Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them

Abstract

Disclosed herein are pharmaceutically acceptable complex formulations comprising complexes of Lumacaftor, or a salt, or derivative thereof together with complexation agents and, optionally, pharmaceutically acceptable excipients; processes for the preparation thereof and pharmaceutical compositions containing them. The complex formulations have improved dissolution and permeability in fasted and fed state simulation that is expected to deliver full absorption and the elimination of the food effect.

1 .- 27 . (canceled) 
     
     
         28 . A method of treatment of a cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease comprising administration of a therapeutically effective amount of a complex comprising:
 Lumacaftor;   at least 50% by weight of a complexation agent which is a copolymer of vinylpyrrolidone and vinyl acetate; and   sodium lauryl sulfate;   wherein the ratio of the copolymer:sodium lauryl sulfate:Lumacaftor is 9:1.2:2, and   wherein the complex has a particle size is between 10 nm and 500 nm, and possesses one or more among the following features:
 a) has an apparent solubility in water of at least 1 mg/mL; and 
 b) has a PAMPA permeability of at least 2×10 −6  cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 month. 
   
     
     
         29 . The method of  claim 28 , wherein said 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/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, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, 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. 
     
     
         30 . The method of  claim 28 , wherein the complex has a particle size in the range between 10 nm and 250 nm. 
     
     
         31 . The method of  claim 28 , wherein the complex exhibits X-ray amorphous character in the solid form. 
     
     
         32 . The method of  claim 28 , wherein the complex has an apparent solubility in water of at least 1 mg/mL and a PAMPA permeability of at least 2×10 −6  cm/s in FaSSIF and FeSSIF biorelevant media. 
     
     
         33 . The method of  claim 28 , wherein the complex is characterized by infrared (ATR) peaks at 635 cm −1 , 703 cm −1 , 747 cm −1 , 837 cm −1 , 1021 cm −1 , 1165 cm −1 , 1231 cm −1 , 1288 cm −1 , 1369 cm −1 , 1423 cm −1 , 1462 cm −1 , 1494 cm −1 , 1667 cm −1  and 1731 cm −1 . 
     
     
         34 . The method of  claim 28 , wherein the complex is characterized by Raman shifts at 553 cm −1 , 602 cm −1 , 635 cm −1 , 654 cm −1 , 747 cm −1 , 841 cm −1 , 899 cm −1 , 934 cm −1 , 1002 cm −1 , 1021 cm −1 , 1117 cm −1 , 1205 cm −1 , 1232 cm −1 , 1310 cm −1 , 1352 cm −1 , 1372 cm −1 , 1428 cm −1 , 1444 cm −1 , 1497 cm −1 , 1592 cm −1 , 1609 cm −1 , 1677 cm −1  and 1737 cm −1 . 
     
     
         35 . The method of  claim 28 , wherein the complex is instantaneously redispersable in physiological relevant media. 
     
     
         36 . The method of  claim 28 , wherein the complex is stable in solid form and in colloid solution and/or dispersion.