METHODS OF TREATMENT FOR CYSTIC FIBROSIS
This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof. The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents.
1 .- 11 . (canceled)
12 . A pharmaceutical composition comprising
(a) 250 mg of Compound I:
or an equivalent amount of a pharmaceutically acceptable salt thereof,
(b) 21.24 mg of Compound II calcium salt hydrate Form D:
and
(c) 100 mg of Compound III:
or
an equivalent amount of a pharmaceutically acceptable salt thereof.
13 . The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition comprises
(a) 250 mg of Compound I,
(b) 21.24 mg of Compound II calcium salt hydrate Form D, and
(c) 100 mg of Compound III.
14 . A pharmaceutical composition comprising
(a) 125 mg of Compound I:
or an equivalent amount of a pharmaceutically acceptable salt thereof,
(b) 10.62 mg of Compound II calcium salt hydrate Form D:
and
(c) 50 mg of Compound III:
or
an equivalent amount of a pharmaceutically acceptable salt thereof.
15 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises
(a) 125 mg of Compound I,
(b) 10.62 mg of Compound II calcium salt hydrate Form D, and
(c) 50 mg of Compound III.
16 . A tablet comprising:
(a) 156.3 mg of a solid dispersion comprising Compound I:
wherein the solid dispersion comprises:
(i) 80 wt % Compound I, by weight of the solid dispersion,
(ii) 19.5 wt % hypromellose acetate succinate, by weight of the solid dispersion, and
(iii) 0.5 wt % sodium lauryl sulfate, by weight of the solid dispersion;
(b) 10.6 mg of Compound II calcium salt hydrate Form D:
(c) 62.5 mg of a solid dispersion comprising Compound III, wherein the solid dispersion comprises:
(i) 80 wt % Compound III:
by weight of the solid dispersion, and
(ii) 20 wt % hypromellose, by weight of the solid dispersion;
(d) 124.5 mg of microcrystalline cellulose;
(e) 22.8 mg of croscarmellose sodium; and
(f) 3.8 mg of magnesium stearate.
17 . (canceled)
18 . A tablet comprising:
(a) 156.3 mg of a solid dispersion comprising Compound I:
wherein the solid dispersion comprises:
(i) 80 wt % Compound I, by weight of the solid dispersion,
(ii) 19.5 wt % hypromellose acetate succinate, by weight of the solid dispersion, and
(iii) 0.5 wt % sodium lauryl sulfate, by weight of the solid dispersion;
(b) 10.6 mg of Compound II calcium salt hydrate Form D:
and
(c) 62.5 mg of a solid dispersion comprising Compound III:
wherein the solid dispersion comprises:
(i) 80 wt % Compound III, by weight of the solid dispersion, and
(ii) 20 wt % hypromellose, by weight of the solid dispersion.
19 . The tablet of claim 18 , wherein the tablet further comprises 70-170 mg of microcrystalline cellulose.
20 . The tablet of claim 18 , wherein the tablet further comprises 10-40 mg of croscarmellose sodium.
21 . The tablet of claim 18 , wherein the tablet further comprises 70-170 mg of microcrystalline cellulose and 10-40 mg of croscarmellose sodium.
22 . (canceled)
23 . The tablet of claim 16 , wherein the tablet further comprises
15.9 mg of a film coat.
24 . (canceled)
25 . The tablet of claim 23 , wherein the film coat is Opadry 20A100021.
26 . The pharmaceutical composition of claim 12 , wherein the Compound II calcium salt hydrate Form D is characterized by an X-ray powder diffractogram (XRPD) having signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta.
27 . The pharmaceutical composition of claim 26 , wherein the Compound II calcium salt hydrate Form D is characterized by an XRPD having (a) signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta; and (b) one or more signals selected from 5.5±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 21.5±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.0±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta.
28 . The pharmaceutical composition of claim 26 , wherein the Compound II calcium salt hydrate Form D is characterized by an XRPD having signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta.
29 . The pharmaceutical composition of claim 26 , wherein the Compound II calcium salt hydrate Form D is characterized by an XRPD having signals at 6.1±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 22.8±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta.
30 . The pharmaceutical composition of claim 12 , wherein the Compound II calcium salt hydrate Form D is characterized by an X-ray powder diffractogram substantially similar to FIG. 5 .
31 . The pharmaceutical composition of claim 12 , wherein the Compound II calcium salt hydrate Form D is characterized by a triclinic crystal system, a P1 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cu K α radiation (λ=1.5478 Å) of
a
12.78
±
.01
Å
α
64.93
±
.02
°
b
16.64
±
.01
Å
β
75.1
±
.02
°
c
18.19
±
.01
Å
γ
68.22
±
.02
°
.
32 . The pharmaceutical composition of claim 12 , wherein the Compound II calcium salt hydrate Form D is characterized by a 13 C solid state nuclear magnetic resonance ( 13 C ss NMR) spectrum with one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm.
33 . The pharmaceutical composition of claim 32 , wherein the Compound II calcium salt hydrate Form D is characterized by a 13 C ss NMR spectrum with one or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm.
34 . The pharmaceutical composition of claim 32 , wherein the Compound II calcium salt hydrate Form D is characterized by a 13 C ss NMR spectrum with (a) one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm; and (b) one or more peaks selected from 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm.
35 . The pharmaceutical composition of claim 12 , wherein the Compound II calcium salt hydrate Form D is characterized by a 13 C solid state nuclear magnetic resonance spectrum substantially similar to FIG. 6 .
36 . The pharmaceutical composition of claim 12 , wherein at least 85% of the Compound II is Compound II calcium salt hydrate Form D.
37 . The pharmaceutical composition of claim 12 , wherein at least 95% of the Compound II is Compound II calcium salt hydrate Form D.