received by the International Bureau on 07 November 2017 (07.1 1.2017)

A pharmaceutical combination composition with improved physicochemical characteristics d enhanced biological performance comprising i. complex Ivacaftor formulation or its pharmaceutical composition; and ii. complex Lumacator formulation or its pharmaceutical composition; and iii. optionally, pharmaceutically acceptable excipients; lerein said complex Ivacaftor formulation or its pharmaceutical composition comprising i. Ivacaftor or a salt 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, 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. pharmaceutically acceptable excipients; lerein said complex Lumacaftor formulation or its pharmaceutical composition comprises i. Lumacaftor or a salt 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

1 iii. 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 has 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 for at least 6 month; e) has increased dissolution rate: 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; g) has improved bioavailability both for Ivacaftor and Lumacaftor.

2. The pharmaceutical combination composition as recited in Claim 1, wherein said complexes have particle size in the range between 10 nm and 400 nm.

3. The pharmaceutical combination composition as recited in Claim 1, wherein said complexes exhibit X-ray amorphous character in the solid form.

4. The pharmaceutical combination composition as recited in Claim 1, wherein said complexes or their pharmaceutical compositions or said pharmaceutical combination composition possess at least two of the properties described in a)— g).

5. The pharmaceutical combination composition as recited in Claim 4, wherein said complexes or their pharmaceutical compositions or pharmaceutical combination composition possess at least three of the properties described in a)— g).

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6. The complex as recited in Claim 5, wherein said pharmaceutical combination composition or said complexes or their pharmaceutical compositions possess instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/ mL, exhibits no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted pharmaceutical combination composition in solution form.

7. The pharmaceutical combination composition as recited in Claim 5, wherein said complexes or their pharmaceutical combination compositions possess instantaneous redispersibility, have a PAMPA permeability of at least 0.2* cm/s for Ivacaftor and 2* 1CT⁶ cm/s for Lumacaftor when dispersed in water, FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 6 month, exhibits no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted pharmaceutical combination composition in solution form.

8. The pharmaceutical combination composition as recited in Claim 1, wherein the complexing agent of complex Ivacaftor formulation is a copolymer of vinylpyrrolidone and vinylacetate and optionally a poloxamer; and the complexing agent of complex Lumacaftor formulation is a copolymer of vinylpyrrolidone and vinylacetate.

9. The pharmaceutical combination composition as recited in Claim 1, wherein said pharmaceutically acceptable excipient of said complex Ivacaftor and complex Lumacaftor formulations is chosen from sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.

10. The pharmaceutical combination composition as recited in Claim 9, wherein said pharmaceutically acceptable excipient is sodium lauryl sulfate.

11. The pharmaceutical combination composition as recited in Claim 1 comprising i. complex Ivacaftor formulation; and ii. complex Lumacaftor formulation; and iii. optionally, pharmaceutically acceptable excipients; wherein said complex Ivacaftor formulation comprising i. Ivacaftor;

3 ii. as complexing agent a copolymer of vinylpyrrolidone and vinylacetate, and optionally a poloxamer; and iii. as an excipient sodium lauryl sulfate; wherein said complex Ivacaftor formulation is characterized by infrared (ATR) peaks at 588 cm⁴, 628 cm¹, 767 cm¹, 842 cm¹, 962 cm¹, 1019 cm¹, 1108 cm¹, 1148 cm¹, 1240 cm¹, 1343 cm¹, 1370 cm¹, 1425 cm¹, 1465 cm¹, 1525 cm¹, 1567 cm¹, 1666 cm⁴ and 1732 cm⁴; and is characterized by Raman shifts at 552 cm¹, 648 cm¹, 826 cm¹, 845 cm⁴, 888 cm¹, 932 cm⁴, 1026 cm¹, 1062 cm¹, 1082 cm¹, 1129 cm , 1140 cm¹, 1208 cm¹, 1233 cm¹, 1262 cm¹, 1284 cm¹, 1295 cm¹, 1361 cm¹, 1450 cm¹, 1528 cm¹, 1573 cm¹, 1618 cm¹, 1677 cm¹, 1738 cm¹, 746 cm , 2884 cm⁴ and 2936 cm . and wherein said complex Lumacaftor formulation composition comprises i. Lumacaftor; ii. as complexing agent a copolymer of vinylpyrrolidone and vinylacetate; and iii. as an excipient sodium lauryl sulfate; wherein said complex Lumacaftor formulations is characterized by infrared (ATR) peaks at 635 cm¹, 703 cm¹, 747 cm¹, 837 cm¹, 1021 cm , 1165 cm¹, 1231 cm¹, 1288 cm⁴, 1369 cm¹, 1423 cm⁴, 1462 cm⁴, 1494 cm⁴, 1667 cm⁴ and 1731 cm⁴; and is characterized by Raman shifts at 553 cm⁴, 602 cm⁴, 635 cm⁴, 654 cm⁴, 747 cm⁴, 841 cm⁴, 899 cm⁴, 934 cm⁴, 1002 cm⁴, 1021 cm⁴, 1117 cm⁴, 1205 cm⁴, 1232 cm⁴, 1310 cm⁴, 1352 cm⁴, 1372 cm⁴, 1428 cm⁴, 1444 cm⁴, 1497 cm 1592 cm⁴, 1609 cm⁴, 1677 cm⁴ and 1737 cm⁴.

12. The pharmaceutical combination composition as recited in Claim 1, wherein said pharmaceutical combination composition comprises of 50 to 300 mg Ivacaftor equivalent complex Ivacaftor formulation in combination with 25 to 250 mg Lumacaftor equivalent complex Lumacaftor formulation.

13. A pharmaceutical combination composition to either of Claims 1 or 11 comprising complex Ivacaftor formulation or its pharmaceutical composition and complex Lumacaftor formulation or its pharmaceutical composition in a total amount ranging from about 10.0 weight % to 100.0 weight % based on the total weight of the pharmaceutical composition.

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14. A pharmaceutical combination composition to either of Claims 1 or 11 comprising complex Ivacaftor formulation or its pharmaceutical composition and complex Lumacaftor formulation or its pharmaceutical composition in a total amount ranging from about 50.0 weight % to 100.0 weight % based on the total weight of the pharmaceutical composition.

15. The pharmaceutical combination composition as recited in Claim 1, wherein said pharmaceutical composition has an increased dissolution rate.

16. A process for the preparation of the complexes of Ivacaftor according to Claim 1, said process comprising the step of mixing a pharmaceutically acceptable solution containing Ivacaftor and a complexing agent which is a copolymer of vinylpyrrolidone and vinylacetate and optionally a poloxamer with an aqueous solution containing at least one pharmaceutically acceptable excipient which is sodium lauryl sulfate.

17. A process for the preparation of the complexes of Lumacaftor according to Claim 1, said process comprising the step of mixing a pharmaceutically acceptable solution containing Lumacaftor, and complexing agent which is a copolymer of vinylpyrrolidone and vinylacetate with an aqueous solution containing at least one pharmaceutically acceptable excipient which is sodium lauryl sulfate.

18. A process for the preparation of the complexes of Ivacaftor and Lumacaftor according to Claim 1, said process comprising the step of mixing a pharmaceutically acceptable solution containing Ivacaftor and Lumacaftor, and a complexing agent which is a copolymer of vinylpyrrolidone and vinylacetate with an aqueous solution containing at least one pharmaceutically acceptable excipient which is sodium lauryl sulfate.

19. The process as recited in Claim 16-18, wherein said process are performed in a continuous flow instrument.

20. The process as recited in Claim 19, wherein said continuous flow instrument is a micro fluidic flow instrument.

21. The process as recited in Claim 16-20, wherein the pharmaceutically acceptable solvent of said pharmaceutically acceptable solvent is chosen from water, methanol, ethanol, isopropanol, n- propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, or combinations thereof.

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22. The process as recited in Claim 21, wherein the pharmaceutically acceptable solvent of said pharmaceutically acceptable solution is methanol, tetrahydrofuran or a solvent mixture of tetrahydrofuran and methanol.

23. The process as recited in Claim 16-18, wherein said pharmaceutically acceptable solvents are miscible with each other and the aqueous solution; and the aqueous solvent comprises 0.1 to 99.9% weight of the final solution.

24. A pharmaceutical combination composition comprising the pharmaceutical combination composition as recited in Claim 1 together with a pharmaceutically acceptable carrier.

25. The pharmaceutical combination composition as recited in Claim 24, wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.

26. The pharmaceutical combination composition as recited in Claim 25, wherein said composition is suitable for oral administration.

27. The pharmaceutical combination composition comprising the pharmaceutical composition according to Claim 24, wherein said composition comprises fast dissolving granules of the complex formulations according to Claim 1.

28. The pharmaceutical combination composition according to Claim 27, wherein said fast dissolving granules are suitable for the preparation of sachet dosage form.

29. A pharmaceutical combination composition according to Claim 1 for use in the treatment of CFTR mediated diseases.

30. The complex for use according to 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

6 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, Straus sler-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. A method of treatment of CFTR mediated diseases comprising administration of a therapeutically effective amount of the pharmaceutical combination composition according to Claim 1 or the pharmaceutical composition according to Claim 24.

32. The pharmaceutical combination composition as recited in Claim 1, wherein said pharmaceutical composition further comprises one or more additional active agents.

33. The pharmaceutical combination composition as recited in Claim 32, wherein said additional active agent chosen from agents used for the treatment of CFTR mediated diseases.

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