LIQUID PHARMACEUTICAL COMPOSITION
The invention relates to a liquid pharmaceutical composition comprising a dose of a compound which is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the liquid pharmaceutical composition provides a blood plasma concentration of ensifentrine after administration by inhalation to a human subject having COPD, which blood plasma concentration of ensifentrine has: a mean C max of from about 400 pg/mL to about 720 pg/mL; and/or a mean AUC 0-tau of from about 2000 pg/mL*h to about 3000 pg/mL*h; and/or a mean T max at from about 0.6 hours to about 1.5 hours. The invention also provides a method of treating COPD.
1 . A method of treating chronic obstructive pulmonary disease (COPD) in a human subject, the method comprising administering to the human subject by inhalation a liquid pharmaceutical composition comprising a therapeutically effective dose of ensifentrine or a pharmaceutically acceptable salt thereof,
wherein the liquid pharmaceutical composition provides a blood plasma concentration of ensifentrine after administration by inhalation to the human subject, the blood plasma concentration of ensifentrine comprising one or more of:
a mean C max of from about 400 pg/mL to about 720 pg/mL;
a mean AUC 0-tau of from about 2000 pg/mL*h to about 3000 pg/mL*h; and
a mean T max of from about 0.6 hours to about 1.5 hours.
2 . The method of claim 1 , wherein the blood plasma concentration of ensifentrine comprises a mean C max of from about 500 pg/mL to about 600 pg/mL.
3 . The method of claim 1 , wherein the blood plasma concentration of ensifentrine comprises a mean AUC 0-tau of from about 2300 pg/mL*h to about 2600 pg/mL*h.
4 . The method of claim 1 , wherein the blood plasma concentration of ensifentrine comprises a mean T max of from about 0.8 hours to about 1.3 hours.
5 . The method of claim 1 , wherein the blood plasma concentration of ensifentrine comprises:
a mean C max of from about 500 pg/mL to about 600 pg/mL; and
a mean AUC 0-tau of from about 2350 pg/mL*h to about 2550 pg/mL*h; and
a mean T max of from about 0.8 hours to about 1.3 hours.
6 . The method of claim 1 , wherein the mean C max , the mean AUC 0-tau , and the mean T max are measured at intervals,
wherein the intervals comprise two or more of 1.0 h (±0.5 h), 1.5 h (±0.5 h), 2.5 h (±0.5 h), 3.0 h (±0.5 h), 4.0 h (±1 h), 6.0 h (±1 h), 8.0 h (±1 h), 10.0 h (±1 h), 12.0 h (±1 h), 24.0 h (±1 h), 36.0 h (±1 h), 48.0 h (±1 h), 56.0 h (±1 h) and 60.0 h (±1 h) after the administering to the human subject.
7 . The method of claim 1 , wherein the blood plasma concentration of ensifentrine is determined using an analytical method having a lower limit of quantitation (LLOQ) of no greater than 5.0 pg/mL.
8 . The method of claim 1 , wherein the COPD is moderate COPD.
9 . The method of claim 1 , wherein a renal function of the human subject comprises normal renal function to mild renal impairment.
10 . The method of claim 1 , wherein the administering to the human subject provides a mean increase in baseline FEV 1 of at least 20 mL.
11 . The method of claim 1 , wherein the therapeutically effective dose comprises about 2 mg to about 4 mg of ensifentrine or the pharmaceutically acceptable salt thereof.
12 . The method of claim 11 , wherein the therapeutically effective dose comprises about 3 mg of ensifentrine or the pharmaceutically acceptable salt thereof.
13 . The method of claim 1 , wherein ensifentrine is in the form of ensifentrine free base.
14 . The method of claim 1 , wherein the liquid pharmaceutical composition comprises (a) a suspension of ensifentrine particles comprising the ensifentrine or the pharmaceutically acceptable salt thereof and (b) a diluent.
15 . The method of claim 14 , wherein the ensifentrine particles comprise at least 95 weight percent of the ensifentrine or the pharmaceutically acceptable salt thereof.
16 . The method of claim 14 , wherein the ensifentrine particles comprise at least 95 weight percent of ensifentrine free base.
17 . The method of claim 14 , wherein the liquid pharmaceutical composition comprises:
(a) ensifentrine particles at a concentration of from about 1 mg/mL to about 1.4 mg/mL;
(b) a buffer at a concentration of from about 1 mg/mL to about 2 mg/mL;
(c) one or more surfactants at a total concentration of from about 0.3 mg/mL to about 0.8 mg/mL;
(d) a tonicity adjuster at a concentration of from about 5 mg/mL to about 10 mg/mL,
wherein a total weight of ensifentrine or the pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is from about 2.7 mg to about 3.3 mg.
18 . The method of claim 17 , wherein the liquid pharmaceutical composition comprises:
(a) ensifentrine particles at a concentration of from about 1 mg/mL to about 1.4 mg/mL;
(b) polysorbate 20 (Tween 20) at a concentration of from about 0.3 mg/mL to about 0.7 mg/mL;
(c) sorbitan monolaurate (Span 20) at a concentration of from 0 mg/mL to about 0.1 mg/mL;
(d) sodium dihydrogen phosphate dihydrate at a concentration of from about 0.5 mg/mL to about 1 mg/mL;
(e) disodium hydrogen phosphate dihydrate at a concentration of from about 0.5 mg/mL to about 1 mg/mL; and
(f) sodium chloride at a concentration of from about 5 mg/mL to about 10 mg/mL,
wherein the total weight of ensifentrine or the pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is from about 2.7 mg to about 3.3 mg.
19 . The method of claim 18 , wherein the liquid pharmaceutical composition comprises:
(a) ensifentrine particles at a concentration of 1.2 mg/mL;
(b) polysorbate 20 (Tween 20) at a concentration of 0.5 mg/mL;
(c) sorbitan monolaurate (Span 20) at a concentration of 0.05 mg/mL;
(d) sodium dihydrogen phosphate dihydrate at a concentration of 0.744 mg/mL;
(e) disodium hydrogen phosphate dihydrate at a concentration of 0.853 mg/mL; and
(f) sodium chloride at a concentration of 8.6 mg/mL,
wherein the total weight of ensifentrine or the pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is 3 mg.
20 . The method of claim 14 , wherein the ensifentrine particles have a Dv10 of from about 0.3 μm to about 0.9 μm.
21 . The method of claim 14 , wherein the ensifentrine particles have a Dv50 of from about 0.2 μm to about 5 μm.
22 . The method of claim 14 , wherein the ensifentrine particles have a Dv90 of from about 2 μm to about 4.5 μm.
23 . The method of claim 1 , wherein the liquid pharmaceutical composition is administered to the human subject by inhalation from a nebulizer.
24 . The method of claim 1 , wherein the administering to the human subject is once per day, twice per day, or three times per day.
25 . The method of claim 24 , wherein the administering to the human subject is twice per day in a first dose and a second dose.
26 . The method of claim 25 , wherein the first dose is administered to the human subject in the morning and the second dose is administered to the human subject in the evening.
27 . The method of claim 25 , wherein the first dose is administered within three hours after the human subject waking, and the second dose is administered within three hours before the human subject sleeps.
28 . The method of claim 25 , wherein the first dose and the second dose are administered about 10 hours to about 14 hours apart.