Claims for Patent: 12,251,384

Summary for Patent: 12,251,384

Title:	Particulate composition
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.
Inventor(s):	Peter Lionel Spargo, Kevin Stephen Turner
Assignee:	Verona Pharma PLC
Application Number:	US18/949,105
Patent Claims:	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.