WO2017187336A4 - Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents

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

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WO2017187336A4
WO2017187336A4 PCT/IB2017/052370 IB2017052370W WO2017187336A4 WO 2017187336 A4 WO2017187336 A4 WO 2017187336A4 IB 2017052370 W IB2017052370 W IB 2017052370W WO 2017187336 A4 WO2017187336 A4 WO 2017187336A4
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complex
recited
disease
pharmaceutically acceptable
weight
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PCT/IB2017/052370
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WO2017187336A1 (en
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Richard Balázs Kárpáti
Gergö PATYI
Orsolya Basa-Dénes
Erzsébet Réka ANGI
Tamás Jordán
Tamás SOLYMOSI
Hristos Glavinas
Genovéva FILIPCSEI
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Druggability Technologies Ip Holdco Limited
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Priority to JP2019506560A priority Critical patent/JP2019515029A/en
Priority to AU2017256180A priority patent/AU2017256180A1/en
Priority to CA3021944A priority patent/CA3021944A1/en
Priority to CN201780039667.4A priority patent/CN109475548A/en
Priority to EP17726697.0A priority patent/EP3448383A1/en
Publication of WO2017187336A1 publication Critical patent/WO2017187336A1/en
Publication of WO2017187336A4 publication Critical patent/WO2017187336A4/en
Priority to IL262489A priority patent/IL262489A/en

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Abstract

The present invention relates to pharmaceutically acceptable complex formulations comprising complexes of Ivacaftor, or a salt, or derivatives thereof and complexation agents and pharmaceutically acceptable excipients, process for the preparation thereof and pharmaceutical compositions containing them. 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 Ivacaftor in solution form.

Claims

AMENDED CLAIMS
received by the International Bureau on 07 November 2017 (07.1 1.17)
1. A stable complex with improved physicochemical characteristics and enhanced biological performance 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; wherein said complex has a particle size is between 10 nm and 600 nm, and possesses one or more among the following features: a) is instantaneously redispersible in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has an apparent solubility in water is of at least 1 mg/ mL; d) has a PAMPA permeability of at least 0.4xl0~6 cm/s when dispersed in distilled water, which does not decrease in time at least for 6 months; e) exhibits no observable food effect.
2. The complex as recited in Claim 1, wherein said complex has a particle size in the range between 10 nm and 400 nm. 3. The complex as recited in Claim 1, wherein said complex exhibits X-ray amorphous character in the solid form.
4. The complex as recited in Claim 1, wherein said complex possesses at least two of the properties described in a)— e).
1
5. The complex as recited in Claim 4, wherein said complex possesses at least three of properties described in a)— e).
6. The complex as recited in Claim 5, wherein said complex possesses 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 complex Ivacaftor in solution form.
7. The complex as recited in Claim 5, wherein said complex possesses instantaneous redispersibility, has a PAMPA permeability of at least 0.4xlCT6 cm/s 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 complex Ivacaftor in solution form.
8. The complex as recited in Claim 4, wherein said complex has an apparent solubility in water of at least 1 mg/ mL and a PAMPA permeability of at least 0.5x1 CT6 cm/ s.
9. The complex as recited in Claim 5, wherein said complex possesses instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/mL, and has a PAMPA permeability of at least 0.5xl0~6 cm/ s.
10. The complex as recited in Claim 1, wherein said complexing agent is selected from the group consisting of copolymers of vinylpyrrolidone and vinylacetate and poloxamers.
11. The complex as recited in Claim 10, wherein said complexation agent is a copolymer of vinylpyrrolidone and vinylacetate.
12. The complex as recited in Claim 1, wherein said pharmaceutically acceptable excipient is chosen from sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
13. The complex as recited in Claim 12, wherein said pharmaceutically acceptable excipient is sodium lauryl sulfate.
14. The complex as recited in Claim 1 comprising a) Ivacaftor;
2 b) as complexing agent a copolymer of vinylpyrrolidone and vinylacetate, and optionally a poloxamer; c) as an excipient sodium lauryl sulfate; wherein said complex is characterized by infrared (ATR) spectrum having characteristic peaks at 588 cm 1, 628 cm 1, 767 cm 1, 842 cm 1, 962 cm 1, 1019 cm 1, 1108 cm 1, 1148 cm 1, 1240 cm"
, 1343 cm , 1370 cm , 1425 cm , 1465 cm , 1525 cm , 1567 cm , 1666 cm 1 and 1732 cm ; characterized by Raman shifts at 552 cm" , 648 cm" , 826 cm" ,845 cm" , 888 cm" , 932 cm , 1026 cm , 1062 cm" , 1082 cm , 1129 cm , 1140 cm , 1208 cm , 1233 cm , 1262 cm" .
1284 cm , 1295 cm , 1361 cm , 1450 cm , 1528 cm , 1573 cm , 1618 cm , 1677 cm , 1738 cm , 746 cm , 2884 cm"1 and 2936 cm .
15. A complex according to either of Claims 1 or 13 comprising a complexation agent which is selected from the group of copolymer of vinylpyrrolidone and vinylacetate and optionally poloxamers and pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.
16. A complex according to either of Claims 1 or 13 comprising a complexation agent which is selected from the group of copolymer of vinylpyrrolidone and vinylacetate and optionally poloxamers and pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 50 weight % to about 95.0 weight % based on the total weight of the complex.
17. The complex as recited in Claim 1, wherein said complex has an increased dissolution rate.
18. A process for the preparation of a stable complex as recited in Claim 1, said process comprising the step of mixing a solution of Ivacaftor, and at least one complexing agent chosen from copolymers of vinylpyrrolidone and vinylacetate and optionally poloxamers, in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically accepted excipient selected from the group of sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
19. The process as recited in Claim 18, wherein said process is performed in a continuous flow instrument.
3
20. The process as recited in Claim 19, wherein said continuous flow instrument is a microfluidic flow instrument.
21. The process as recited in Claim 18, wherein said pharmaceutically acceptable solvent is chosen from water, methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, dimethyl- sulfoxide, tetrahydrofuran, or combinations thereof.
22. The process as recited in Claim 21, wherein said pharmaceutically acceptable solvent is tetrahydrofuran.
23. The process as recited in Claim 18, wherein said solvents are miscible with each other and the aqueous solution comprises 0.1 to 99.9% weight of the final solution. 24. A pharmaceutical composition comprising the stable complex as recited in Claim 1 together with a pharmaceutically acceptable carrier.
25. The pharmaceutical 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 composition as recited in Claim 25, wherein said composition is suitable for oral administration.
27. The pharmaceutical composition comprising the complex according to Claim 26, wherein said composition comprises fast dissolving granules of the complex formulation according to Claim 1. 28. The pharmaceutical composition comprising the complex according to Claim 27, wherein said granules are suitable for the preparation of sachet dosage form.
29. A complex 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
4 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. A method of treatment of CFTR mediated diseases comprising administration of a therapeutically effective amount of the complex according to Claim 1 or the pharmaceutical composition according to Claim 24.
32. A stable complex comprising a) 5— 40% by weight of Ivacaftor or salt thereof; b) 20— 80% by weight of a copolymer of vinylpyrrolidone and vinylacetate; c) 5— 40 % by weight of sodium-lauryl-sulfate; and d) optionally 0— 50 % by weight of a poloxamer; wherein said complex has a controlled particle size in the range between 10 nm and 600 nm; and
5 wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.
33. The complex as recited in Claim 1, wherein said complex further comprises one or more additional active agents. 34. The complex as recited in Claim 26, wherein said additional active agent Lumacaftor, Tezacaftor or chosen from agents used for the treatment of CFTR mediated diseases.
6
PCT/IB2017/052370 2016-04-25 2017-04-25 Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them WO2017187336A1 (en)

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CA3021944A CA3021944A1 (en) 2016-04-25 2017-04-25 Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
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EP17726697.0A EP3448383A1 (en) 2016-04-25 2017-04-25 Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
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