Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof

• US 10,076,513 B2
• Filed: 01/19/2016
• Issued: 09/18/2018
• Est. Priority Date: 04/07/2010
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Verwijs, Marinus Jacobus, Alargova, Rossitza Gueorguieva, Kaushik, Ritu Rohit, Kadiyala, Irina Nikolaevna, Young, Christopher
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Singh, Randeep
• Application Number:
  US15/001,036
• Publication Number:
  US 20160303096A1
• Time in Patent Office: 973 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/141 Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers (co) spray-dried products A61K9/16, (co) lyophilised products A61K9/19; the carrier being chemically bound to the active ingredient A61K47/50
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• 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 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• 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: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 : Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 : Antiasthmatics
• CPC Class Codes: A61P 13/02 : of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 : of the kidneys
• CPC Class Codes: A61P 15/00 : Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof

Abstract

A pharmaceutical composition comprising Compound 1, (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid), and at least one excipient selected from: a filler, a diluent, a disintegrant, a surfactant, a binder, 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 an oral pharmaceutical formulation of Compound 1 to the patient.

Claims

1. A tablet for oral administration comprising:

a. 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) Form I in an amount ranging from about 25 mg to about 400 mg;

b. a filler;

c. a disintegrant;

d. a surfactant;

e. a lubricant; and

f. at least one of a binder and a glidant;

wherein the tablet comprises a binder which is a polyvinylpyrrolidone;

wherein Compound 1 Form I is present in an amount of at least 30 wt% by weight of the tablet.

2. The tablet of claim 1, wherein Compound 1 Form I, is present in the tablet in an amount of 200 mg.

3. The tablet of claim 1, wherein the filler is selected from cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.

4. The tablet of claim 1, wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount ranging from about 20 wt % to about 50 wt % by weight of the tablet.

5. The tablet of claim 1, wherein the disintegrant is selected from agar-agar, aligns, calcium carbonate, carboxmethylcellulose, cellulose, hydroxypropylcellulose, low substitute hydroxypropylcellulose, clays, croscarmellose sodium, crospovidone, gums, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, maize starch, potato starch, tapioca starch, or any combination thereof.

6. The tablet of claim 1, wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of about 2.5 to about 6 wt% by weight of the tablet.

7. The tablet of claim 1, wherein the surfactant is selected from sodium lauryl sulfate, sodium stearyl fumerate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof.

8. The tablet of claim 1, wherein the surfactant is sodium lauryl sulfate and is present in an amount of 0.3 wt% to 2 wt%.

9. The tablet of claim 1, wherein the glidant is colloidal silicon dioxide at a concentration of 5 wt % or less by weight of the tablet.

10. The tablet of claim 1, wherein the tablet comprises an additional therapeutic agent.

11. The tablet of claim 1, wherein the polyvinylpyrrolidone is at a concentration of about 1 to about 8 wt % by weight of the tablet.

12. The tablet of claim 1, wherein the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof.

13. The tablet of claim 12, wherein the lubricant is magnesium stearate at a concentration of about 0.15 to about 4.5 wt% by weight of the tablet.

14. The tablet of claim 1, wherein Compound 1 has a particle size of 0.1 microns to 50 microns.

15. The tablet of claim 1, wherein Compound 1 has a particle size of 0.1 microns to 20 microns.

16. The tablet of claim 1, wherein Compound 1 has a particle size of 0.1 microns to 10 microns.

17. The tablet of claim 1, wherein Compound 1 has a particle size of 1.0 microns to 5 microns.

18. The tablet of claim 1, wherein Compound 1 has a particle size D50 of 2.0 microns.

19. The tablet of claim 2,

wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount of about 25 wt% by weight of the tablet;

wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of about 6 wt% by weight of the tablet;

wherein the surfactant is sodium lauryl sulfate at a concentration of about 0.8 wt% or less by weight of the tablet;

wherein the lubricant is magnesium stearate at a concentration of about 1 wt% by weight of the tablet; and

wherein the binder is polyvinylpyrrolidone at a concentration of about 2 wt% by weight of the tablet.

20. The tablet of claim 19, wherein the tablet further comprises N-(5-hydroxy-2,4-diterbutyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

21. The tablet of claim 2,

wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount of about 20 to about 55 wt% by weight of the tablet;

wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of about 2.5 to about 6 wt% by weight of the tablet;

wherein the surfactant is sodium lauryl sulfate at a concentration of about 0.3 to about 2 wt% or less by weight of the tablet;

wherein the lubricant is magnesium stearate at a concentration of about 0.15 to about 4.5 wt% by weight of the tablet; and

wherein the binder is polyvinylpyrrolidone at a concentration of about 2 to about 5 wt% by weight of the tablet.

22. The tablet of claim 2, wherein Compound 1 Form 1 is present in an amount of about 30 to about 60 wt% by weight of the tablet.

23. The tablet of claim 19, wherein Compound 1 Form I is present in an amount of about 30 to about 60 wt% by weight of the tablet.

24. The tablet of claim 21, wherein Compound 1 Form I is present in an amount of about 30 to about 60 wt% by weight of the tablet.

25. The tablet of claim 10, wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditertbutyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

26. The tablet of claim 21, wherein the tablet further comprises N-(5-hydroxy-2,4-ditertbutyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

27. A method of treating or lessening the severity of a disease in a subject comprising administering to the subject a tablet of claim 19, wherein the disease is selected from cystic fibrosis.

28. The method of claim 27, wherein the method comprises administering an additional therapeutic agent in combination with said tablet.

29. The method of claim 28, wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

30. A method of treating or lessening the severity of a disease in a subject comprising administering to the subject a tablet of claim 21, wherein the disease is selected from cystic fibrosis.

31. The method of claim 30, wherein the method comprises administering an additional therapeutic agent in combination with said tablet.

32. The method of claim 31, wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

33. The tablet of claim 1, wherein Compound 1 Form I is characterized by one or more peaks at 15.4 ±

0.2 degrees, 16.3 ±

0.2 degrees, and 14.5 ±

0.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

44. A method of treating or lessening the severity of a disease in a subject comprising administering to the subject a tablet of claim 1, wherein the disease is selected from cystic fibrosis.

45. The method of claim 44, wherein said subject has a cystic fibrosis transmembrane conductance regulator (CFTR) with a Δ

F508 mutation.

46. The method of claim 44, wherein said subject has a cystic fibrosis transmembrane conductance regulator (CFTR) with a R117H mutation.

47. The method of claim 44, wherein said subject has a cystic fibrosis transmembrane conductance regulator (CFTR) with a G551D mutation.

48. The method of claim 44, wherein the method comprises administering an additional therapeutic agent in combination with said tablet.

49. The method of claim 48, wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

34. A method of producing a pharmaceutical composition comprising the steps of:

a) combining a therapeutically effective amount of Compound 1 Form I, polyvinylpyrrolidone, and at least one granulation excipient selected from;

a glidant;

a surfactant;

a lubricant;

a disintegrant;

a filler, and combinations thereof to form an admixture;

b) mixing and wet granulating the admixture; and

c) compacting the admixture to form the pharmaceutical composition;

wherein Compound 1 Form I is present in an amount of at least 30 wt% in the pharmaceutical composition.

35. The method of claim 34, wherein the pharmaceutical composition comprises a plurality of granules.

36. The method of claim 34, wherein compacting the admixture comprises compacting the admixture in a roller compactor forming compressed sheets of admixture;

and milling the sheets of admixture to form a plurality of granules.

37. The method of claim 35, wherein the plurality of granules further comprises at least one pharmaceutical acceptable excipient to form a tablet.

38. The method of claim 37, wherein the at least one pharmaceutical acceptable excipient is selected from magnesium stearate, croscarmellose sodium and combinations thereof.

39. The method according to claim 38, wherein the plurality of granules are compressed to produce a tablet having a hardness of at least 5 kP.

40. The method of claim 34, wherein the step of compacting the admixture to form the pharmaceutical composition further comprises drying the admixture.

41. The method of claim 34, wherein mixing the admixture comprises mixing the admixture until the admixture is substantially homogenous.

42. The method of claim 35, wherein the plurality of granules are formed by combining Compound 1 Form I with a granulation fluid comprising a surfactant and polyvinylpyrrolidone.

43. The method of claim 42, wherein the surfactant is sodium lauryl sulfate.