FORMULATION PRODUCTION PROCESS
The present invention relates to a process for producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles, wherein the process comprises: (a) heating ensifentrine particles at a temperature of from 100° C. to 220° C. to obtain sterile ensifentrine particles; and (b) combining the sterile ensifentrine particles with a sterile liquid vehicle to produce the sterile liquid pharmaceutical composition suitable for administration by inhalation. A process for producing an ampule comprising the sterile liquid pharmaceutical composition is also described.
1 . An ampule comprising a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles and a liquid vehicle, wherein the ensifentrine particles are sterilized by dry heat treatment, followed by combining the sterilized ensifentrine particles with a sterile liquid vehicle to form the sterile liquid pharmaceutical composition, which is then filled into the ampule under aseptic conditions.
2 . The ampule of claim 1 , wherein the dry heat treatment is performed at a temperature of 155° C. to 165° C. for 110 minutes to 130 minutes.
3 . The ampule of claim 1 , wherein the sterile ensifentrine particles comprise at least 95% by weight of ensifentrine or a pharmaceutically acceptable salt thereof relative to a total weight of the sterile ensifentrine particles.
4 . The ampule of claim 1 , wherein the sterile ensifentrine particles comprise at least 95% by weight of ensifentrine free base relative to a total weight of the sterile ensifentrine particles.
5 . The ampule of claim 1 , wherein the sterile ensifentrine particles have a particle size distribution with a Dv10 of from 0.1 μm to 1.0 μm.
6 . The ampule of claim 1 , wherein the sterile ensifentrine particles have a particle size distribution with a Dv50 of from 0.5 μm to 5.0 μm.
7 . The ampule of claim 1 , wherein the sterile ensifentrine particles have a particle size distribution with a Dv90 of from 2.5 μm to 6 μm.
8 . The ampule of claim 1 , wherein the sterile liquid vehicle is produced by subjecting a liquid vehicle to aseptic filtration to produce the sterile liquid vehicle.
9 . The ampule of claim 1 , wherein the sterile liquid vehicle comprises a diluent and optionally one or more additional excipients selected from surfactants, buffers, and tonicity adjusters.
10 . The ampule of claim 9 comprising
(a) sterile ensifentrine particles at a concentration of from 0.5 mg/mL to 6 mg/mL;
(b) one or more surfactants at a concentration of from 0.01 mg/ml to 2 mg/mL;
(c) a buffer at a concentration of from 0.6 mg/mL to 4 mg/mL;
(d) a tonicity adjuster at a concentration of from 5 mg/ml to 12 mg/mL.
11 . The ampule of claim 10 , wherein the sterile liquid vehicle comprises water, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, polysorbate 20, or sorbitan laurate.
12 . The ampule of claim 11 , comprising
(a) sterile ensifentrine particles at a concentration of from 0.5 mg/mL to 6 mg/ml;
(b) polysorbate 20 at a concentration of from 0.1 mg/mL to 1.5 mg/mL;
(c) sorbitan monolaurate at a concentration of from 0.01 mg/ml to 0.5 mg/mL;
(d) sodium dihydrogen phosphate dihydrate at a concentration of from 0.3 mg/mL to 2 mg/mL;
(e) disodium hydrogen phosphate dihydrate at a concentration of from 0.3 mg/mL to 2
mg/mL; and
(f) sodium chloride at a concentration of from 5 mg/mL to 12 mg/mL, wherein a total weight of ensifentrine in the sterile liquid pharmaceutical composition is from 2.7 to 3.3 mg.
13 . The ampule of claim 1 , wherein the sterile liquid pharmaceutical composition comprises the sterile ensifentrine particles at a concentration of from 0.1 mg/mL to 5 mg/mL.
14 . The ampule of claim 13 , wherein the sterile liquid pharmaceutical composition comprises the sterile ensifentrine particles at a concentration of from 1 mg/mL to 2 mg/mL.