 wt % to 0.20 wt % of the 9-des-methyl impurity; and

from 0.01 wt % to 0.20 wt % of the 10-des-methyl impurity,

wherein the wt % is relative to the total weight of the particulate composition.

14 . The method of claim 13 , wherein the particulate composition comprises:

from 99.5 to 99.9 wt % of ensifentrine;

from 0.02 wt % to 0.10 wt % of BMIQU;

from 0.01 wt % to 0.04 wt % of the biuret impurity;

from 0.01 wt % to 0.10 wt % of the 9-des-methyl impurity; and

from 0.01 wt % to 0.10 wt % of the 10-des-methyl impurity,

wherein the wt % is relative to the total weight of the particulate composition.

15 . The method of claim 13 , wherein the particulate composition consists of:

from 99.6 to 99.9 wt % of ensifentrine;

from 0.02 wt % to 0.10 wt % of BMIQU;

from 0.01 wt % to 0.04 wt % of the biuret impurity;

from 0.01 wt % to 0.10 wt % of the 9-des-methyl impurity;

from 0.01 wt % to 0.10 wt % of the 10-des-methyl impurity; and

no greater than 0.36 wt % total of other related substances,

wherein the wt % is relative to the total weight of the particulate composition.

16 . The method of claim 1 , wherein the particulate composition has a Dv50 of from about 0.2 to about 5.0 μm.

17 . The method of claim 15 , wherein the particulate composition has a Dv50 of from about 1.0 μm to about 2.2 μm.

18 . The method of claim 1 , wherein the particulate composition has a Dv10 of from about 0.3 μm to about 0.9 μm or a Dv90 of from about 2.3 μm to about 4.5 μm.

19 . The method of claim 1 , wherein the particulate composition is combined with a diluent to provide a liquid pharmaceutical composition suitable for administration by inhalation.

20 . The method of claim 18 , wherein the particulate composition is suspended in the diluent.

21 . The method of claim 18 , wherein the liquid pharmaceutical composition comprises no more than 1.0 wt % of BMIQU relative to the total weight of ensifentrine.

22 . The method of claim 20 , wherein the liquid pharmaceutical composition comprises no more than 0.50 wt % of BMIQU relative to the total weight of ensifentrine.

23 . The method of claim 21 , wherein the liquid pharmaceutical composition comprises:

a. the particulate composition at a concentration of from 0.8 to 1.6 mg/ml;

b. one or more surfactants at a total concentration of from 0.1 to 1.0 mg/ml;

c. one or more buffers at a total concentration of from 1.0 to 2.0 mg/ml; and

d. water.

24 . The method of claim 22 , wherein the liquid pharmaceutical composition comprises:

a. the particulate composition at a concentration of from 1.0 to 1.4 mg/ml;

b. polysorbate 20 at a concentration of 0.3 to 0.7 mg/ml;

c. sorbitan monolaurate at a concentration of 0.0 to 0.1 mg/ml;

d. sodium dihydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg/mL;

e. disodium hydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg/mL;

f. sodium chloride at a concentration of 5 to 10 mg/mL; and

g. water.

25 . The method of claim 19 , wherein the liquid pharmaceutical composition comprises from about 2.0 mg to about 4.0 mg of the particulate composition.

26 . The method of claim 23 , wherein the liquid pharmaceutical composition is a suspension comprising:

a. 1.2 mg/mL particulate composition;

b. 0.5 mg/ml polysorbate 20;

c. 0.05 mg/ml sorbitan monolaurate;

d. 0.744 mg/ml sodium dihydrogen phosphate dihydrate;

e. 0.853 mg/ml disodium hydrogen phosphate dihydrate;

f. 8.6 mg/ml sodium chloride; and

g. water.

27 . The method of claim 23 , wherein the liquid pharmaceutical composition is a suspension comprising:

a. 1.4 mg/mL particulate composition;

b. 0.55 mg/ml polysorbate 20;

c. 0.744 mg/ml sodium dihydrogen phosphate dihydrate;

d. 0.853 mg/ml disodium hydrogen phosphate dihydrate;

e. 8.6 mg/ml sodium chloride; and

f. water.

28 . The method of claim 23 , wherein the liquid pharmaceutical composition is a suspension comprising:

a. 1.4 mg/mL particulate composition;

b. 0.55 mg/ml sorbitan monolaurate;

c. 0.744 mg/ml sodium dihydrogen phosphate dihydrate;

d. 0.853 mg/ml disodium hydrogen phosphate dihydrate;

e. 8.6 mg/ml sodium chloride; and

f. water.

29 . The method of claim 23 , wherein the liquid pharmaceutical composition is a suspension comprising:

a. 0.8 mg/mL particulate composition;

b. 0.5 mg/ml polysorbate 20;

c. 0.05 mg/ml sorbitan monolaurate;

d. 1.1 mg/ml sodium dihydrogen phosphate dihydrate;

e. 0.9 mg/ml disodium hydrogen phosphate dihydrate;

f. 13 mg/ml sodium chloride; and

g. water.

30 . The method of claim 23 , wherein the liquid pharmaceutical composition is a suspension comprising:

a. 1.4 mg/mL particulate composition;

b. 0.4 mg/ml polysorbate 20;

c. 0.04 mg/ml sorbitan monolaurate;

d. 0.744 mg/ml sodium dihydrogen phosphate dihydrate;

e. 0.853 mg/ml disodium hydrogen phosphate dihydrate;

f. 8.6 mg/ml sodium chloride; and

g. water.

31 . The method of claim 23 , wherein the liquid pharmaceutical composition is a suspension comprising:

a. 1.4 mg/mL particulate composition;

b. 0.4 mg/ml polysorbate 20;

c. 0.04 mg/ml sorbitan monolaurate;

d. 1.4 mg/ml sodium dihydrogen phosphate dihydrate;

e. 8.6 mg/ml sodium chloride; and

f. water.

32 . The method of claim 21 , wherein the liquid pharmaceutical composition comprises:

a. the particulate composition at a concentration of from 0.8 to 1.6 mg/ml;

b. one or more surfactants at a total concentration of from 0.1 to 1.0 mg/ml;

c. one or more buffers at a total concentration of from 1.0 to 2.0 mg/ml;

d. one or more tonicity adjusters at a concentration of from 1.0 to 20.0 mg/ml and

e. water.