Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof

• US 10,058,546 B2
• Filed: 11/03/2016
• Issued: 08/28/2018
• Est. Priority Date: 07/16/2012
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Alargova, Rossitza Gueorguieva, Dunbar, Craig Antony, Kadiyala, Irina Nikolaevna
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US15/342,999
• Publication Number:
  US 20170266176A1
• Time in Patent Office: 663 Days
• Field of Search: 514311, 514464, 514851
• 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 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A pharmaceutical composition comprising Compound 1, (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, and at least one excipient selected from: a filler, a disintegrant, a surfactant, a glidant and a lubricant, the composition being suitable for oral administration to a patient in need thereof to treat a CFTR mediated disease such as Cystic Fibrosis. Methods for treating a patient in need thereof include administering the pharmaceutical composition of Compound 1 are also disclosed.

Claims

1. A method for treating cystic fibrosis in a patient, comprising coadministering:

a) a pharmaceutical composition comprising 5 to 250 mg of (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 a pharmaceutically acceptable carrier, wherein Compound 1 is in a spray dried dispersion; and

b) another pharmaceutical composition comprising 100 to 300 mg N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound

     2) and a pharmaceutically acceptable carrier;

wherein the patient has a Δ

F508 or G551D cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation and a second CFTR gene mutation selected from R117H, A455E, 2789+5G→

A, and 3849+10kbC→

T;

wherein the pharmaceutical composition of step (a) is administered concurrently with the pharmaceutical composition of step (b).

2. The method of claim 1, wherein Compound 1 is substantially amorphous, wherein less than 15% of Compound 1 is in crystalline form.

3. The method of claim 2, wherein less than 10% of Compound 1 is in crystalline form.

4. The method of claim 3, wherein less than 5% of Compound 1 is in crystalline form.

5. The method of claim 4, wherein less than 1% of Compound 1 is in crystalline form.

6. The method of claim 1, wherein Compound 1 is present in an amount of about 100 mg.

7. The method of claim 1, wherein the pharmaceutical composition of step (a) and the pharmaceutical composition of step (b) are administered once a day.

8. The method of claim 1, wherein 150 mg of Compound 2 is administered.

9. The method of claim 1, wherein the method comprises administering an additional therapeutic agent.

10. The method of claim 9, wherein the additional therapeutic agent is a mucolytic agent, bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 2, or a nutritional agent.

11. The method of claim 9, wherein the additional therapeutic agent is a CFTR modulator other than Compound 2.

12. The method of claim 1, wherein the second CFTR gene mutation is A455E.

13. The method of claim 1, wherein the second CFTR gene mutation is 2789+5G→

A.

14. The method of claim 1, wherein the second CFTR gene mutation is 3849+10kbC→

T.