COMPLEXES OF LUMACAFTOR AND ITS SALTS AND DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract

Disclosed herein are pharmaceutically acceptable complex formulations comprising complexes of Lumacaftor, or a salt, or derivative thereof together with complexation agents and, optionally, pharmaceutically acceptable excipients; processes for the preparation thereof and pharmaceutical compositions containing them. The complex formulations have improved dissolution and permeability in fasted and fed state simulation that is expected to deliver full absorption and the elimination of the food effect.

Claims

1. A stable complex comprising i. Lumacaftor, or a salt or derivative thereof; ii. at least one complexation agent chosen from the group consisting of 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), copolymer 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, 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 has a particle size is between 10 nm and 500 nm, and possesses one or more among the following features: a) is instantaneously redispersable in physiological relevant media; b) is stable in solid form and in colloid solution and/or dispersion; c) has an apparent solubility in water of at least 1 mg/mL; and d) has a PAMPA permeability of at least 2×10.sup.−6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 month.

2. The complex as recited in claim 1, wherein said complex has a particle size in the range between 10 nm and 250 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)-d).

5. The complex as recited in claim 4, wherein said complex possesses at least three of the properties described in a)-d).

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, improved permeability in fasted and fed state simulation, exhibits no observable food effect which deliver full absorption and the opportunity of precise dosing and ease of administration of the reconstituted complex Lumacaftor in solution form.

7. The complex as recited in claim 5, wherein said complex possesses instantaneous redispersibility, has a PAMPA permeability of at least 2×10.sup.−6 cm/s when dispersed in, FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 month, exhibits no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex Lumacaftor 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 2×10.sup.−6 cm/s in FaSSIF and FeSSIF biorelevant media.

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 2×10.sup.−6 cm/s in FaSSIF and FeSSIF biorelevant media.

10. The complex as recited in claim 1, wherein said complexing agent is a copolymer of vinylpyrrolidone and vinylacetate.

11. 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.

12. The complex as recited in claim 11, wherein said pharmaceutically acceptable excipient is sodium lauryl sulfate.

13. The complex as recited in claim 1 comprising a) Lumacaftor; b) a complexation agent which is a copolymer of vinylpyrrolidone and vinylacetate; and c) a pharmaceutically acceptable excipient which is sodium lauryl sulfate; wherein said complex 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.

14. A complex according claim 1 comprising a complexing agent which is copolymer of vinylpyrrolidone and vinylacetate and pharmaceutically acceptable excipient which is sodium lauryl sulfate, are present in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.

15. A complex according to claim 14, wherein said complexing agent and pharmaceutically acceptable excipient, are present in a total amount ranging from about 50 weight % to about 95.0 weight % based on the total weight of the complex.

16. The complex as recited in claim 1, wherein said complex has an increased dissolution rate.

17. A process for the preparation of a stable complex as recited in claim 1, said process comprising the step of mixing a pharmaceutically acceptable solution containing Lumacaftor, and at least one complexing which is copolymer of vinylpyrrolidone and vinylacetate 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.

18. The process as recited in claim 17, wherein said process is performed in a continuous flow instrument.

19. The process as recited in claim 18, wherein said continuous flow instrument is a microfluidic flow instrument.

20. The process as recited in claim 17, wherein the pharmaceutically acceptable solvent of said pharmaceutically acceptable solution is chosen from methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, or combinations thereof.

21. The process as recited in claim 20, wherein said pharmaceutically acceptable solvent is methanol.

22. The process as recited in claim 18, wherein said pharmaceutically acceptable solution and said aqueous solution are miscible with each other and the aqueous solvent comprises 0.1 to 99.9% weight of the final solution.

23. A pharmaceutical composition comprising the stable complex as recited in claim 1 together with one or more pharmaceutically acceptable carriers.

24. The pharmaceutical composition as recited in claim 23, wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.

25. The pharmaceutical composition as recited in claim 24, wherein said composition is suitable for oral administration.

26. The pharmaceutical composition comprising the complex according to claim 25, wherein said composition comprises fast dissolving granules of the complex formulation according to claim 1.

27. The pharmaceutical composition comprising the complex according to claim 26, wherein said granules are suitable for the preparation of sachet dosage form.

28. A method of treatment of CFTR mediated diseases comprising administration of a therapeutically effective amount of the complex according to claim 1.

29. The method of claim 28, 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 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.

30. A stable complex comprising d) 5-40% by weight of Lumacaftor, its salt, or derivatives thereof; e) 50-90% by weight of a copolymer of vinylpyrrolidone and vinylacetate; and f) 0.01-50% by weight of sodium lauryl sulfate wherein said complex has a controlled particle size in the range between 10 nm and 500 nm; and wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.

31. The complex as recited in claim 1, wherein said complex further comprises one or more additional active agents.

32. The complex as recited in claim 31, wherein said additional active agent Ivacaftor, Tezacaftor or chosen from agents used for the treatment of CFTR mediated diseases.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0186] The accompanying figures, which are incorporated and form part of the specification, merely illustrate certain embodiments of the present invention and should not be construed as limiting the invention. They are meant to serve to explain specific modes of the present invention to those skilled in the art.

[0187] FIG. 1. shows redispersibility of complex Lumacaftor compositions in ultrapurified water.

[0188] FIG. 2. shows redispersibility and PAMPA permeability of complex Lumacaftor compositions in purified water.

[0189] FIG. 3. shows PAMPA permeability of complex Lumacaftor formulations containing vinylpyrrolidone and vinylacetate copolymer and sodium lauryl sulfate in different ratios.

[0190] FIG. 4. shows optimization of production parameters.

[0191] FIG. 5. shows Lumacaftor dissolution from crystalline Lumacaftor and complex Lumacaftor formulation.

[0192] FIG. 6. shows PAMPA permeabilities of Lumacaftor formulations measured at different time points.

[0193] FIG. 7. shows SEM photo of complex Lumacaftor formulation.

[0194] FIG. 8. shows Raman spectra of crystalline Lumacaftor (A), amorphous Lumacaftor (B), complex Lumacaftor formulation (C), placebo (D), Luviscol VA64 (E), SDS (F).

[0195] FIG. 9. shows ATR spectra of crystalline Lumacaftor (A), amorphous Lumacaftor (B), complex Lumacaftor formulation (C), placebo (D), Luviscol VA64 (E), SDS (F).

[0196] FIG. 10. shows XRD diffractograms of crystalline Lumacaftor and complex Lumacaftor formulation.

[0197] FIG. 11. shows apparent solubility of Lumacaftor formulations.

[0198] FIG. 12. shows PAMPA permeability of Lumacaftor formulations.

EXAMPLES

[0199] Specific embodiments of the present invention 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 of the present invention.

Selection of Complex Lumacaftor Formulations with Improved Material Properties

[0200] Several complexation agents and pharmaceutically acceptable excipients and their combinations were tested in order to select the formulae having instantaneous redispersibility as shown in FIG. 1.

[0201] Examples that displayed an acceptable level of redispersibility were selected for further analysis.

[0202] PAMPA permeability of the selected formulations was measured in order to select complex Lumacaftor formulation having the best in-vitro performance (FIG. 2). 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 (VWR UV-3100PC Scanning Spectrophotometer).

[0203] Copolymer of vinylpyrrolidone and vinylacetate was selected as complexing agents and sodium lauryl sulfate was selected as pharmaceutically acceptable excipient in order to prepare complex Lumacaftor formulations having improved material characteristics.

[0204] Solid complexes of Lumacaftor were prepared by using different ratios of complexation agent and pharmaceutically acceptable excipient. PAMPA permeability measurements were used to select the best performing complex formulation (FIG. 3). The best performing ratio of the copolymer of vinylpyrrolidone and vinylacetate: sodium lauryl sulfate: Lumacaftor (API) was found to be 9:1.2:2.

Production of Complex Lumacaftor Formulations

[0205] 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 with different flow rates. The solution mixture of the complex Lumacaftor formulation was produced at atmospheric pressure and ambient temperature. The appearance and the particle size of the produced colloid solution were monitored. Based on the physical appearance and particle size of the produced complex Lumacaftor formulation in colloid solution, the best composition was selected for further experiments (FIG. 4). 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.

[0206] In order to make the production process industrially feasible process intensification was performed by increasing the concentrations of the starting solutions. A colloid solution of complex Lumacaftor formulation of the present invention was prepared by mixing process. Solution 1 containing 200 mg Ivacaftor and 900 mg copolymer of vinylpyrrolidone and vinylacetate in 20 mL methanol was mixed with aqueous Solution 2 containing 120 mg sodium lauryl sulfate in 80 mL ultrapurified water at 1:4 volume ratio in order to produce complex Lumacaftor formulation. 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.

Preparation of Liquid Dispersible Granules Comprising Complex Lumacaftor Formulation

[0207] Liquid dispersible granules comprising the complex Lumacaftor formulations of the present invention can be obtained by wet or dry granulation processes.

[0208] 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 excipients chosen from the group consisting of fillers, extenders, binders, disintegrating agents, wetting agents, lubricants, taste masking, sweetening, flavoring, and perfuming agents.

[0209] 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 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.

[0210] Wet granulation process covers the moisturizing of the powder formulations of complex Lumacaftor (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 Lumacaftor (indirect granulation). The particle size of the granules can be controlled by physical impact before and after the drying step.

[0211] Liquid dispersible granules of complex Lumacaftor formulation of the present invention 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, optionally, 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 micrometers particle size. The Hausner-ratio of the granule was between 1.00 and 1.18 and the Carr's index was ≦15.

Comparative Solubility Tests

[0212] The apparent solubility of complex Lumacaftor formulation of the present invention was measured by UV-VIS spectroscopy at room temperature. The solid complex Lumacaftor formulations were dispersed in ultrapurified in 1, 10 and 20 mg/mL Lumacaftor equivalent concentration range. The resulting solutions were filtered by 100 nm disposable syringe filter. The Lumacaftor content in the filtrate was measured by UV-Vis spectrophotometry and the apparent solubility was calculated. The filtrate may contain Lumacaftor complex particles which could not be filtrated out using 100 nm pore size filter.

[0213] The apparent solubility of complex Lumacaftor formulation of the present invention 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.

[0214] Solubility of complex Lumacaftor formula was 1 mg/mL.

Comparative Dissolution Tests

[0215] Comparative dissolution tests were performed by dispersing 1 mg/mL Lumacaftor equivalent complex Lumacaftor formulation and crystalline Lumacaftor in 15 mL FaSSIF and FeSSIF media under stirring. The dissolved amount was measured with HPLC after filtration with 220 nm pore size filter at different time points. Dissolution of Lumacaftor from the complex formulation was instantaneous, while the dissolution of crystalline Lumacaftor was slower (FIG. 4). Within 10 minutes the Lumacaftor dissolution from the complex formulation of the present invention was almost complete (100%), while it was below 1% from the crystalline Lumacaftor.

Comparative In-Vitro PAMPA Assays

[0216] Since Lumacaftor should be administered with food in order to improve its biological performance, PAMPA permeabilities of amorphous Lumacaftor, crystalline Lumacaftor and complex Lumacaftor formulation were measured and compared in simulated fasted state. PAMPA permeability of amorphous Lumacaftor, crystalline Lumacaftor and complex Lumacaftor formulation was 1.1798×10.sup.−6 cm/s, 0.53053×10.sup.−6 cm/s and 3.9615×10.sup.−6 cm/s, respectively.

Stability of the Complex Lumacaftor Formulation in Solid Form

[0217] PAMPA permeabilities of the solid complex Lumacaftor formulations were used to monitor the physical stability of the formulations. PAMPA permeability was measured in FaSSIF biorelevant media and after storage at different conditions. 1 month storage at RT or 40° C. 75% relative humidity showed no significant decrease in the measured PAMPA permeability (FIG. 5).

Structural Analysis

[0218] Morphology of complex Lumacaftor formulation was investigated using FEI Quanta 3D scanning electron microscope. Complex Lumacaftor formulation of the present invention comprises spherical particles in the size range of less than 100 nm (FIG. 6).

[0219] Structural analysis was performed by using Vertex 70 FT-IR with ATR and HORIBA JobinYvon LabRAM HR UV-VIS-NIR instruments.

[0220] Complex Lumacaftor formulation or its pharmaceutical composition 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, 1677 cm.sup.−1 and 1737 cm.sup.−1 shown in FIG. 7.

[0221] Complex Lumacaftor formulation or its pharmaceutical composition 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.

[0222] Complex Lumacaftor formulation or its pharmaceutical composition 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. 8.

[0223] Complex Lumacaftor formulation or its pharmaceutical composition 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.

[0224] The structure of the complex Lumacaftor formulation of the present invention was investigated by powder X-ray diffraction (XRD) analysis (Philips PW1050/1870 RTG powder-diffractometer). The measurements showed that the Lumacaftor in the complex formulations was XRD amorphous (FIG. 9). Characteristic reflections on the diffractograms of complex Lumacaftor formulation at 43 and 44 2Theta could be attributed to sample holder.

[0225] Based on in-vitro data which shows fast and full dissolution and increased permeability in fasted and fed state simulation it is expected that the complex Lumacaftor formulation delivers full absorption and the elimination of the food effect.

Comparative Formulation Studies

[0226] 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: [0227] Speed: 500 rpm [0228] Milling time: 1 hour [0229] Number of the balls: 25 pcs with 10 mm diameter [0230] Milling vessel's material: Si.sub.2N.sub.3 [0231] Quantity of the milled samples: 100 mg API equivalent mass in 12 mL Milli-Q water
After the milling the vessel was washed out with 5 mL Milli-Q water. The product was 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 formulation of the present invention.

[0232] Particle size of the formulations was measured in reconstituted dispersion/solution. It was d(90)=782 nm and d(90)=282 nm for the ball milled Lumacaftor with Kollidon VA64 and SDS and complex Lumacaftor formulation, respectively. Ball milled crystalline Lumacaftor was hardly redispersible in purified water resulting in a suspension with visible particles, the particle size could not be determined.

[0233] Apparent solubility of complex Lumacaftor formulation was 14.913 mg/mL when 20 mg Lumacaftor equivalent formulation was redispersed (FIG. 10).

[0234] PAMPA permeability of the formulations was measured in FaSSIF biorelevant media and compared. PAMPA permeability of the complex Lumacaftor formulation was 4.651×10.sup.−6 cm/s, while it was 0.288×10.sup.−6 cm/s for the ball milled crystalline Lumacaftor (FIG. 11).

[0235] 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.