Pharmaceutical composition and administrations thereof

Abstract

The present invention relates to pharmaceutical compositions containing a solid dispersion of N—[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide including formulations of the solid dispersions into powders, granules and mini-tablets, methods for manufacturing and processing the powders, granules and mini-tablets, and methods for treating cystic fibrosis employing the pharmaceutical composition.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of about 30 to about 50 percent by weight of the pharmaceutical composition;   sucralose in an amount of between about 1.5 wt % to about 2.5 wt % percent by weight of the pharmaceutical composition;   croscarmellose sodium in an amount from about 4 to about 8 percent of by weight of the pharmaceutical composition;   colloidal silicon dioxide in an amount from about 0.5 wt % to about 1.5 wt % percent by weight of the pharmaceutical composition;   magnesium stearate in an amount from about 0.5 wt % to about 1.5 wt % percent by weight of the pharmaceutical composition; and   one or more fillers, collectively, in an amount of about 30 to about 60 percent of by weight of the pharmaceutical composition.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the one or more fillers comprises mannitol. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the one or more fillers comprise lactose. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the filler comprises mannitol and lactose in a ratio of about 3:1 mannitol to lactose. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein the filler comprises mannitol and lactose in a ratio of about 1:1 mannitol to lactose. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein the filler comprises mannitol and lactose in a ratio of about 1:3 mannitol to lactose. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the one or more fillers comprises mannitol in an amount of about 13.5 percent by weight of the composition. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the one or more fillers comprises lactose. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein lactose is present in an amount of about 41 percent by weight of the composition. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the croscarmellose sodium is present in an amount of about 6 percent of by weight of the pharmaceutical composition. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition. 
     
     
         12 . A pharmaceutical composition comprising:
 about 35 wt % of a solid dispersion by weight of the composition, wherein the dispersion comprises about 80 wt % of substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt % of HPMCAS by weight of the dispersion, and about 0.5 wt % SLS by weight of the dispersion;   about 13.5 wt % of mannitol by weight of the composition;   about 41 wt % of lactose by weight of the composition;   about 2 wt % of sucralose by weight of the composition;   about 6 wt % of croscarmellose sodium by weight of the composition;   about 1 wt % of colloidal silicon dioxide by weight of the composition; and   about 1.5 wt % of magnesium stearate by weight of the composition.   
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the pharmaceutical composition is a unit dose form comprising one or a plurality of granules, pellets, particles or mini-tablets, and wherein the unit dose form comprises from about 1 mg to about 100 mg of substantially amorphous or amorphous Compound 1. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the unit dose form comprises from about 50 mg of substantially amorphous or amorphous Compound 1. 
     
     
         15 . The pharmaceutical composition of  claim 13 , wherein the unit dose form comprises from about 75 mg of substantially amorphous or amorphous Compound 1. 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the unit dose form comprises from about 25 to about 40 mini-tablets. 
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition and the unit dose form comprises from about 26 mini-tablets. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the unit dose form comprises about 50 mg of substantially amorphous or amorphous Compound 1. 
     
     
         19 . The pharmaceutical composition of  claim 13 , wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition and the unit dose form comprises from about 39 mini-tablets. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the unit dose form comprises from about 75 mg of substantially amorphous or amorphous Compound 1. 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein the mini-tablet has a shape that is cylinder-like, oval-like, cone-like, sphere-like, ellipsis-like, polygon-like or combinations thereof, wherein the mini-tablet has as its longest dimension or diameter a length of about 2 mm. 
     
     
         22 . A method of treating or lessening the severity of CFTR mediated disease in a pediatric patient comprising administering to the pediatric patient a pharmaceutical composition of  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Gerstmann-Sträussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia. 
     
     
         24 . The method of  claim 23 , wherein the CFTR mediated disease is cystic fibrosis, COPD, emphysema, dry-eye disease or osteoporosis. 
     
     
         25 . The method of  claim 24 , wherein the CFTR mediated disease is cystic fibrosis. 
     
     
         26 . The method of  claim 25 , wherein the patient possesses a CFTR gating mutation. 
     
     
         27 . The method according to  claim 26 , wherein the CFTR gating mutation is selected from G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. 
     
     
         28 . The method according to  claim 26 , wherein the CFTR gating mutation is in at least one allele. 
     
     
         29 . The method according to  claim 26 , wherein the CFTR gating mutation is in both alleles. 
     
     
         30 . The method according to 25, wherein the patient possesses one or both of the following mutations of human cystic fibrosis transmembrane regulator gene (CFTR): ΔF508 and R117H. 
     
     
         31 . The method according to  claim 25 , wherein the patient is 2 through 5 years of age. 
     
     
         32 . The method according to  claim 25 , wherein the patient is 0 through 2 years of age. 
     
     
         33 . The method according to  claim 25 , wherein the patient weighs about 14 kilograms or more than about 14 kilograms. 
     
     
         34 . The method according to  claim 25 , wherein the patient weighs less than 14 kilograms.