Pharmaceutical composition and administration thereof

Abstract

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

1 - 111 . (canceled) 
     
     
         112 . A pharmaceutical composition comprising:
 a. a solid dispersion comprising substantially amorphous Compound 1 and a polymer;   b. a filler;   c. a disintegrant;   d. a surfactant;   e. a binder;   f. a glidant; and   g. a lubricant.   
     
     
         113 . The pharmaceutical composition of  claim 112 , wherein the solid dispersion comprises substantially amorphous Compound 1 and a polymer, and the polymer comprises HPMC, HPMCAS, PVP/VA, PVP, methacrylic acid/methacrylate copolymer, HPC, or any combination thereof. 
     
     
         114 . The pharmaceutical composition of  claim 113 , wherein the solid dispersion has a mean particle diameter of greater than about 5 μm. 
     
     
         115 . The pharmaceutical composition of  claim 113 , wherein the solid dispersion has a bulk density of about 0.10 g/cc or greater. 
     
     
         116 . The pharmaceutical composition of  claim 113 , wherein the solid dispersion comprises substantially amorphous Compound 1, and Compound 1 is present in a concentration of at least 20 wt % by weight of the solid dispersion. 
     
     
         117 . The pharmaceutical composition of  claim 116 , wherein the solid dispersion comprises 80 wt % or less of HPMCAS or PVP/VA. 
     
     
         118 . The pharmaceutical composition of  claim 116 , wherein the solid dispersion further comprises a surfactant. 
     
     
         119 . The pharmaceutical composition of  claim 118 , wherein the solid dispersion comprises less than 10 wt % of surfactant by weight of solid dispersion. 
     
     
         120 . The pharmaceutical composition of  claim 119 , wherein the surfactant is SLS. 
     
     
         121 . The pharmaceutical composition of  claim 120 , wherein the solid dispersion comprises amorphous Compound 1. 
     
     
         122 . The pharmaceutical composition of  claim 112 , wherein the solid dispersion comprises from about 45 wt % to about 85 wt % of substantially amorphous Compound 1, from about 0.45 wt % to about 0.55 wt % of SLS, and from about 14.45 wt % to about 55.55 wt % of HPMCAS or PVP/VA by weight of the solid dispersion. 
     
     
         123 . The pharmaceutical composition of  claim 112 , wherein the filler is lactose, sorbitol, cellulose, calcium phosphate, starch, sugar, or any combination thereof. 
     
     
         124 . The pharmaceutical composition of  claim 123 , wherein the filler is lactose and has a concentration of at least about 10 wt % by weight of the composition. 
     
     
         125 . The pharmaceutical composition of  claim 112 , wherein the disintegrant is sodium croscarmellose, sodium starch glycolate, or a combination thereof. 
     
     
         126 . The pharmaceutical composition of  claim 125 , wherein the disintegrant is sodium croscarmellose and has a concentration of about 10 wt % or less by weight of the composition. 
     
     
         127 . The pharmaceutical composition of  claim 112 , wherein the surfactant is sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof. 
     
     
         128 . The pharmaceutical composition of  claim 127 , wherein the surfactant is sodium lauryl sulfate and has a concentration of about 10 wt % or less by weight of the composition. 
     
     
         129 . The pharmaceutical composition of  claim 112 , wherein the binder is microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, modified cellulose, or any combination thereof. 
     
     
         130 . The pharmaceutical composition of  claim 129 , wherein the binder is microcrystalline cellulose and has a concentration of at least about 1 wt % by weight of the composition. 
     
     
         131 . The pharmaceutical composition of  claim 112 , wherein the glidant is colloidal silicon dioxide, talc, or a combination thereof. 
     
     
         132 . The pharmaceutical composition of  claim 131 , wherein the glidant is colloidal silicon dioxide and has a concentration of 2 wt % or less by weight of the composition. 
     
     
         133 . The pharmaceutical composition of  claim 112 , wherein the lubricant is magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof. 
     
     
         134 . The pharmaceutical composition of  claim 133 , wherein the lubricant is magnesium stearate and has a concentration of about 2 wt % by weight of the composition. 
     
     
         135 . The pharmaceutical composition of  claim 112  further comprising a colorant. 
     
     
         136 . The pharmaceutical composition of  claim 135 , wherein the colorant is a blue pigment having a concentration of about 3wt % by weight of the composition. 
     
     
         137 . The pharmaceutical composition of  claim 136 , wherein the composition is formed into a tablet and the tablet comprises the colorant as a tablet coating. 
     
     
         138 . The pharmaceutical composition of  claim 137 , wherein the blue pigment is OPADRY®II. 
     
     
         139 . The pharmaceutical composition of  claim 135  further comprising a wax. 
     
     
         140 . The pharmaceutical composition of  claim 139 , wherein the wax comprises Carnauba wax powder. 
     
     
         141 . A pharmaceutical composition comprising
 a. from about 5 wt % to about 50 wt % of a solid dispersion, by weight of the composition, comprising from about 70 wt % to about 90 wt % of substantially amorphous Compound 1, by weight of the dispersion, and from about 30 wt % to about 10 wt % of a polymer, by weight of the dispersion;   b. from about 25 wt % to about 50 wt % of a filler;   c. from about 1 wt % to about 10 wt % of a disintegrant;   d. from about 2 wt % to about 0.3 wt % of a surfactant;   e. from about 5 wt % to about 50 wt % of a binder;   f. from about 2 wt % to about 0.05 wt % of a glidant; and   h. from about 2 wt % to about 0.1 wt % of a lubricant.   
     
     
         142 . The pharmaceutical composition of  claim 141 , wherein the composition is formed as a tablet, a capsule, or a suspension. 
     
     
         143 . The pharmaceutical composition of  claim 142 , wherein the composition is formed as a tablet and the tablet has a hardness of at least 5 Kp. 
     
     
         144 . The pharmaceutical composition of  claim 143 , wherein the tablet has a dissolution of at least about 50% in about 30 minutes, and the solid dispersion comprises substantially amorphous Compound 1. 
     
     
         145 . The pharmaceutical composition of  claim 144 , wherein the solid dispersion comprises substantially amorphous Compound 1 and HPMCAS. 
     
     
         146 . A pharmaceutical composition consisting of a tablet comprising
 a. a solid dispersion comprising from about 20 wt % to about 99 wt % of substantially amorphous Compound 1 by weight of the dispersion and HPMCAS;   b. from about 27 wt % to about 45 wt % of a filler comprising lactose;   c. from about 2.5 wt % to about 6.0 wt % of a disintegrant comprising sodium croscarmellose;   d. from about 2.0 wt % to about 0.3 wt % of a surfactant comprising sodium lauryl sulfate;   e. from about 20 wt % to about 45 wt % of a binder comprising microcrystalline cellulose;   f. from about 1.0 wt % to about 0.09 wt % of a glidant comprising colloidal silicon dioxide; and   g. from about 1.3 wt % to about 0.3 wt % of a lubricant comprising magnesium stearate.   
     
     
         147 . The pharmaceutical composition of  claim 146 , wherein the composition comprises a. about 34.1 wt % of a solid dispersion by weight of the composition, wherein the dispersion comprises about 80 wt % of substantially 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;
 b. about 30.5 wt % of microcrystalline cellulose by weight of the composition;   c. about 30.4 wt % of lactose by weight of the composition;   d. about 3 wt % of sodium croscarmellose by weight of the composition;   e. about 0.5 wt % of SLS by weight of the composition;   f. about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and   g. about 1.0 wt % of magnesium stearate by weight of the composition.   
     
     
         148 . The pharmaceutical composition of  claim 147 , wherein the tablet further comprises a coating. 
     
     
         149 . The pharmaceutical composition of  claim 148 , wherein the coating comprises a colorant. 
     
     
         150 . The pharmaceutical composition of  claim 149 , wherein the colorant comprises OPADRY® H. 
     
     
         151 . The pharmaceutical composition of  claim 150 , wherein the coating further comprises a wax coating. 
     
     
         152 . The pharmaceutical composition of  claim 151 , wherein the wax coating comprises a Carnauba wax powder. 
     
     
         153 . The pharmaceutical composition of  claim 152 , wherein the tablet further comprises ink images or ink text printed on the coating. 
     
     
         154 . The pharmaceutical composition of  claim 147 , wherein the tablet has a hardness of about 10 Kp±20 percent. 
     
     
         155 . The pharmaceutical composition of  claim 147 , wherein the tablet contains about 150 mg of Compound 1. 
     
     
         156 . The pharmaceutical composition of  claim 147 , wherein the tablet contains about 100 mg of Compound 1. 
     
     
         157 . A method of producing a pharmaceutical composition comprising providing an admixture comprising:
 a. a solid dispersion comprising substantially amorphous Compound 1;   b. a binder;   c. a glidant;   d. a surfactant;   e. a lubricant;   f. a disintegrant; and   g. a filler, and   compressing the admixture into a tablet having a dissolution of at least about 50% in about 30 minutes.   
     
     
         158 . The method of  claim 157 , wherein the admixture is compressed to produce a tablet having a hardness of at least 5 Kp. 
     
     
         159 . The method of  claim 157 , further comprising mixing the admixture until the admixture is substantially homogenous. 
     
     
         160 . A method of administering a pharmaceutical composition comprising orally administering to a patient at least once per day at least one tablet comprising:
 a. a solid dispersion comprising from about 20 wt % to about 99 wt % of substantially amorphous Compound 1 by weight of the dispersion and HPMCAS;   b. from about 27 wt % to about 45 wt % of a filler comprising lactose;   c. from about 2.5 wt % to about 6.0 wt % of a disintegrant comprising sodium croscarmellose;   d. from about 2.0 wt % to about 0.3 wt % of a surfactant comprising sodium lauryl sulfate;   e. from about 20 wt % to about 45 wt % of a binder comprising microcrystalline cellulose;   f. from about 1.0 wt % to about 0.09 wt % of a glidant comprising colloidal silicon dioxide; and   g. from about 1.3 wt % to about 0.3 wt % of a lubricant comprising magnesium stearate.   
     
     
         161 . The method of  claim 160 , wherein the composition comprises
 a. about 34.1 wt % of a solid dispersion by weight of the composition, wherein the dispersion comprises about 80 wt % of substantially 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;   b. about 30.5 wt % of microcrystalline cellulose by weight of the composition;   c. about 30.4 wt % of lactose by weight of the composition;   d. about 3 wt % of sodium croscarmellose by weight of the composition;   e. about 0.5 wt % of SLS by weight of the composition;   f. about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and   g. about 1.0 wt % of magnesium stearate by weight of the composition.   
     
     
         162 . The method of  claim 161 , wherein the tablet contains about 150 mg of Compound 1. 
     
     
         163 . The method of  claim 162 , wherein the tablet contains about 100 mg of Compound 1. 
     
     
         164 . The method of  claim 161 , wherein the tablet is orally administered to the patient once per day or about every 12 hours. 
     
     
         165 . The method of  claim 164 , wherein the tablet is orally administered about every 12 hours. 
     
     
         166 . A method of treating or lessening the severity of a disease in a patient comprising administering to said patient a pharmaceutical composition according to  claim 112 , wherein said 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 polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or 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, hyperekplexia, 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. 
     
     
         167 . A method of treating or lessening the severity of a disease in a patient comprising administering to said patient a pharmaceutical composition according to  claim 147 , wherein said 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/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or 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, hyperekplexia, 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. 
     
     
         168 . The method of  claim 167 , wherein said disease is cystic fibrosis. 
     
     
         169 . The method of  claim 168 , wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a ΔF508 mutation. 
     
     
         170 . The method of  claim 168 , wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a R117H mutation. 
     
     
         171 . The method of  claim 168 , wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a G551D mutation.