IP Library › Granted Patent US 12,251,384
Granted Patent B1
US 12,251,384 · App. 18/949,105 · Granted Mar 18, 2025

Particulate composition

Inventors: Peter Lionel Spargo (Cardiff, GB); Kevin Stephen Turner (Cardiff, GB)
Assignee: Verona Pharma PLC
A61K31/519A61K9/0073
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Quick Facts
Patent No.
US 12,251,384
App. No.
18/949,105
Granted
Mar 18, 2025
Kind
B1
Abstract

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.

Claims (66)

1. 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. A particulate composition as claimed in claim 1 , further comprising a biuret impurity of formula (A):

3. A particulate composition as claimed in claim 1 , wherein there is no detectable biuret impurity of formula (A):

based on HPLC measurement.

4. A particulate composition as claimed in claim 2 , wherein there is from 0.01 wt % to 1.0 wt % of the biuret impurity of formula (A) relative to the total weight of ensifentrine.

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

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

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

8. 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.

9. The particulate composition 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 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).

11. 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.

12. The particulate composition 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 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.

14. A particulate composition 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 particulate composition 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 particulate composition of claim 1 , wherein the particulate composition has a Dv50 of from about 0.2 to about 5.0 μm.

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

18. 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.

19. A liquid pharmaceutical composition suitable for administration by inhalation comprising (a) the particulate composition of claim 1 ; and (b) a diluent.

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

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

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 dihydrate;

e) 0.853 mg/ml disodium hydrogen phosphate dihydrate;

f) 8.6 mg/ml sodium chloride; and

g) water.

Assignments (1)
CHANGE OF NAME Recorded Jan 12, 2026
From: VERONA PHARMA PLC
To: VERONA PHARMA LIMITED
Reel/Frame 073534/0491 →
Priority Claims (1)
GB 2309605 · Jun 26, 2023 · national
Continuity (3)
Continuation 18753759 · Jun 25, 2024
Provisional Application 63550786 · Feb 7, 2024
Provisional Application 63550792 · Feb 7, 2024
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US 12,409,180