Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them

Abstract

Disclosed herein is a pharmaceutical combination composition comprising stable complexes with controlled particle size, increased apparent solubility and increased dissolution rate comprising as active compound Ivacaftor and Lumacaftor, their salts, or derivatives thereof, which is useful in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease. More specifically, the pharmaceutical composition comprising the complexes possesses instantaneous redispersibility, increased apparent solubility and permeability, no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form. Further disclosed are methods of formulating and manufacturing said complexes, pharmaceutical compositions containing said complexes, and methods of treatment using said complexes and their pharmaceutical compositions.

1 .- 28 . (canceled) 
     
     
         29 . A method of treatment of a cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising a binary complex formulation and one or more pharmaceutically acceptable carriers,
 wherein the binary complex formulation comprises:
 Ivacaftor, or a salt thereof; 
 Lumacaftor, or a salt thereof; 
 a copolymer of vinylpyrrolidone and vinyl acetate; 
 sodium lauryl sulfate, and 
 optionally, at least one pharmaceutically acceptable excipient
 wherein the binary complex formulation has a particle size between 10 nm and 600 nm, 
 wherein the binary complex formulation has a parallel artificial membrane permeability assay (PAMPA) permeability of at least 0.2*10 −6  cm/s for Ivacaftor when dispersed in fasted state simulating intestinal fluid (FaSSIF) or fed state simulating intestinal fluid (FeSSIF) biorelevant media; 
 wherein the binary complex formulation has a PAMPA permeability of at least 0.2*10 −6  cm/s for Lumacaftor when dispersed in FaSSIF or FeSSIF biorelevant media, 
 wherein the binary complex formulation is prepared by spray drying; and 
 wherein the PAMPA permeability is stable over time. 
 
   
     
     
         30 . The method of  claim 29 , 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. 
     
     
         31 . The method of  claim 30 , wherein the binary complex formulation has a particle size in the range between 10 nm and 400 nm. 
     
     
         32 . The method of  claim 30 , wherein the binary complex formulation exhibits X-ray amorphous character in the solid form. 
     
     
         33 . The method of  claim 30 , wherein the binary complex formulation comprises 50 to 300 mg Ivacaftor in combination with 25 to 250 mg Lumacaftor. 
     
     
         34 . The method of  claim 30 , wherein the pharmaceutical composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration. 
     
     
         35 . The method of  claim 34 , wherein the pharmaceutical composition is suitable for oral administration. 
     
     
         36 . The method of  claim 30 , wherein the pharmaceutical composition is in the form of fast dissolving granules. 
     
     
         37 . The method of  claim 36 , wherein the granules are suitable for the preparation of sachet dosage form. 
     
     
         38 . The method of  claim 30 , wherein the pharmaceutical composition further comprises one or more additional active agents. 
     
     
         39 . The method of  claim 38 , wherein the additional active agent is chosen from agents used for the treatment of CFTR mediated diseases.