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

• US 10,206,877 B2
• Filed: 04/14/2015
• Issued: 02/19/2019
• Est. Priority Date: 04/15/2014
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• 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.
• Primary Examiner(s): Pipic, Alma
• Application Number:
  US14/686,117
• Publication Number:
  US 20150320736A1
• Time in Patent Office: 1,407 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/14 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 Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/04 Indoles; Hydrogenated indoles
• CPC Class Codes: C07D 215/00 Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

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.

Claims

1. A pharmaceutical composition comprising a blend of a first solid dispersion and a second solid dispersion,

wherein the first solid dispersion comprises 70 wt % to 90 wt % of 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) relative to the total weight of the first solid dispersion and 10 wt % to 30 wt % of hydroxypropyl methylcellulose relative to the total weight of the first solid dispersion,

wherein the second solid dispersion comprises 70 wt % to 90 wt % of amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 2) relative to the total weight of the second solid dispersion, and

wherein the pharmaceutical composition is a tablet which comprises 25 mg to 125 mg of Compound 1 and 100 mg to 200 mg of Compound 2.

2. The pharmaceutical composition of claim 1, wherein the second solid dispersion further comprises 10 wt % to 30 wt % of a polymer relative to the total weight of the second solid dispersion.

3. The pharmaceutical composition of claim 2, wherein the polymer in the second solid dispersion comprises hydroxypropyl methylcellulose acetate succinate.

4. The pharmaceutical composition of claim 1, wherein the first solid dispersion comprises 80 wt % of amorphous Compound 1 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.

5. The pharmaceutical composition of claim 1, wherein the tablet comprises 100 mg of Compound 1.

6. The pharmaceutical composition of claim 1, wherein the tablet comprises 150 mg of Compound 2.

7. The pharmaceutical composition of claim 1, wherein the tablet comprises one or more excipients selected from a filler, a disintegrant, a lubricant, or any combination thereof.

8. The pharmaceutical composition of claim 7, wherein the tablet comprises a filler in an amount of 30 wt % to 50 wt % relative to the total weight of the tablet.

9. The pharmaceutical composition of claim 8, wherein the filler comprises microcrystalline cellulose.

10. The pharmaceutical composition of claim 7, wherein the tablet comprises a disintegrant in an amount of 1 wt % to 10 wt % relative to the total weight of the tablet.

11. The pharmaceutical composition of claim 10, wherein the disintegrant comprises croscarmellose sodium.

12. The pharmaceutical composition of claim 7, wherein the tablet comprises a lubricant in an amount of 1 wt % relative to the total weight of the tablet.

13. The pharmaceutical composition of claim 12, wherein the lubricant comprises magnesium stearate.

14. The pharmaceutical composition of claim 7, wherein the tablet comprises 100 mg to 300 mg of a filler.

15. The pharmaceutical composition of claim 7, wherein the tablet comprises 12 mg to 36 mg of a disintegrant.

16. The pharmaceutical composition of claim 7, wherein the tablet comprises 5.9 mg of a lubricant.

17. The pharmaceutical composition of claim 1, wherein the tablet comprises:

125 mg of a first solid dispersion which comprises 80 wt % of amorphous Compound 1 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,

187.5 mg of a second solid dispersion which comprises 80 wt % of amorphous Compound 2 relative to the total weight of the second solid dispersion, 19.5 wt % of hydroxypropyl methylcellulose acetate succinate relative to the total weight of the second solid dispersion, and 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion,

243.9 mg microcrystalline cellulose,

29.6 mg croscarmellose sodium, and

5.9 mg magnesium stearate.

18. A method of treating cystic fibrosis in a patient comprising orally administering to the patient the pharmaceutical composition of claim 1.

19. The method of claim 18, wherein the pharmaceutical composition is administered once per day.

20. The method of claim 18, wherein the pharmaceutical composition is administered once per day followed by the administration of 150 mg of Compound 2 once per day.

21. The method of claim 18, wherein the patient is heterozygous for a Δ

F508 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation and a second CFTR gene mutation.

22. The method of claim 21, wherein the second CFTR gene mutation is selected from E56K, P67L, R74W, D110E, D110H, R117C, E193K, L206W, R347H, R352Q, A455E, D579G, 711+3A→

G, S945L, S977F, F1052V, K1060T, A1067T, R1070W, F1074L, D1152H, D1270N, 2789+5G→

A, 3272−

26A→

G, and 3849+10kbC→

T.

23. The method of claim 21, wherein the second CFTR gene mutation is selected from R117H, G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.

24. The method of claim 21, wherein the second CFTR gene mutation is selected from G576A and R668C.

25. The method of claim 18, wherein the patient is homozygous for the Δ

F508 CFTR gene mutation.

27. The method of claim 18, wherein the method produces an increase in chloride transport which is greater than or equal to 10% above the baseline chloride transport.

26. A method of treating cystic fibrosis in a patient comprising orally administering to the patient a tablet comprisingmg of a first solid dispersion which comprises 80 wt % of amorphous Compound 1 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,

187.5 mg of a second solid dispersion which comprises 80 wt % of amorphous Compound 2 relative to the total weight of the second solid dispersion, 19.5 wt % of hydroxypropyl methylcellulose acetate succinate relative to the total weight of the second solid dispersion, and 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion,

22.9 mg microcrystalline cellulose,

29.6 mg croscarmellose sodium, and

5.9 mg magnesium stearate.