WO2017187340A4 - 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 - Google Patents

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 Download PDF

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Publication number
WO2017187340A4
WO2017187340A4 PCT/IB2017/052374 IB2017052374W WO2017187340A4 WO 2017187340 A4 WO2017187340 A4 WO 2017187340A4 IB 2017052374 W IB2017052374 W IB 2017052374W WO 2017187340 A4 WO2017187340 A4 WO 2017187340A4
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical combination
complex
pharmaceutical
ivacaftor
lumacaftor
Prior art date
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PCT/IB2017/052374
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French (fr)
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WO2017187340A1 (en
Inventor
Richard Balázs Kárpáti
Gergö PATYI
Orsolya Basa-Dénes
Betti SZABÓNÉ ORDASI
Erzsébet Réka ANGI
Hristos Glavinas
Genovéva FILIPCSEI
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Druggability Technologies Ip Holdco Limited
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Application filed by Druggability Technologies Ip Holdco Limited filed Critical Druggability Technologies Ip Holdco Limited
Priority to CN201780039649.6A priority Critical patent/CN109475546A/en
Priority to EP17726698.8A priority patent/EP3448384A1/en
Priority to CA3022203A priority patent/CA3022203A1/en
Priority to JP2018555738A priority patent/JP2019514898A/en
Priority to AU2017256184A priority patent/AU2017256184A1/en
Publication of WO2017187340A1 publication Critical patent/WO2017187340A1/en
Publication of WO2017187340A4 publication Critical patent/WO2017187340A4/en
Priority to IL262494A priority patent/IL262494A/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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Abstract

The invention is directed to 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 of the present invention possess 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. The invention also relates to methods of formulating and manufacturing complexes according to the invention, pharmaceutical compositions containing it, its uses and methods of treatment using the complex and its compositions.

Claims

AMENDED CLAIMS
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).
2
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.
4
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.
5
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.
7
PCT/IB2017/052374 2016-04-25 2017-04-25 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 WO2017187340A1 (en)

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CN201780039649.6A CN109475546A (en) 2016-04-25 2017-04-25 Including according to the pharmaceutical combination composition for the compound formulation for cutting down Kato and Lu Makatuo and its salt and derivative, preparation method and containing their pharmaceutical composition
EP17726698.8A EP3448384A1 (en) 2016-04-25 2017-04-25 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
CA3022203A CA3022203A1 (en) 2016-04-25 2017-04-25 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
JP2018555738A JP2019514898A (en) 2016-04-25 2017-04-25 PHARMACEUTICAL COMBINATION COMPOSITION COMPRISING IVACAHUFTOL AND LUMACAFUTOL PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF
AU2017256184A AU2017256184A1 (en) 2016-04-25 2017-04-25 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
IL262494A IL262494A (en) 2016-04-25 2018-10-21 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

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