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

A pharmaceutical combination composition comprising

• i. complex Ivacaftor formulation or its pharmaceutical composition;
• ii. complex Lumacator formulation or its pharmaceutical composition;
• and
• iii. optionally, pharmaceutically acceptable excipients;
• wherein said complex Ivacaftor formulation or its pharmaceutical composition comprising
• i. Ivacaftor, or a salt or derivative thereof;
• ii. at least one complexing agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymers of vinylpyrrolidone and vinyl acetate copolymer, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate;
• and
• iii. optionally, one or more pharmaceutically acceptable excipients;
• wherein said complex Lumacaftor formulation or its pharmaceutical composition comprises
• i. Lumacaftor, or a salt or derivative thereof;
• ii. at least one complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), vinylpyrrolidone/vinyl acetate copolymer, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate;
• and
• iii. optionally, one or more pharmaceutically acceptable excipients;
• wherein said complex formulations or their pharmaceutical combination compositions have particle size between 10 nm and 600 nm, and the said pharmaceutical combination composition possesses at least one of following features:
• a) is instantaneously redispersable in physiological relevant media;
• b) is stable in solid form and in colloid solution and/or dispersion;
• c) complex Ivacaftor and complex Lumacaftor formulations or their pharmaceutical composition have an apparent solubility in water of at least 1 mg/mL;
• d) complex Ivacaftor and complex Lumacaftor formulations or their pharmaceutical compositions have a PAMPA permeability of at least 0.2*10−6 cm/s for Ivacaftor and 2*10−6 cm/s for Lumacaftor when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 6 months;
• e) has increased dissolution rate compared to KALYDECO® and ORKAMBI® like formulations:
• 80% of Ivacaftor and 80% of Lumacaftor released from the pharmaceutical composition within 5 minutes in biological relevant media;
• f) exhibits no observable food effect;
• and
• g) has improved bioavailability both for Ivacaftor and Lumacaftor compared to KALYDECO® and ORKAMBI® like formulations.