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.

Claims

1. 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.sup.−6 cm/s for Ivacaftor and 2*10.sup.−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.

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).

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 0.2×10.sup.−6 cm/s for Ivacaftor and 2×10.sup.−6 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 composition in solution form.

8. The pharmaceutical combination composition as recited in claim 1, wherein the complexing agent of complex Ivacaftor formulation is chosen from the group consisting of a copolymer of vinylpyrrolidone and vinylacetate and a poloxamer, or combinations thereof; 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; ii. complex Lumacator formulation; and iii. optionally, pharmaceutically acceptable excipients; wherein said complex Ivacaftor formulation comprising i. Ivacaftor; ii. a complexing agent chosen from the group consisting of a copolymer of vinylpyrrolidone and vinylacetate and a poloxamer, or combinations thereof; and iii. an excipient that is sodium lauryl sulfate; wherein said complex Ivacaftor formulation is characterized by infrared (ATR) peaks at 588 cm.sup.−1, 628 cm.sup.−1, 767 cm.sup.−1, 842 cm.sup.−1, 962 cm.sup.−1, 1019 cm.sup.−1, 1108 cm.sup.−1, 1148 cm.sup.−1, 1240 cm.sup.−1, 1343 cm.sup.−1, 1370 cm.sup.−1, 1425 cm.sup.−1, 1465 cm.sup.−1, 1525 cm.sup.−1, 1567 cm.sup.−1, 1666 cm.sup.−1 and 1732 cm.sup.−1; and is characterized by Raman shifts at 552 cm.sup.−1, 648 cm.sup.−1, 826 cm.sup.−1 ,845 cm.sup.−1, 888 cm.sup.−1, 932 cm.sup.−1, 1026 cm.sup.−1, 1062 cm.sup.−1, 1082 cm.sup.−1, 1129 cm.sup.−1, 1140 cm.sup.−1, 1208 cm.sup.−1, 1233 cm.sup.−1, 1262 cm.sup.−1, 1284 cm.sup.−1, 1295 cm.sup.−1, 1361 cm.sup.−1, 1450 cm.sup.−1, 1528 cm.sup.−1, 1573 cm.sup.−1, 1618 cm.sup.−1, 1677 cm.sup.−1, 1738 cm.sup.−1, 746 cm.sup.−1, 2884 cm.sup.−1 and 2936 cm.sup.−1. and wherein said complex Lumacaftor formulation composition comprises i. Lumacaftor; ii. a complexing agent that is a copolymer of vinylpyrrolidone and vinylacetate; and iii. an excipient that is sodium lauryl sulfate; wherein said complex Lumacaftor formulations is characterized by infrared (ATR) peaks at 635 cm.sup.−1, 703 cm.sup.−1, 747 cm.sup.−1, 837 cm.sup.−1, 1021 cm.sup.−1, 1165 cm.sup.−1, 1231 cm.sup.−1, 1288 cm.sup.−1, 1369 cm.sup.−1, 1423 cm.sup.−1, 1462 cm.sup.−1, 1494 cm.sup.−1, 1667 cm.sup.−1 and 1731 cm.sup.−1; and is characterized by Raman shifts at 553 cm.sup.−1, 602 cm.sup.−1, 635 cm.sup.−1, 654 cm.sup.−1, 747 cm.sup.−1, 841 cm.sup.−1, 899 cm.sup.−1, 934 cm.sup.−1, 1002 cm.sup.−1, 1021 cm.sup.−1, 1117 cm.sup.−1, 1205 cm.sup.−1, 1232 cm.sup.−1, 1310 cm.sup.−1, 1352 cm.sup.−1, 1372 cm.sup.−1, 1428 cm.sup.−1, 1444 cm.sup.−1, 1497 cm.sup.−1, 1592 cm.sup.−1, 1609 cm.sup.−1, 1677 cm.sup.−1 and 1737 cm.sup.−1.

12. The pharmaceutical combination composition as recited in claim 1, wherein said pharmaceutical 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 claim 1 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.

14. A pharmaceutical combination composition to claim 13 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 complexing agents which is a copolymer of vinylpyrrolidone and vinylacetate with an aqueous solution containing at least one pharmaceutically accepted 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 copolymer of vinylpyrrolidone and vinylacetate with an aqueous solution containing at least one pharmaceutically accepted 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 complexing agent which is copolymer of vinylpyrrolidone and vinylacetate with an aqueous solution containing at least one pharmaceutically accepted excipient which is sodium lauryl sulfate.

19. The process as recited in claim 18 wherein said processes are performed in a continuous flow instrument.

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 20, 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 methanol, tetrahydrofuran or a solvent mixture of tetrahydrofuran and methanol.

23. The process as recited in claim 18, wherein said 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 one or more pharmaceutically acceptable carriers.

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.

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

29. A method of treatment of CFTR mediated diseases comprising administration of a therapeutically effective amount of the pharmaceutical composition according to claim 1.

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

32. The pharmaceutical combination composition as recited in claim 31, wherein said additional active agent chosen from agents used for the treatment of CFTR mediated diseases.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0296] The accompanying figures, which are incorporated and form part of the specification, merely illustrate certain embodiments and should not be construed as limiting. They are meant to serve to explain specific modes to those skilled in the art.

[0297] FIG. 1. shows physical appearance and stability of the produced complex Ivacaftor formula during the flow optimization.

[0298] FIG. 2. shows apparent solubility of complex Ivacaftor and Lumacaftor formulations alone and in combinations.

[0299] FIG. 3. shows GI tract simulated dissolution of Ivacaftor and Lumacaftor from the pharmaceutical composition disclosed herein.

[0300] FIG. 4. Ivacaftor and Lumacaftor dissolution from the pharmaceutical combination composition prepared by spray drying in combination and powder blending.

[0301] FIG. 5. shows PAMPA permeabilities of complex Ivacaftor formulation and complex Lumacaftor formulation.

[0302] FIG. 6. shows PAMPA permeabilities of complex Ivacaftor formulation and complex Lumacaftor formulation in the pharmaceutical combination composition prepared by powder blending.

[0303] FIG. 7. shows PAMPA permeabilities of complex Ivacaftor formulation and complex Lumacaftor formulation in the pharmaceutical combination composition prepared by spray-drying in combination.

[0304] FIG. 8. shows PAMPA permeability of complex Ivacaftor and complex Lumacaftor formulations stored at different conditions.

[0305] FIG. 9. shows PAMPA permeability of complex Ivacaftor and complex Lumacaftor formulations in the pharmaceutical composition stored at different conditions.

[0306] FIG. 10. shows SEM photos of complex Ivacaftor (A) and complex Lumacaftor (B) formulations.

[0307] FIG. 11. shows Raman spectra of crystalline Ivacaftor (A), freeze-dried Ivacaftor (B), Complex Ivacaftor formulation (C), Placebo sample (prepared in the absence of Ivacaftor) (D), Luviskol VA64 (E), sodium-lauryl-sulfate (F) and poloxamer (Poloxamer 338-Pluronic F108) Pluronic F108 (G).

[0308] FIG. 12. shows ATR spectra of crystalline Ivacaftor (A), amorphous Ivacaftor (B), complex Ivacaftor formulation (C), placebo (prepared in the lack of Ivacaftor) (D), Luviscol VA64 (E), sodium-lauryl-sulfate (F) and poloxamer (Poloxamer 338-Pluronic F108) Pluronic F108 (G).

[0309] FIG. 13. shows Raman spectra of crystalline Lumacaftor (A), amorphous Lumacaftor (B), complex Lumacaftor formulation (C), placebo (D), Luviscol VA64 (E), SDS (F)

[0310] FIG. 14. shows ATR spectra of crystalline Lumacaftor (A), amorphous Lumacaftor (B), complex Lumacaftor formulation (C), placebo (D), Luviscol VA64 (E), SDS (F).

[0311] FIG. 15. shows PXRD diffractograms of crystalline Ivacaftor (A, C), complex Ivacaftor formulation (A), crystalline Lumacaftor (B, C) and complex Lumacaftor formulation (B) and Spray-dried complex Ivacaftor and complex Lumacaftor formulations in combination (C)

[0312] FIG. 16. shows PAMPA permeability of crystalline Ivacaftor, solid dispersion of Ivacaftor and complex Ivacaftor formulation.

[0313] FIG. 17. shows comparative apparent solubility data of different Ivacaftor formulations.

[0314] FIG. 18. shows comparative dissolution tests of solid dispersion of Ivacaftor and complex Ivacaftor formulation.

[0315] FIG. 19. shows particle size of different of Ivacaftor and Lumacaftor formulation.

[0316] FIG. 20. shows apparent solubility of Lumacaftor formulations.

[0317] FIG. 21. shows comparative PAMPA permeability of Lumacaftor formulations.

[0318] FIG. 22. shows dissolution of Ivacaftor from different pharmaceutical formulations.

[0319] FIG. 23. shows dissolution of Lumacaftor from different pharmaceutical formulations.

[0320] FIG. 24. shows comparative PAMPA permeability of different, Orkambi equivalent Ivacaftor and Lumacaftor formulations.

[0321] FIG. 25. shows plasma concentrations of Ivacaftor following the oral administration of novel complex in the fasted and in the fed state to beagle dogs at 3 mg/kg dose (N=4).

[0322] FIG. 26. shows pharmacokinteic parameters following the oral administration of novel complex in the fasted and in the fed state to beagle dogs at 3 mg/kg dose (N=4).

EXAMPLES

[0323] Specific embodiments will further be demonstrated by the following examples. It should be understood that these examples are disclosed only by way of illustration and should not be construed as limiting the scope.

Manufacturing of Complex Ivacaftor Formulation

[0324] A solution mixture of complex Ivacaftor formulation was prepared by mixing process. Solution 1 containing 500 mg Ivacaftor and 1500 mg vinylpyrrolidone and vinylacetate copolymer (Luviskol VA 64) and 1000 mg poloxamer (Poloxamer 338-Pluronic F108) in 100 mL tetrahydrofuran was mixed with aqueous Solution 2 containing 500 mg sodium lauryl sulfate in 100 mL ultrapurified water in different flow rates. 1:1 Solvent 1:Solvent 2 ratio was used. The colloid solution of the complex Ivacaftor formulation was produced at atmospheric pressure and 20-50° C. temperature. The appearance and stability of the produced colloid solution were monitored. Based on the physical appearance and stability of the produced complex Ivacaftor formulation in colloid solution, the best composition was selected for spray-drying experiments. FIG. 1 summarizes the results.

[0325] The solidification of the colloid solution was performed by spray-drying technique. 5 mg/mL Ivacaftor, 15 mg/mL vinylpyrrolidone and vinylacetate copolymer (Luviskol VA 64) and 10 mg/mL poloxamer (Poloxamer 338-Pluronic F108) in tetrahydrofuran and 5 mg/mL sodium lauryl sulfate in water were chosen for starting concentrations. The ratio of the solutions was found to be optimal at 1:1 ratio. The colloid solution of the complex Ivacaftor formulation prepared by the optimal parameter sets was spray-dried (Yamato DL-410/GAS410) in order to obtain solid powder. The spray-drying process was optimized. The optimal production parameters were found to be T.sub.inlet=95° C., V.sub.air=0.8 m.sup.3/min, M.sub.in=18 mL/min, p=1 bar, T.sub.out=58-59° C.

Manufacturing of Complex Lumacaftor Formulation

[0326] A solution mixture of Lumacaftor complex formulation was prepared by continuous flow mixing approach. 20 mL Solution 1 was prepared by dissolving 40 mg Lumacaftor and 180 mg copolymer of vinylpyrrolidone and vinylacetate in 20 mL methanol. The prepared Solution 1 was mixed with Solution 2 containing 24 mg sodium lauryl sulfate in 80 mL water at 1:4 volume ratio in order to produce complex Lumacaftor formulation. The solution mixture of the complex Lumacaftor formulation was produced at atmospheric pressure and ambient temperature. The produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with −110° C. ice condenser, with a vacuum pump. Spray-drying was also applicable to produce solid powder from the solution mixture of complex Lumacaftor formulation.

Manufacturing of Pharmaceutical Combination Composition

[0327] Pharmaceutical composition was prepared by blending the powders of complex Ivacaftor and Lumacaftor formulations. The resulted pharmaceutical composition contained the complex Ivacaftor and complex Lumacaftor formulation in 125:200 active compound equivalent ratio.

[0328] A solution mixture of pharmaceutical combination composition was prepared by mixing process. Solution 1 containing 192 mg Ivacaftor and 308 mg Lumacaftor and 1000 mg vinylpyrrolidone and vinylacetate copolymer (Luviskol VA 64) in 100 mL solvent mixture of methanol and tetrahydrofuran having volume ratio of 5:2 was mixed with aqueous Solution 2 containing 150 mg sodium lauryl sulfate in 400 mL ultrapurified water in different flow rates. Solvent 1:Solvent 2 ratio was 1:4. The colloid solution of the complex Ivacaftor formulation was produced at atmospheric pressure and 25° C. temperature. The solidification of the colloid solution was performed by spray-drying technique. 1.92 mg/mL Ivacaftor, 3.08 mg/mL Lumacaftor and 10 mg/mL vinylpyrrolidone and vinylacetate copolymer (Luviskol VA 64) in methanol:tetrahydrofuran solvent mixture at volume ratio of 5:2 and 0.375 mg/mL sodium lauryl sulfate in water were chosen for starting concentrations. The ratio of the Solution 1 and Solution 2 was found to be optimal at 1:4 ratio. The prepared solution mixture was spray-dried (Yamato DL-410/GAS410) in order to obtain solid powder. The optimal spray-drying parameters were found to be T.sub.inlet=90° C., V.sub.air=0.85 m.sup.3/min, M.sub.in=20 mL/min, atomizing pressure=1 bar, T.sub.out=50° C.

Preparation of Liquid Dispersible Granules of Complex Ivacaftor Formulation

[0329] Liquid dispersible granules comprising the complex Ivacaftor formulations can be obtained by wet or dry granulation processes.

[0330] Dry granulation process includes, but not limited to the slugging or roll compaction of the powder formulation of complex Ivacaftor into compacts and breaking of the compacts into granules with appropriate mesh size. The obtained granules can be mixed with excipients chosen from the group consisting of fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents.

[0331] Dry granulation technique can be also applied on the powder blend of complex Ivacaftor formulations. Powder blend consists of the powder formulation of complex Ivacaftor and excipients chosen from the group consisting of fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents and prepared by mixing of powders. Slugging or roll compaction are used to manufacture compacts from the powder blend. Then the compacts are broken into granules with appropriate mesh size.

[0332] Wet granulation process covers the moisturizing of the powder formulations of complex Ivacaftor (direct granulation) or moisturizing the excipients chosen from the group consisting of fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents with aqueous solution of pharmaceutically acceptable binders and mixing it with the powder formulations of complex Ivacaftor (indirect granulation). The particle size of the granules can be controlled by physical impact before and after the drying step.

[0333] Liquid dispersible granules of complex Ivacaftor formulation were prepared by compacting appropriate amount of complex Ivacaftor powder blend using 0.5 ton load. The powder blend comprised of the solid formulation of the complex of Ivacaftor and, optionally, sweetening, flavouring, aromatizing, and perfuming agents. The height of the compact was found to be optimal between 0.8-1.0 mm. The compacts were broken up by physical impact to form granulates. The particle size of the granules was controlled by sieving with appropriate mesh size to achieve 160-800 micrometres particle size.

Preparation of Liquid Dispersible Granules of Complex Lumacaftor Formulation

[0334] Liquid dispersible granules comprising the complex Lumacaftor formulations can be obtained by wet or dry granulation processes.

[0335] Dry granulation process includes, but not limited to the slugging or roll compaction of the powder formulation of complex Lumacaftor into compacts and breaking of the compacts into granules with appropriate mesh size. The obtained granules can be mixed with fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents.

[0336] Dry granulation technique can be also applied on the powder blend of complex Lumacaftor formulations. Powder blend consists of the powder formulation of complex Lumacaftor and fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents and prepared by mixing of powders. Slugging or roll compaction are used to manufacture compacts from the powder blend. Then the compacts are broken into granules with appropriate mesh size.

[0337] Wet granulation process covers the moisturizing of the powder formulations of complex Lumacaftor (direct granulation) or moisturizing the fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents with aqueous solution of pharmaceutically acceptable binders and mixing it with the powder formulations of complex Lumacaftor (indirect granulation). The particle size of the granules can be controlled by physical impact before and after the drying step.

[0338] Liquid dispersible granules of complex Lumacaftor formulation were prepared by compacting appropriate amount of complex Lumacaftor powder blend using 0.5 ton load. The powder blend comprised of the solid formulation of the complex of Lumacaftor and sweetening, flavoring, aromatizing and perfuming agents. The height of the compact was found to be optimal between 0.8-1.0 mm. The compacts were broken up by physical impact to form granulates. The particle size of the granules was controlled by sieving with appropriate mesh size to achieve 160-800 micrometres particle size.

Preparation of Liquid Dispersible Granules of Pharmaceutical Combination Composition

[0339] Liquid dispersible granules of pharmaceutical combination composition can be obtained by blending the liquid dispersible granule or pellets of complex Ivacaftor formulation and complex Lumacaftor formulation; or mixing the complex Ivacaftor formulation with the complex Lumacaftor formulation before granulation, pelletising; or blending the liquid dispersible granules or pellets of the complex Ivacaftor formulation or complex Lumacaftor formulation with the solid form of the complex Ivacaftor formulation or complex Lumacaftor formulation.

[0340] Liquid dispersible granules of pharmaceutical combination composition can be obtained by compacting appropriate amount of pharmaceutical combination composition prepared by spray-drying in combination using 0.5-3 ton load. The powder comprised of the solid formulation of the pharmaceutical combination composition and sweetening, flavouring, aromatizing and perfuming agents. The height of the compact was found to be optimal between 0.8-1.0 mm. The compacts were broken up by physical impact to form granulates. The particle size of the granules was controlled by sieving with appropriate mesh size to achieve 160-800 μm particle size.

[0341] Blending and mixing include but not limited to container rotating or high shear mixing.

Comparative Solubility Tests

[0342] The apparent solubility was measured by UV-VIS spectroscopy or RP-HPLC at room temperature. The samples were dispersed in ultrapurified water in 1-20 mg/mL active ingredient equivalent concentration range. The resulting solutions were filtered by 100 nm disposable syringe filter. The active ingredient content in the filtrate was measured by UV-Vis spectrophotometry or RP-HPLC and the apparent solubility was calculated. The filtrate may contain particles which could not be filtrated out using 100 nm pore size filter. FIG. 2 shows the results.

[0343] The apparent solubility of complex Ivacaftor formulation was 0.991; 2.356; 4.924; 9.463 mg/mL and 18.474, when 1; 2.5; 5; 10 and 20 mg/mL Ivacator equivalent formulations were dispersed in ultrapurified water, respectively.

[0344] Apparent solubility of complex Ivacaftor formulation was 18.474 mg/mL.

[0345] The apparent solubility of complex Lumacaftor formulation was 0.950; 9.839 and 14.913 mg/mL, when 1; 10 and 20 mg/mL Lumacaftor equivalent formulations were dispersed in ultrapurified water, respectively. The apparent solubility of unformulated crystalline Lumacaftor was found to be 0.032 mg/mL.

[0346] Solubility of complex Lumacaftor formula was 14.913 mg/mL.

[0347] The apparent solubility of pharmaceutical combination composition prepared by powder blending was 1.009; 4.6967; 9.591 mg/mL and 19.9493 mg/mL for Lumacaftor and 0.6117; 2.8444; 5.7553 mg/mL and 11.3187 mg/mL for Ivacaftor, when 1; 5; 10 and 20 mg/mL Lumacaftor equivalent formulations were dispersed in ultrapurified water, respectively.

[0348] Apparent solubility of pharmaceutical combination composition prepared by powder blending was 19.9493 mg/mL for Lumacaftor and 11.3187 mg/mL for Ivacaftor.

[0349] The apparent solubility of pharmaceutical combination composition prepared by spray drying in combination was 0.9656; 4.8253; 8.9099 mg/mL and 19.2660 mg/mL for Lumacaftor and 0.5969; 3.0105; 5.5397 mg/mL and 12.0467 mg/mL for Ivacaftor, when 1; 5; 10 and 20 mg/mL Lumacaftor equivalent formulations were dispersed in ultrapurified water, respectively.

[0350] Apparent solubility of pharmaceutical combination composition prepared by spray drying was 19.2660 mg/mL for Lumacaftor and 12.0467 mg/mL for Ivacaftor.

Dissolution Test

[0351] Gastro-intestinal tract simulated drug dissolution tests were performed by dispersing the blended pharmaceutical combination composition described above in purified water. The dispersion contained 1 mg/mL Lumacaftor and 0.625 mg/mL Ivacaftor (identical mixture to ORKAMBI®). After 30 minutes holding time, simulated gastric fluid (SGF V2) was added to dispersion in order to set-up the pH to 1.6 (fasted state simulation) or FeSSIF buffer to increase the pH to 5.8 (fed state simulation). After 60 minutes holding time, the pH of the fasted state simulated dispersion was set-up to pH=6.5 adding maleic acid solution. FaSSIF solution was also added to the dispersion to ensure the fasted condition in the intestine simulation. In case of fed state simulation FeSSIF solution was added to the dispersion.

[0352] The dissolved amount of Lumacaftor and Ivacaftor from the blended pharmaceutical combination composition was measured by RP-HPLC after filtration with 0.1 μm pore size filter at different time points. Dissolution of Ivacaftor and Lumacaftor from the blended and granulated complex formulation was instantaneous, within 5 minutes more than 85% of the Ivacaftor and Lumacaftor dissolved from the pharmaceutical composition of present invention both in fasted and fed state simulated condition. (FIG. 3).

[0353] Drug dissolution tests were performed by dispersing the pharmaceutical combination composition prepared by powder blending or spray-drying in combination in water. The dissolved amount of Lumacaftor and Ivacaftor was measured by RP-HPLC after filtration with 0.1 μm pore size filter at different time points. Dissolution of Ivacaftor and Lumacaftor prepared by spray drying in combination was instantaneous, within 5 minutes more than 85% of the Ivacaftor and Lumacaftor dissolved from the pharmaceutical composition of present invention in water. (FIG. 4).

Comparative In-Vitro PAMPA Assays

[0354] PAMPA permeability of the complex formulations was measured and compared to the unformulated crystalline reference active compounds. PAMPA permeability measurements were performed as described by M. Kansi et al. (Journal of medicinal chemistry, 41, (1998) pp 1007) with modifications based on S. Bendels et al (Pharmaceutical research, 23 (2006) pp 2525). Permeability was measured in a 96-well plate assay across an artificial membrane composed of dodecane with 20% soy lecithin supported by a PVDF membrane (Millipore, USA). The receiver compartment was phosphate buffered saline (pH 7.0) supplemented with 1% sodium dodecyl sulfate. The assay was performed at room temperature; incubation time was 4 hours in ultrapurified water, FaSSIF and FeSSIF, respectively. The concentration in the receiver compartment was determined by UV-VIS spectrophotometry or RP-HPLC method (Thermo Scientific multiscan GO spectrophotometer or Thermo Surveyor HPLC or Rigol L-3000 series HPLC).

[0355] PAMPA permeabilities of complex Ivacaftor formulation and complex Lumacaftor formulation were measured in FaSSIF and FeSSIF media and were found to be above 0.5×10.sup.−6 cm/s for Ivacaftor and 2×10.sup.−6 cm/s for Lumacaftor measured by UV-VIS (FIG. 5).

[0356] PAMPA permeabilities of pharmaceutical combination composition prepared by powder blending was measured in water; FaSSIF and FeSSIF media and were found to be above 0.5×10.sup.−6 cm/s for Ivacaftor and 2×10.sup.−6 cm/s for Lumacaftor measured by UV-VIS (FIG. 6).

[0357] PAMPA permeabilities of pharmaceutical combination composition prepared by spray-drying in combination was measured in water; FaSSIF and FeSSIF media and were found to be above 0.2×10.sup.−6 cm/s for Ivacaftor and 1.5×10.sup.−6 cm/s for Lumacaftor measured by HPLC (FIG. 7).

Stability on the Solid Complex Formulations

[0358] Physical stability of the complex Ivacaftor, complex Lumacaftor formulations and pharmaceutical composition was monitored using PAMPA assays. PAMPA permeability was measured in FaSSIF and FeSSIF media after storage of the samples at different conditions. 6 month storage at RT or 40° C./75% relative humidity showed no significant decrease in the measured PAMPA permeability of complex Ivacaftor and complex Lumacaftor under any of the tested condition measured by RP-HPLC (FIG. 8). Pharmaceutical combinations showed stability over 2 months when stored at 40° C./75% relative humidity (FIG. 9).

Structural Analysis

[0359] Morphology of complex Ivacaftor formulation and complex Lumacaftor formulation was investigated using FEI Quanta 3D scanning electron microscope. Complex Ivacaftor formulation comprises spherical particles with particle size less than 50 nm, while spherical particles of complex Lumacaftor formulation have particle size in the range of less than 100 nm (FIG. 10).

[0360] Structural analysis was performed by using Vertex 70 FT-IR with ATR and HORIBA JobinYvon LabRAM FIR UV-VIS-NIR instruments.

[0361] Complex Ivacaftor formulation is characterized by the Raman spectrum shown in FIG. 11 and ATR spectrum shown in FIG. 12.

[0362] Complex Ivacaftor formulation is characterized by Raman shifts at 552 cm.sup.−1, 648 cm.sup.−1, 826 cm.sup.−1, 845 cm.sup.−1, 888 cm.sup.−1, 932 cm.sup.−1, 1026 cm.sup.−1, 1062 cm.sup.−1, 1082 cm.sup.−1, 1129 cm.sup.−1, 1140 cm.sup.−1, 1208 cm.sup.−1, 1233 cm.sup.−1, 1262 cm.sup.−1, 1284 cm.sup.−1, 1295 cm.sup.−1, 1361 cm.sup.−1, 1450 cm.sup.−1, 1528 cm.sup.−1, 1573 cm.sup.−1, 1618 cm.sup.−1, 1677 cm.sup.−1, 1738 cm.sup.−1, 746 cm.sup.−1, 2884 cm.sup.−1 and 2936 cm.sup.−1.

[0363] Complex Ivacaftor formulation is characterized by Raman shifts at 1082 cm.sup.−1, 1233 cm.sup.−1, 1284 cm.sup.−1, 1361 cm.sup.−1, 1528 cm.sup.−1, 1618 cm.sup.−1 and 1738 cm.sup.−1.

[0364] Complex Ivacaftor formulation is characterized by infrared (ATR) spectrum having characteristic peaks at 588 cm.sup.−1, 628 cm.sup.−1, 767 cm.sup.−1, 842 cm.sup.−1, 962 cm.sup.−1, 1019 cm.sup.−1, 1108 cm.sup.−1, 1148 cm.sup.−1, 1240 cm.sup.−1, 1343 cm.sup.−1, 1370 cm.sup.−1, 1425 cm.sup.−1, 1465 cm.sup.−1, 1525 cm.sup.−1, 1567 cm.sup.−1, 1666 cm.sup.−1 and 1732 cm.sup.−1.

[0365] Complex Ivacaftor formulation is characterized by ATR spectrum having characteristic peaks at 628 cm.sup.−1, 767 cm.sup.−1, 1108 cm.sup.−1, 1370 cm.sup.−1, 1465 cm.sup.−1 and 1666 cm.sup.−1.

[0366] Complex Lumacaftor formulation is characterized by characteristic Raman shifts at 553 cm.sup.−1, 602 cm.sup.−1, 635 cm.sup.−1, 654 cm.sup.−1, 747 cm.sup.−1, 841 cm.sup.−1, 899 cm.sup.−1, 934 cm.sup.−1, 1002 cm.sup.−1, 1021 cm.sup.−1, 1117 cm.sup.−1, 1205 cm.sup.−1, 1232 cm.sup.−1, 1310 cm.sup.−1, 1352 cm.sup.−1, 1372 cm.sup.−1, 1428 cm.sup.−1, 1444 cm.sup.−1, 1497 cm.sup.−1, 1592 cm.sup.−1, 1609 cm.sup.−1 and 1677 cm.sup.−1 shown in FIG. 13.

[0367] Complex Lumacaftor formulation is characterized by characteristic Raman shifts at 553 cm.sup.−1, 654 cm.sup.−1, 747 cm.sup.−1, 841 cm.sup.−1, 899 cm.sup.−1, 1117 cm.sup.−1, 1205 cm.sup.−1, 1310 cm.sup.−1, 1372 cm.sup.−1, 1428 cm.sup.−1, 1677 cm.sup.−1 and 1737 cm.sup.−1.

[0368] Complex Lumacaftor formulation is characterized by characteristic infrared (ATR) peaks at 635 cm.sup.−1, 703 cm.sup.−1, 747 cm.sup.−1, 837 cm.sup.−1, 1021 cm.sup.−1, 1165 cm.sup.−1, 1231 cm.sup.−1, 1288 cm.sup.−1, 1369 cm.sup.−1, 1423 cm.sup.−1, 1462 cm.sup.−1, 1494 cm.sup.−1, 1667 cm.sup.−1 and 1731 cm.sup.−1 shown in FIG. 1.

[0369] Complex Lumacaftor formulation is characterized by characteristic infrared (ATR) peaks at 703 cm.sup.−1, 837 cm.sup.−1, 1231 cm.sup.−1, 1369 cm.sup.−1 and 1667 cm.sup.−1.

[0370] The structure of the complex Ivacaftor, complex Lumacaftor formulation and the pharmaceutical combination compositions were investigated by powder X-ray diffraction (XRD) analysis (Philips PW1050/1870 RTG powder-diffractometer). The measurements showed that both the Ivacaftor and Lumacaftor in the complex and in the combination formulations were XRD amorphous (FIG. 15). Characteristic reflections on the diffractograms at 43 and 44 2Theta could be attributed to sample holder.

Comparative Formulation Study

[0371] Ivacaftor is marketed in its solid dispersion form under the trade name of KALYDECO®. Manufacturing of solid dispersion of Ivacaftor is described in US 20140221424 A1 patent application. Using the manufacturing method described in the patent application, solid dispersion of Ivacaftor was prepared for comparative analytical assays. A solvent system of methyl ethyl ketone (MEK) and water in the ratio of 90 wt % MEK:10 wt % water was heated to 20-30° C. in a reaction vessel equipped with a magnetic stirrer and thermal circuit. Into this solvent system, hypromellose acetate succinate polymer (HPMCAS), sodium lauryl sulfate and Ivacaftor were added in the ratio of 19.5 wt % hypromellose acetate succinate:0.5 wt % SLS:80 wt % Ivacaftor. The resulting mixture was solid formulated by spray-drying method.

[0372] Comparative analytical assays were used to investigate the physicochemical properties of the formulation prepared by solid dispersion technology and continuous flow mixing.

[0373] PAMPA permeability of the solid dispersion could not be detected in water FaSSIF, while it was 70% of the permeability of the complex Ivacaftor formulation in FeSSIF condition (FIG. 16).

[0374] Comparative apparent solubility measurements showed that the apparent solubility of complex Ivacaftor formulation was at least 0.99 mg/mL, while apparent solubility of crystalline Ivacaftor, Ivacaftor in physical mixture, amorphous Ivacaftor in aqueous sodium lauryl sulfate solution and solid dispersion was below 0.1 mg/mL (FIG. 17).

[0375] Comparative dissolution tests performed in water showed that the dissolution of Ivacaftor from the granulated complex formulation was instantaneous, within 10 minutes 90% of the Ivacaftor dissolved from the complex Ivacaftor formulation, while 0% Ivacaftor dissolved from the solid dispersion in 60 minutes (FIG. 18).

[0376] Ivacaftor was ball milled in the presence of the excipients used for the preparation of solid dispersion. Crystalline Lumacaftor was ball milled in the absence of complexation agent (Luviscol VA64) and pharmaceutically acceptable excipient (SDS) and in the presence of them. Ball milling parameters were the following: [0377] Speed: 500 rpm [0378] Milling time: 1 hour [0379] Number of the balls: 25 pcs with 10 mm diameter [0380] Milling vessel's material: Si.sub.2N.sub.3 [0381] Quantity of the milled samples: 100 mg API equivalent mass in 12 mL Milli-Q water

[0382] After the milling, the vessel was washed out with 5 mL Milli-Q water. The products were frozen on salted ice and then it was lyophilized using a freeze-drier equipped with −110° C. ice condenser, with a vacuum pump. The material and in-vitro properties of the resulted formulations were compared to the complex Lumacaftor and Ivacaftor formulations.

[0383] Particle size of the formulations was measured by DLS technique in reconstituted dispersion/solution. The results are summarized in FIG. 19. Ball milled crystalline Lumacaftor was hardly redispersible in purified water resulting in a suspension with visible particles, the particle size could not be determined.

[0384] Apparent solubility of complex Lumacaftor formulation was 14.913 mg/mL when 20 mg Lumacaftor equivalent formulation was redispersed (FIG. 20).

[0385] PAMPA permeability of the formulations was measured in FaSSIF biorelevant media and compared. PAMPA permeability of the complex Lumacaftor formulation was 4.651, while it was 0.288 for the ball milled crystalline Lumacaftor (FIG. 21).

[0386] GI simulated dissolution of the powder mixture of complex Ivacaftor and Lumacaftor formulations shows completely eliminated food effect both for Ivacaftor and Lumacaftor in in-vitro. Based the dissolution data, significantly increased or full absorption is expected in in-vitro studies. Dissolution of Ivacaftor and Lumacaftor from the powder blend was above 80% within 5 minutes (FIG. 22 and FIG. 23).

[0387] In comparison, dissolution of crystalline Ivacaftor showed 5-fold increase in FessiF condition indicating significant different in its absorption in fed state in-vivo. The increase in apparent solubility was 3-fold and 1.5 fold for the ball milled crystalline Ivacaftor and ball milled Ivacaftor with Luviskol VA 64 Pluronic F108 and SDS, respectively. Apparent solubility of Lumacaftor from the crystalline material was below 10% both in FaSSIF and FeSSIF media. The apparent solubility of Lumacaftor increased when the particle size was decreased, however it did not exceed 40% in any of the tested condition. 2-fold difference in apparent solubility was observed in FeSSIF medium compared to the FaSSIF condition (FIG. 22 and FIG. 23).

[0388] PAMPA permeabilities of different compositions were measured and compared. PAMPA permeability of complex Ivacaftor and complex Lumacaftor formulation in the pharmaceutical composition outperformed the in-vitro performance of the tested formulations (FIG. 24).

Pharmacokinetics

In-Vitro Assays

[0389] Based on in-vitro data (FIG. 2, FIG. 3, FIG. 19 and FIG. 20) which shows fast and full dissolution and increased permeability in fasted and fed state simulation it is expected that the complex Lumacaftor formula delivers full absorption and the elimination of the food effect.

In-Vivo PK Test in Large Animals

[0390] A beagle dog study using the granulated complex Ivacaftor formulation at a dose of 3 mg/kg was performed in the fasted and fed state. The granulated complex formulation was administered to the animals orally as reconstituted dispersion. Food effect was only 1.1-fold (food effect in humans is 2-4-fold higher in the fed state, that is why the drug has to be taken after a high fat meal). Exposure was 1.25-times higher than the reference exposure. C.sub.max was somewhat lower for the complex Ivacaftor formulation, however, for the more important parameter, C.sub.24h, the complex Ivacaftor was 1.4-times higher (FIG. 25 and FIG. 26).

[0391] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.