Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same

Abstract

The disclosure relates to granulate formulations of pirfenidone and methods of making such formulations.

1 .- 36 . (canceled) 
     
     
         37 . A tablet comprising granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone, comprising granules comprising: 5-methyl-1-phenyl-2-(1H)-pyridone and a glidant. 
     
     
         38 .- 45 . (canceled) 
     
     
         46 . A method of making a granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone, comprising:
 mixing the 5-methyl-1-phenyl-2-(1H)-pyridone and intragranular excipients in a fluid bed granulator to form granules, wherein the intragranular excipients comprise a glidant; and   optionally adding one or more extragranular excipients to the granules.   
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 46 , further comprising drying the granules to a moisture content of less than 3% as measured by loss on drying. 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 59 , wherein the filler is present in an amount of about 2% to about 30% by weight based on the total weight of the formulation. 
     
     
         53 . The method of  claim 52 , wherein the filler is selected from the group consisting of calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium silicate, tribasic calcium sulfate, calcium carboxymethylcellulose and salts thereof, cellulose, dextrin derivatives, dextrin, dextrose, fructose, isomalt, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, mannitol, microcrystalline cellulose, sodium bicarbonate, sodium carbonate, sorbitol, starch, sucrose, sugar, xylitol, and combinations thereof. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 59 , wherein the binder is in an aqueous solution, an aqueous suspension, an alcoholic solution, an alcoholic suspension, or an aqueous-alcoholic mixture, and applied to form the granules as a wet granulation. 
     
     
         56 . The method of  claim 59 , wherein the binder is present in an amount of about 1% to about 10% by weight based on the total weight of the formulation. 
     
     
         57 . The method of  claim 56  wherein the binder is selected from the group consisting hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, calcium carbonate, dicalcium phosphate, carbomers, cellulose acetate phthalates, copovidone, hydroxypropyl methyl cellulose, ethylene glycol and vinyl glycol grafted copolymer, isomalt, poloxamer, polyethylene oxide, polymethacrylates, and combinations thereof. 
     
     
         58 . The method of  claim 46 , wherein the extragranular excipients comprise one or more of a disintegrant, a lubricant, and a glidant. 
     
     
         59 . The method of  claim 46 , comprising adding the one or more extragranular excipients to the granules, wherein the intragranular excipients comprise one or more of a binder, a filler, and disintegrant. 
     
     
         60 . The method of  claim 58 , wherein the lubricant is present in an amount of about 0.05% to about 2% by weight based on the total weight of the formulation. 
     
     
         61 . The method of  claim 60 , wherein the lubricant is selected from the group consisting of agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycols, sodium benzoate, sodium lauryl sulfate, sodium stearate, sorbitol, stearic acid, talc, zinc stearate, and combinations thereof. 
     
     
         62 . The method of  claim 58 , wherein the distinegrant is present in an amount of about 0.1% to about 10% by weight based on the total weight of the formulation. 
     
     
         63 . (canceled) 
     
     
         64 . The method of  claim 63 , wherein the disintegrant is selected from the group consisting of agar-agar, algins, calcium carbonate, carboxmethylcellulose and salts thereof, cellulose, clays, corn starch, croscarmellose sodium, crospovidone, gums, methyl cellulose, polacrilin potassium, sodium alginate, cross-linked polyvinylpyrrolidone, sodium starch glycolate, starch, and combinations thereof. 
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 58 , wherein the extragranular glidant is in an amount of about 0.1% to about 5% by weight based on the total weight of the formulation. 
     
     
         67 . The method of  claim 66 , wherein the glidant is selected from the group consisting of silica, silicified cellulose, sodium stearate, magnesium aluminum silicate, pyrogenic silica, hydrated sodium silioaluminate, cellulose, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, and physical or coprocessed combinations thereof. 
     
     
         68 . The method of  claim 46 , wherein the granules comprise the glidant in an amount of at least about 1% by weight based on total weight of the formulation. 
     
     
         69 . (canceled) 
     
     
         70 . (canceled) 
     
     
         71 . The method of  claim 46 , further comprising applying a compression pressure to the granulate formulation to form a tablet. 
     
     
         72 . (canceled) 
     
     
         73 . (canceled) 
     
     
         74 . (canceled) 
     
     
         75 . The method of  claim 46 , further comprising heating the 5-methyl-1-phenyl-2-(1H)-pyridone and intragranular excipients prior to or during mixing. 
     
     
         76 . (canceled) 
     
     
         77 . (canceled) 
     
     
         78 . (canceled) 
     
     
         79 . (canceled) 
     
     
         80 . (canceled) 
     
     
         81 . (canceled) 
     
     
         82 . (canceled) 
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         85 . (canceled) 
     
     
         86 . (canceled) 
     
     
         87 . A method of administering a pirfenidone therapy to a patient in need thereof, comprising administering a therapeutically effective amount of a granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone, comprising granules comprising: 5-methyl-1-phenyl-2-(1H)-pyridone and a glidant. 
     
     
         88 . The method of  claim 87 , wherein the patient suffers from a disease selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, bronchiolitis obliterans, chronic lung transplant rejection, scleroderma, primary focal segmental glomerulosclerosis (FSGC) or membranoproliferative glomerulonephritis (MPGN), idiopathic interstitial pneumonia, interstitial lung disease in systemic sclerosis, a fibrosis condition of the lung, autoimmune lung diseases, benign prostate hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, or skin lesions, lymph node fibrosis associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; rheumatoid arthritis-associated interstitial lung disease; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome (MPS); Shigellosis; asthma; adult respiratory distress syndrome; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis including hepatic fibrosis; acute or chronic renal disease; renal fibrosis; diabetic nephropathy; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke or ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute or chronic pain; allergies, including allergic rhinitis or allergic conjunctivitis; cardiac hypertrophy, chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synoviitis; muscle degeneration, bursitis; tendonitis; tenosynoviitis; herniated, ruptured, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as osteoporosis or multiple myeloma-related bone disorders; cancer, including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; graft-versus-host reaction; or auto-immune diseases, such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus, Severe Acute Respiratory Syndrome (SARS) or cytomegalovirus; or diabetes mellitus, proliferative disorders (including both benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma, breast cancer, including metastatic breast carcinoma; colorectal. carcinoma; malignant melanoma; gastric cancer; non-small cell lung cancer (NSCLC); bone metastases; pain disorders including neuromuscular pain, headache, cancer pain, dental pain, or arthritis pain; angiogenic disorders including solid tumor angiogenesis, ocular neovascularization, or infantile hemangioma; conditions associated with the cyclooxygenase or lipoxygenase signaling pathways, including conditions associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); organ hypoxia; thrombin-induced platelet aggregation; or protozoal diseases. 
     
     
         89 . A method for treating a fibrotic condition or inhibiting the actions of cytokines, comprising administering a granulate formulation of 5 methyl-1-phenyl-2-(1H)-pyridone, comprising granules comprising: 5-methyl-1-phenyl-2-(1H)-pyridone and a glidant to a patient suffering from said fibrotic condition or suffering from a disorder mediated by said cytokines. 
     
     
         90 . The method of  claim 89 , wherein the fibrotic condition is selected from the group consisting of pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, keloid, dermal fibrosis, coronary restenosis, post-surgical adhesions, and combinations thereof. 
     
     
         91 . The method of  claim 90 , wherein said pulmonary fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis and Hermansky-Pudlak Syndrome. 
     
     
         92 . The method of  claim 89 , wherein the cytokines comprises one or more selected from the group consisting of TNF-α, TGF-β1, bFGF, PDGF, and EGF. 
     
     
         93 . The method of  claim 92 , wherein said disorder is selected from the group consisting of multiple sclerosis, arthritis, asthma, chronic rhinitis, and edema. 
     
     
         94 . (canceled) 
     
     
         95 . (canceled) 
     
     
         96 . The method of  claim 87 , wherein the granulate formulation is provided as a tablet. 
     
     
         97 . (canceled) 
     
     
         98 . The method of  claim 96 , wherein the tablets comprise 267 mg, 534 mg, or 801 mg of the 5-methyl-1-phenyl-2-(1H)-pyridone. 
     
     
         99 . The method of  claim 87 , wherein the total intake of the 5-methyl-1-phenyl-2-(1H)-pyridone is about 800 mg per day to about 2405 mg per day. 
     
     
         100 . The method of  claim 99 , comprising administering 267 mg of the 5-methyl-1-phenyl-2-(1H)-pyridone three times per day; or administering 534 mg of the 5-methyl-1-phenyl-2-(1H)-pyridone three times per day; or administering 801 mg of the 5-methyl-1-phenyl-2-(1H)-pyridone three times per day. 
     
     
         101 . (canceled) 
     
     
         102 . (canceled)