Granulate formulation of pirfenidone and pharmaceutically acceptable excipients

1. A granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone, wherein said granulate formulation comprises 5-methyl-1-phenyl-2-(1H)-pyridone and pharmaceutically acceptable excipients, said excipients comprising an effective amount of binder to increase the AUC of the 5-methyl-1-phenyl-2-(1H)-pyridone at least 45% upon oral administration, as compared to pirfenidone without excipients orally administered in a capsule shell.

2. The granulate formulation of claim 1 , wherein said excipients further comprise one or more selected from the group consisting of a disintegrator, a filler, a lubricant, and combinations thereof.

3. The granulate formulation of claim 2 , wherein said disintegrator comprises one or more selected from the group consisting of agar-agar, algins, calcium carbonate, carboxymethylcellulose, cellulose, clays, colloidal 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 granulate formulation of claim 1 , wherein said binder comprises one or more selected from the group consisting of microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, and polyvinylpyrrolidone.

5. The granulate formulation of claim 2 , wherein said filler comprises 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, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol.

6. The granulate formulation of claim 2 , wherein said lubricant comprises 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 granulate formulation of claim 2 , wherein said disintegrator is 2-10%, said binder is 2-30%, said filler is 2-30%, and said lubricant is 0.3-0.8% by weight of the granulate formulation.

8. The granulate formulation of claim 2 , wherein said binder comprises povidone.

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

10. The granulate formulation of claim 9 , comprising 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 granulate formulation 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 form 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. The method of claim 11 , wherein said cytokines comprise one or more selected from the group consisting of TNF-α, TGF-β1, bFGF, PDGF, and EGF.

15. The method of claim 14 , wherein said disorder is one selected from the group consisting of multiple sclerosis, arthritis, asthma, chronic rhinitis, and edema.

16. The method of claim 11 , comprising administering said granulate formulation 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.

17. The method of claim 16 , wherein said granulate formulation is administered to the patient twice a day or three times a day.

18. The method of claim 11 , wherein said fibrotic condition is a pulmonary fibrotic condition.

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

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

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

22. The granulate formulation of claim 9 , wherein the binder further comprises microcrystalline cellulose.

23. The granulate formulation of claim 1 , wherein the total amount of binder is 2-30% by weight of the formulation.

24. The granulate formulation of claim 1 , wherein said effective amount of binder increases the AUC of 5-methyl-1-phenyl-2-(1H)-pyridone at least 50% upon oral administration, as compared to pirfenidone without excipients orally administered in a capsule shell.

25. The granulate formulation of claim 1 , wherein said effective amount of binder increases the AUC of 5-methyl-1-phenyl-2-(1H)-pyridone at least 55% upon oral administration, as compared to pirfenidone without excipients orally administered in a capsule shell.

26. The granulate formulation of claim 1 , wherein said effective amount of binder increases the AUC of 5-methyl-1-phenyl-2-(1H)-pyridone at least 60% upon oral administration, as compared pirfenidone without excipients orally administered in a capsule shell.

27. The method of claim 11 , wherein the fibrotic condition is idiopathic pulmonary fibrosis.