Capsule formulation of pirfenidone and pharmaceutically acceptable excipients

• US 8,753,679 B2
• Filed: 02/25/2013
• Issued: 06/17/2014
• Est. Priority Date: 09/22/2005
• Status: Active Grant

• Current Assignee: Intermune Incorporated (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Radhakrishnan, Ramachandran, Vladyka, Ronald, Sultzbaugh, Kenneth
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US13/776,079
• Publication Number:
  US 20130165484A1
• Time in Patent Office: 477 Days
• Field of Search: 424/452, 514/345
• US Class Current: 424/452
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 9/4841 Filling excipients; Inactive ingredients
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A capsule formulation of pirfenidone is provided that includes pharmaceutically acceptable excipients. In one embodiment, this capsule formulation is capable of sustaining desirable pharmacokinetic responses in a patient. Further provided are methods of treating fibrotic conditions and other cytokine-mediated disorders by administering pirfenidone capsules of such formulation to a patient in need.

Claims

1. A capsule comprising a pharmaceutical formulation of 5-methyl-1-phenyl-2-(1H)-pyridone, wherein said pharmaceutical formulation comprises pharmaceutically acceptable excipients and 5-methyl-1-phenyl-2-(1H)-pyridone, and the formulation is stable for at least 9 months at 40°

C. at 75% relative humidity, as measured by a dissolution of at least 85% of the 5-methyl-1-phenyl-2-(1H)-pyridone after the at least 9 months.

2. The capsule of claim 1, wherein said excipients comprise one or more selected from the group consisting of disintegrators, binders, fillers, and lubricants.

3. The capsule of claim 2, wherein said disintegrators comprise one or more selected from the group consisting of agar-agar, algins, calcium carbonate, carboxmethylcellulose, cellulose, clays, colloid silicon dioxide, croscarmellose sodium, crospovidone, gums, magnesium aluminium silicate, methylcellulose, polacrilin potassium, sodium alginate, low substituted hydroxypropylcellulose, and cross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium starch glycolate, and starch.

4. The capsule of claim 2, wherein said binders comprise one or more selected from the group consisting of microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, and polyvinylpyrrolidone.

5. The capsule of claim 2, wherein said fillers comprise one or more selected from the group consisting of calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrates, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, matitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol.

6. The capsule of claim 2, wherein said lubricants comprise one or more selected from the group consisting of agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycols, sodium benzoate, sodium lauryl sulfate, sodium stearyl, sorbitol, stearic acid, talc, and zinc stearate.

7. The capsule of claim 2, wherein by weight said disintegrator is 2-10%, said binder is 2-30%, said filler is 2-30%, and said lubricant is 0.3-0.8%.

8. The capsule of claim 2, wherein said excipients further comprise povidone.

9. The capsule of claim 8, wherein by weight said povidone is 1-4%.

10. The capsule of claim 9, wherein the capsule comprises 100-400 mg 5-methyl-1-phenyl-2-(1H)-pyridone.

11. A method for treating a fibrotic condition or inhibiting actions of cytokines, comprising administering the capsule of claim 1 to a patient suffering from said fibrotic condition or suffering from a disorder mediated by said cytokines.

12. The method of claim 11, wherein said fibrotic condition is one selected from the group consisting of pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, keloid, dermal fibrosis, coronary restenosis, and post-surgical adhesions.

13. The method of claim 12, wherein said pulmonary fibrosis is one selected from the group consisting of idiopathic pulmonary fibrosis and Hermansky-Pudlak Syndrome.

14. A method of claim 11, wherein said fibrotic condition is scleroderma with pulmonary fibrosis.

15. The method of claim 11, wherein said cytokines comprise one or more selected from the group consisting of TNF-α

, TGF-β

1, bFGF, PDGF, and EGF.

16. The method of claim 15, wherein said disorder is one selected from the group consisting of multiple sclerosis, arthritis, asthma, chronic rhinitis, and edema.

17. The method of claim 11, further comprising administering one or more said capsules to said patient one or more times a day, wherein the total intake of 5-methyl-1-phenyl-2-(1H)-pyridone is at least 1200 mg a day.

18. The method of claim 17, wherein said one or more capsules are administered to the patient twice a day.

19. The method of claim 18, wherein said one or more capsules are administered to the patient three times a day.

20. The capsule of claim 8, wherein said povidone comprises at least about 1.85% by weight of the formulation.

21. The capsule of claim 8, wherein said povidone comprises at least about 1% by weight of the formulation.

22. The capsule of claim 2, wherein the formulation comprises a wet-granulated mixture comprising 5-methyl-1-phenyl-2-(1H)-pyridone, binder, filler, and disintegrator.

23. The capsule of claim 2, wherein:

the pharmaceutically acceptable excipients comprise a lubricant, a filler, and a disintegrator;

the binder comprises microcrystalline cellulose and povidone;

the povidone is included in an amount of 1-4% by weight of the formulation;

the total amount of binder is 2-30% by weight of the formulation; and

the formulation comprises a wet-granulated mixture comprising the 5-methyl-1-phenyl-2-(1H)-pyridone , the binder, the filler, and the disintegrator.

24. The capsule of claim 1, wherein said pharmaceutical formulation comprises, by weight, 5-30% of the pharmaceutically acceptable excipients and 70-95% of the 5-methyl-1-phenyl-2- (1H)-pyridone.

25. The method of claim 11, wherein the fibrotic condition is a pulmonary fibrotic condition.

26. A capsule comprising a pharmaceutical formulation of 5 methyl-1-phenyl-2-(1H)-pyridone, wherein said pharmaceutical formulation comprises pharmaceutically acceptable excipients and 5-methyl-1-phenyl-2-(1H)-pyridone, and the formulation is stable for at least 18 months at 25°

C. at 60% relative humidity, as measured by a dissolution of at least 93% of the 5-methyl-1-phenyl-2-(1H)-pyridone after the at least 18 months.