Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases

Patent metadata

Field	Value
Publication number	US-10980746-B2
Application number	US-201816232540-A
Country	US
Kind code	B2
Filing date	Dec 26, 2018
Priority date	Apr 15, 2014
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

Abstract

The present invention features compositions comprising a plurality of therapeutic agents wherein the presence of one therapeutic agent enhances the properties of at least one other therapeutic agent. In one embodiment, the therapeutic agents are cystic fibrosis transmembrane conductance regulators (CFTR) such as a CFTR corrector or CFTR potentiator for the treatment of CFTR mediated diseases such as cystic fibrosis. Methods and kits thereof are also disclosed.

First claim

What is claimed is:

1. A solid dispersion comprising substantially amorphous (R)-1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1) and substantially amorphous N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2):
wherein the ratio by weight of Compound 1 to Compound 2 is from about 1:1 to about 1:3;
wherein the solid dispersion optionally further comprises a polymer; and
wherein the solid dispersion comprises less than 15% crystallinity.

2. The solid dispersion of claim 1 , wherein Compound 1 and Compound 2 are co-spray dried with a solvent.

3. The solid dispersion of claim 1 , wherein the ratio of Compound 1 to Compound 2 is about 2:3 by weight.

4. The solid dispersion of claim 1 , wherein the solid dispersion is free of polymer.

5. The solid dispersion of claim 1 , wherein the solid dispersion further comprises a surfactant.

6. The solid dispersion of claim 5 , wherein the surfactant comprises sodium lauryl sulfate in an amount from about 0.5 wt % to about 5 wt % relative to the total weight of the solid dispersion.

7. The solid dispersion of claim 1 , wherein the solid dispersion further comprises a polymer.

8. The solid dispersion of claim 7 , wherein the solid dispersion comprises from about 35 wt % to about 50 wt % of substantially amorphous Compound 1.

9. The solid dispersion of claim 7 , wherein the solid dispersion comprises from about 20 wt % to about 75 wt % of substantially amorphous Compound 2.

10. The solid dispersion of claim 7 , wherein the polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polymethacrylate, and polyvinylpyrrolidone-vinyl acetate (PVP-VA).

11. A pharmaceutical composition comprising the solid dispersion of claim 1 .

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is a tablet.

13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition comprises from about 5 wt % to about 15 wt % of substantially amorphous Compound 1 relative to the total weight of the pharmaceutical composition.

14. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition comprises from about 15 wt % to about 45 wt % of substantially amorphous Compound 2 relative to the total weight of the pharmaceutical composition.

15. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition further comprises one or more excipients selected from a filler, a glidant, a diluent, a disintegrant, a lubricant, a binder, a surfactant, and any combination thereof.

16. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition further comprises from about 30 wt % to about 50 wt % of a filler, from about 1 wt % to about 10 wt % of a disintegrant, and/or about 1 wt % of a lubricant.

17. The pharmaceutical composition of claim 16 , wherein the filler comprises microcrystalline cellulose, wherein the disintegrant comprises croscarmellose sodium, wherein the lubricant comprises magnesium stearate, and/or any combination thereof.

18. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition further comprises an additional therapeutic agent.

19. The pharmaceutical composition of claim 18 , wherein the additional therapeutic agent is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, a CFTR corrector different from Compound 1, a CFTR potentiator different from Compound 2, and an anti-inflammatory agent.

20. The pharmaceutical composition of claim 19 , wherein the additional therapeutic agent is a CFTR corrector different from Compound 1.

21. A method of treating cystic fibrosis in a patient comprising administering the pharmaceutical composition of claim 11 .

22. The pharmaceutical composition of claim 19 , wherein the additional therapeutic agent is a CFTR potentiator different from Compound 2.

23. The solid dispersion of claim 3 , wherein the solid dispersion is free of polymer.

24. The solid dispersion of claim 3 , wherein the solid dispersion further comprises hydroxypropyl methylcellulose (HPMC).

25. The solid dispersion of claim 3 , wherein Compound 1 is present in an amount of about 100 mg and Compound 2 is present in an amount of about 150 mg.

Assignees

• Vertex Pharma

Inventors

• Phenix Brian Dean
• Bagnol Laurent Jean-Claude
• Brodeur Geoffrey Glen
• Chandran Sachin
• Dokou Eleni
• Ferris Lori Ann
• Knezic Dragutin
• Mccarty Katie Lynn
• Medek Ales
• Waggener Sara A

Classifications

• A61K9/14 Primary

  Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)} · CPC title

• C07D215/56

  with oxygen atoms in position 4 · CPC title

• A61P43/00

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

• A61K31/4725

  containing further heterocyclic rings · CPC title

• A61K9/146

  with organic macromolecular compounds · CPC title