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 11,052,075 B2
• Filed: 08/02/2019
• Issued: 07/06/2021
• 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:
  US16/530,240
• Publication Number:
  US 20200197380A1
• Time in Patent Office: 704 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 wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;

b. a filler;

c. a disintegrant;

d. a surfactant;

e. a lubricant; and

f. a binder which is polyvinylpyrrolidone.

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

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

6. The tablet of claim 1, wherein the tablet comprises an additional therapeutic agent, which is a cystic fibrosis transmembrane conductance regulator potentiator.

7. The tablet of claim 6, wherein the additional therapeutic agent is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.

8. The tablet of claim 1, wherein Compound 1 Form I is present in an amount of 30 wt % to 70 wt % by weight of the tablet.

9. The tablet of claim 8, wherein Compound 1 Form I is present in the tablet in an amount of 30 wt % to 60 wt % by weight of the tablet.

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

11. The tablet of claim 1, wherein the Compound 1 Form I is present in the tablet in an amount of 100 mg.

12. 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, and any combination thereof.

13. The tablet of claim 12, wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount ranging from 20 wt % to 55 wt % by weight of the tablet.

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

15. 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, and any combination thereof.

16. The tablet of claim 15, wherein the lubricant is magnesium stearate and is present at a concentration of 0.15 wt % to 4.5 wt % by weight of the tablet.

17. 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 % by weight of the tablet.

18. The tablet of claim 1,

wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of about 6 wt % to about 10 wt % by weight of the tablet;

and

wherein the surfactant is sodium lauryl sulfate and is present in an amount of 0.3 wt % to 2 wt % by weight of the tablet.

19. The tablet of claim 1,

wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of about 6 wt % to about 10 wt % by weight of the tablet.

20. The tablet of claim 1,

wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount of 25 wt % to 50 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 % to about 10 wt % by weight of the tablet;

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

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

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

21. The tablet of claim 1,

wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount of 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 0.8 wt % by weight of the tablet;

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

wherein the polyvinylpyrrolidone is present at a concentration of 3 wt % by weight of the tablet.

22. A method of treating or lessening the severity of cystic fibrosis in a subject, comprising administering to the subject a tablet of claim 1.

2. 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 wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;

b. a filler;

c. a disintegrant;

d. a surfactant which is sodium lauryl sulfate and is present in an amount of 0.3 wt % to 2 wt % by weight of the tablet;

e. a lubricant; and

f. a binder.

3. 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 wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;

b. a filler;

c. a disintegrant;

d. a surfactant;

e. a lubricant; and

f. a binder;

wherein Compound 1 Form I is present in an amount of 30 wt % to 70 wt % by weight of the tablet.