Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients

• US 20090191265A1
• Filed: 04/17/2009
• Published: 07/30/2009
• 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
• Granted Patent: US 7,767,225 B2
• Time in Patent Office: Days
• 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, by weight, 5-30% by weight of pharmaceutically acceptable excipients and 70-95% by weight of 5-methyl-1-phenyl-2-(1H)-pyridone.

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, carboxymethylcellulose, 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 said disintegrator is 2-10% by weight of the capsule, said binder is 2-30% by weight of the capsule, said filler is 2-30% by weight of the capsule, and said lubricant is 0.3-0.8% by weight of the capsule.

8. The capsule of claim 1, wherein said excipients comprise povidone.

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

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

11. The capsule of claim 1, wherein said excipients comprise microcrystalline cellulose.

12. The capsule of claim 1, wherein said formulation comprises a wet-granulated mixture comprising the 5-methyl-1-phenyl-2-(1H)-pyridone and one or more excipients selected from the group consisting of disintegrators, binders, and fillers.

13. The capsule of claim 7, wherein the excipients comprise magnesium stearate as a lubricant, microcrystalline cellulose as a binder, and croscarmellose sodium as a disintegrator.

14. The capsule of claim 13, further comprising povidone as a binder at an amount of 1-4% by weight of the capsule.

20. 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.

15. A capsule comprising 70-90% by weight of an 5-methyl-1-phenyl-2-(1H)-pyridone and 5-30% by weight of pharmaceutically acceptable excipients, wherein said capsule is capable of sustaining a measurable pharmacokinetic response in a patient, wherein said pharmacokinetic response is characterized by (a) a one or more fold increase in the T_max values compared to a capsule of 5-methyl-1-phenyl-2-(1H)-pyridone containing no pharmaceutically acceptable excipients, or (b) a one or more fold increase in the AUC values compared to a capsule of 5-methyl-1-phenyl-2-(1H)-pyridone containing no pharmaceutically acceptable excipients.

16. The capsule of claim 15, wherein the excipients comprise 2-10% by weight of a disintegrator, 2-25% by weight of a binder, 2-25% by weight of a filler, and 0.3-0.8% by weight of a lubricant.

17. The capsule of claim 15, wherein the excipients comprise microcrystalline cellulose.

18. The capsule of claim 15, wherein said excipients comprise povidone.

19. The capsule of claim 15, wherein the capsule comprises a wet-granulated mixture comprising the 5-methyl-1-phenyl-2-(1H)-pyridone and one or more excipients selected from the group consisting of disintegrators, binders, and fillers.