Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases

• US 10,231,932 B2
• Filed: 10/31/2014
• Issued: 03/19/2019
• Est. Priority Date: 11/12/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Swinney, Kelly Ann, Hurter, Patricia Nell, Nadig, David E., Smith, David, Thomas, Vance Hayden, Warman, Martin Paul
• Primary Examiner(s): Theisen, Mary Lynn F
• Application Number:
  US15/035,969
• Publication Number:
  US 20160354316A1
• Time in Patent Office: 1,600 Days
• Field of Search: None
• 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 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• 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

Abstract

Processes of preparing pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) in Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2), methods of treating, lessening the severity of or symptomatically treating CFTR mediated diseases, such as cystic fibrosis, methods of administering, and kits thereof are disclosed.

Claims

1. A continuous process for preparing a tablet comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (“

Compound 1”

) Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (“

Compound 2”

) comprising the steps of;

a) mixing Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, a filler, and a disintegrant in a blender to form a blend;

b) preparing a granulation solution with water, a binder, and a surfactant;

c) feeding the blend from step a) into a continuous twin screw granulator while adding the granulation solution from step b) to produce granules;

d) drying the granules from step c) and milling them;

e) blending the milled granules from step d) with a filler, disintegrant, and lubricant to form a blend; and

f) compressing the blend from step e) into a tablet;

wherein at least one of the above steps comprises process analytical technology; and

wherein step f) comprises monitoring solid, form identity of Compound 1 and/or Compound 2 in the tablet using Raman spectroscopy.

2. The process of claim 1, wherein the process analytic technology comprises NIR and/or laser diffraction to monitor defined standards.

3. The process of claim 2, wherein the defined standard is selected from blend uniformity, granule uniformity, moisture, particle size distribution, active pharmaceutical ingredient solid form identity, weight, thickness, hardness, and coating thickness.

4. The process of claim 1, wherein step a) comprises monitoring blend uniformity using NIR.

5. The process of claim 1, wherein step c) comprises monitoring granule uniformity and/or moisture using NIR.

6. The process of claim 1, wherein step c) comprises monitoring particle size distribution using laser diffraction.

7. The process of claim 1, wherein step e) comprises monitoring blend uniformity and/or moisture using NIR.

8. The process of claim 1, wherein step f) further comprises monitoring tablet weight, thickness, and/or hardness using a tablet tester.