Pharmaceutical compositions for treating cystic fibrosis

Patent metadata

Field	Value
Publication number	US-2022257564-A1
Application number	US-202117475606-A
Country	US
Kind code	A1
Filing date	Sep 15, 2021
Priority date	Feb 5, 2018
Publication date	Aug 18, 2022
Grant date	—

Abstract

A pharmaceutical composition comprising Compound I:

Methods of treating cystic fibrosis comprising administering one or more of such pharmaceutical compositions to a patient.

First claim

1 . A pharmaceutical composition comprising
(a) 75 mg to 125 mg of Compound I:

(b) a first solid dispersion comprising 25 mg to 75 mg of Compound II:

and 10 wt % to 30 wt % of a polymer relative to the total weight of the first solid dispersion; and
(c) a second solid dispersion comprising 50 mg to 100 mg of Compound III:

and 10 wt % to 30 wt % of a polymer relative to the total weight of the second solid dispersion.

2 . The pharmaceutical composition of claim 1 , comprising
75 mg to 125 mg of Compound I; and wherein the first solid dispersion comprises 50 mg of Compound II; and the second solid dispersion comprises 75 mg of Compound III.

3 . A pharmaceutical composition comprising:
(a) Compound I:

(b)
a first solid dispersion comprising 70 wt % to 90 wt % of Compound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of the first solid dispersion; and
(c)
a second solid dispersion comprising 70 wt % to 90 wt % of Compound III relative to the total weight of the second solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of the second solid dispersion, wherein the the weight ratio of Compound I in (a):Compound II in (b):Compound III in (c) is in a range of 4:2:3-6.

4 . (canceled)

5 . (canceled)

6 . (canceled)

7 . The pharmaceutical composition of claim 1 , wherein Compound I is Crystalline Form A.

8 . The pharmaceutical composition of claim 7 , wherein Compound I Crystalline Form A is in substantially pure form.

9 . The pharmaceutical composition of claim 7 , wherein Compound I Crystalline Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.6±0.2, 7.6±0.2, 9.6±0.2, 12.4±0.2, 13.1±0.2, 15.2±0.2, 16.4±0.2, 18.2±0.2, and 18.6±0.2.

10 . A method of treating cystic fibrosis in a patient comprising orally administering to the patient one or more of the pharmaceutical composition of claim 1 .

11 . The method according to claim 10 , wherein said patient having cystic fibrosis is chosen from patients with F508del/minimal function genotypes, patients with F508del/F508del genotypes, patients with F508del/gating genotypes, and patients with F508del/residual function genotypes.

12 . (canceled)

13 . (canceled)

14 . The pharmaceutical composition of claim 3 , wherein at least one of the first and second solid dispersions is a spray-dried dispersion.

15 . The pharmaceutical composition of claim 3 , wherein both of the first and second solid dispersions are spray-dried dispersions.

16 . The pharmaceutical composition of claim 3 , wherein said polymer in the first solid dispersion is hydroxypropyl methylcellulose; and said polymer in the second solid dispersion is hydroxypropyl methylcellulose acetate succinate.

17 . The pharmaceutical composition of claim 3 , wherein:
the first solid dispersion comprises 70 wt % to 85 wt % of Compound II relative to the total weight of the first solid dispersion, and the polymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30 wt % relative to the total weight of the first solid dispersion; and the second solid dispersion comprises 70 wt % to 85 wt % of Compound III relative to the total weight of the second solid dispersion, 0.5% sodium lauryl sulfate relative to the total weight of the second solid dispersion, and the polymer is hydroxypropyl methylcellulose acetate succinate in an amount of 14.5 wt % to 29.5 wt % relative to the total weight of the second solid dispersion.

18 . The pharmaceutical composition of claim 3 , wherein the first solid dispersion comprises 80 wt % of Compound II relative to the total weight of the first solid dispersion; and 20 wt % of hydroxypropyl methylcellulose relative to the total weight of the first solid dispersion.

19 . The pharmaceutical composition of claim 3 , wherein the second solid dispersion comprises 80 wt % of Compound III relative to the total weight of the second solid dispersion; 0.5% of sodium lauryl sulfate relative to the total weight of the second solid dispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetate succinate relative to the total weight of the second solid dispersion.

20 . The pharmaceutical composition of claim 3 , further comprising one or more pharmaceutically acceptable excipients chosen from one or more fillers, disintegrants, and lubricants.

21 . The pharmaceutical composition of claim 3 , wherein:
said fillers are chosen from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium phosphate, mannitol, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum; said disintegrants are chosen from croscarmellose sodium, sodium starch glycolate, crospovidone, corn or pre-gelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and microcrystalline cellulose; and said lubricants are chosen from magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium stearate, stearic acid, and talc.

22 . The pharmaceutical composition of claim 3 , wherein
Compound I is substantially crystalline, and wherein each of Compounds II and III is independently substantially amorphous.

23 . The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is a tablet or in the form of granules.

24 . The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition further comprises microcrystalline cellulose; croscarmellose sodium; and
magnesium stearate.

25 . The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition comprises 15 wt % to 45 wt % of microcrystalline cellulose relative to the total weight of the pharmaceutical composition; 1 wt % to 10 wt % of croscarmellose sodium relative to the total weight of the pharmaceutical composition; and 0.5 wt % to 3 wt % mg of magnesium stearate relative to the total weight of the pharmaceutical composition.

26 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises 80 mg to 120 mg of Compound I.

27 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises 100 mg of Compound I; and wherein the first solid dispersion comprises 50 mg of Compound II; and the second solid dispersion comprises 75 mg of Compound III.

28 . A single tablet having the following formulation:

Assignees

• Vertex Pharma

Inventors

• Chu Cathy
• Dhamankar Varsha
• Dokou Eleni
• Haseltine Eric L
• Moskowitz Samuel
• Robertson Sarah
• Waltz David
• Chen Weichao George

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K9/2095

  Tabletting processes · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K31/4045 Primary

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title