Particulate composition
The disclosure relates to a particulate composition comprising ensifentrine, wherein the particulate composition further comprises: from greater than 0.00 wt % to 0.60 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; and from 0.00 wt % to 0.50 wt % of a biuret impurity of formula (A) relative to the total weight of ensifentrine. Further disclosed herein are liquid pharmaceutical compositions comprising the particulate composition, and a process for producing the particulate composition are also described.
1. A particulate composition comprising ensifentrine, wherein the particulate composition further comprises:
from greater than 0.005 wt % to 0.60 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; and
from 0.01 wt % to 0.50 wt % of a biuret impurity of formula (A) relative to the total weight of ensifentrine:
2. The particulate composition of claim 1 , wherein the particulate composition comprises from 0.01 wt % to 0.30 wt % of the biuret impurity relative to the total weight of ensifentrine.
3. The particulate composition of claim 2 , wherein the particulate composition comprises from 0.01 wt % to 0.05 wt % of the biuret impurity relative to the total weight of ensifentrine.
4. The particulate composition 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.
5. The particulate composition of claim 4 , wherein the particulate composition comprises from 0.02 wt % to 0.06 wt % of BMIQU relative to the total weight of ensifentrine.
6. The particulate composition 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).
7. The particulate composition of claim 1 , wherein the particulate composition comprises at least 98.0 wt % of ensifentrine relative to the total weight of the particulate composition.
8. The particulate composition of claim 7 , 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.
9. The particulate composition 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.
10. A particulate composition of claim 9 , 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.
11. The particulate composition of claim 10 , 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.
12. The particulate composition of claim 1 , wherein the particulate composition has a Dv50 of from about 0.2 to about 5.0 μm.
13. The particulate composition of claim 12 , wherein the particulate composition has a Dv50 of from about 1.0 μm to about 2.2 μm.
14. The particulate composition 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.
15. A liquid pharmaceutical composition suitable for administration by inhalation comprising (a) the particulate composition of claim 1 ; and (b) a diluent.
16. The liquid pharmaceutical of claim 15 , wherein the particulate composition is suspended in the diluent.
17. The liquid pharmaceutical composition of claim 15 , wherein the liquid pharmaceutical composition comprises no more than 1.00 wt % of BMIQU relative to the total weight of ensifentrine.
18. The liquid pharmaceutical composition of claim 17 , wherein the liquid pharmaceutical composition comprises no more than 0.50 wt % of BMIQU relative to the total weight of ensifentrine.
19. The liquid pharmaceutical composition of claim 18 , wherein the liquid pharmaceutical composition comprises, relative to the total weight of the liquid pharmaceutical composition:
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.
20. The liquid pharmaceutical composition of claim 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 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.
21. The liquid pharmaceutical composition of claim 15 , wherein the liquid pharmaceutical composition comprises from about 2.0 mg to about 4.0 mg of the particulate composition.
22. The liquid pharmaceutical composition of claim 20 , wherein the liquid pharmaceutical composition is a suspension comprising, relative to the total weight of the liquid pharmaceutical composition:
a) 1.2 mg/mL ensifentrine;
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.