RU2802442C2 - Pharmaceutical composition and its administering - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: claimed group of inventions discloses a pharmaceutical composition for the treatment of cystic fibrosis in pediatric patients in a single dosage form, including one or a plurality of granules or mini-tablets, where the composition contains the following: (a) a solid dispersion in an amount of 30 to 40 wt.% by weight of the composition, where the dispersion contains the following: (i) 80 wt.% essentially amorphous or amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro- 4-oxoquinoline-3-carboxamide (Compound 1) by weight dispersion, (ii) 19.5 wt% hydroxypropyl methylcellulose acetate succinate (HPMCAS) by weight dispersion and (iii) 0.5 wt% sodium lauryl sulfate (SLS) by weight dispersion; (b) a two-component filler containing mannitol and lactose in a ratio of 1:3 mannitol to lactose; (c) a sweetener which is sucralose; (d) a disintegrant; (e) sliding agent; and (f) a lubricant; where the unit dosage form contains from 1 to 250 mg essentially amorphous or amorphous Compound 1 and where essentially amorphous Compound 1 has less than 15% crystallinity. The group of inventions also relates to a method of treating or reducing the severity of cystic fibrosis in a pediatric patient.

EFFECT: increasing the palatability of the pharmaceutical composition, improvement of the technological properties while maintaining the required bioavailability.

27 cl, 22 tbl, 2 dwg, 22 ex

Description

PRIORITY REQUESTED

[0001] This application claims priority to US Provisional Application No. 61/603882, filed February 27, 2012, and US Provisional Application No. 61/710352, filed October 5, 2012. The entire contents of the priority applications are incorporated herein by reference.

FIELD TO WHICH THE INVENTION RELATES

[0002] The present invention relates to pharmaceutical compositions containing a solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, including compositions solid dispersions in powders, granules and mini-tablets, to methods of preparing and processing the powders, granules and mini-tablets, and to methods of treating cystic fibrosis using this pharmaceutical composition.

PREREQUISITES FOR THE CREATION OF THE INVENTION

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite advances in the treatment of CF, there is no cure.

[0004] CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial chloride ion channel responsible for facilitating the regulation of salt and water absorption and secretion into various tissues. Small molecule drugs known as potentiators, which increase the ability of the CFTR channel to open, represent one possible therapeutic strategy for treating CF.

[0005] More specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it regulates anion flux across the membrane as well as the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is important for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of approximately 1480 amino acids that encode a protein consisting of a tandem repeat transmembrane domain, each containing six transmembrane helices, and a nucleotide-binding domain. The two transmembrane domains are linked by a large polar regulatory (R) domain with multiple phosphorylation sites that regulate channel activity and cell migration.

[0006] The gene encoding CFTR has been identified and sequenced (see Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al (1989) Science 245:1066-1073). A defect or mutation in this gene causes mutations in CFTR, resulting in cystic fibrosis (“CF”), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in 2,500 infants in the United States. In the general population of the United States, up to 10 million people carry one copy of the damaged gene with no apparent pathological effects. In contrast, individuals with two copies of the CF-related gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.

[0007] In patients with CF, mutations in CFTR, endogenously expressed in the airway epithelium, lead to decreased apical anion secretion, causing an imbalance in ion transport and fluid transport. The resulting decrease in anion transport contributes to the increased accumulation of mucus in the lungs and associated microbial infections, which ultimately cause death in patients with CF. In addition to respiratory disease, patients with CF typically suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, ultimately leads to death. Additionally, most men with cystic fibrosis are infertile, and fertility is reduced among women with cystic fibrosis. In contrast to the severe effects of two copies of the CF-related gene, individuals with one copy of the CF-related gene show increased resistance to cholera and dehydration from diarrhea - perhaps explaining the relatively high frequency of the CF gene in the population.

[0008] Sequence analysis of the CFTR gene on CF chromosomes has revealed a number of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870 ; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, >1000 disease-causing mutations have been identified in the CF gene (http://www.genet.sickkids.on.ca/cftr/app). The most predominant mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with severe disease.

[0009] This deletion of residue 508 in ΔF508-CFTR prevents proper folding of the resulting protein. This results in the inability of the mutant protein to leave the ER and move towards the plasma membrane. As a result, the number of channels present in the membrane is much smaller than that observed in cells expressing wild-type CFTR. In addition to impaired trafficking, this mutation results in disruption of the ion channel gating mechanism. Taken together, the reduced number of channels in the membrane and disruption of the gating mechanism leads to a decrease in anion transport through the epithelium, leading to disruption of ion transport and fluid transport. (Quinton, P. M. (1990), FASEB J. 4:2709-2727). Studies have shown, however, that reduced amounts of ΔF508-CFTR in the membrane are functionally active, although less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, other disease-causing mutations in CFTR that result in defective channel trafficking, synthesis, and/or gating could be activated or suppressed to alter anion secretion and alter disease progression and/or severity.

[0010] Although CFTR transports a variety of molecules in addition to anions, it is clear that this role (anion transport) represents one element in an important mechanism for the transport of ions and water through epithelial tissue. Other elements include the epithelial Na ⁺ channel, ENaC, Na ⁺ /2Cl ^- /K ⁺ cotransporter, Na ⁺ -K ⁺ -ATPase pump, and basolateral membrane K ⁺ channels, which are responsible for chloride entry into cells.

[0011] These elements work together to effect targeted transport through epithelial tissue through their selective expression and localization within the cell. Chloride absorption occurs through the coordinated activity of ENaC and CFTR, located on the apical membrane, and the Na ⁺ -K ⁺ -ATPase pump and Cl ^- ion channels expressed on the basolateral cell surface. Secondary active transport of chloride from the inside leads to the accumulation of intracellular chloride, which can then passively leave the cell through ^Cl channels, resulting in vectorial transport. Localization in a specific order of the Na ⁺ /2Cl ^- /K ⁺ cotransporter, Na ⁺ -K ⁺ -ATPase pump and basolateral membrane K ⁺ channels on the basolateral surface and CFTR on the inner side coordinates chloride secretion through CFTR on the inner side. Because water is probably never actively transported, its flow across the epithelium depends on minute transepithelial osmotic gradients generated by the mass movement of sodium and chloride.

[0012] As discussed above, it is believed that deletion of residue 508 in ΔF508-CFTR prevents proper folding of the nascent protein, resulting in the inability of the mutant protein to exit the ER and move to the plasma membrane. As a result, insufficient amounts of mature protein are present at the plasma membrane, and chloride transport in epithelial tissues is significantly reduced. Indeed, this cellular phenomenon of impaired ER processing of ABC transporters by the ER machinery has been shown to be the fundamental basis not only for the disease CF, but also for a number of other individual and inherited diseases.

[0013] N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is an effective and selective stimulator of wild-type and mutant CFTR including, for example, ΔF508, R117H and G551D) forms of human CFTR. N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is used to treat adult patients with cystic fibrosis and at least one G551D- allele CFTR.

[0014] Pediatric patients with CF may require administration of pharmaceutical compositions in a dosage form that is easy to swallow or that can be easily mixed with easily digestible foods. The use of powders and crushed tablets when administering pharmaceutical compositions to children often presents administration and dosing problems. Administration of crushed tablet compositions to children may result in absorption problems, the fragments of which are either too difficult to swallow or are insoluble and remain undigested, resulting in poor treatment outcome or incorrect dosing. Additionally, dosing crushed tablets may result in incorrect dosing due to difficulties associated with handling crushed tablets. The use of powdered mixtures may also result in incorrect dosing. In other cases, active powdered agents may remain adherent to the inner walls of the capsule, pouch or pack during administration, resulting in a therapeutic dose less than required. Such dosing errors are especially prevalent when the person administering the dose is inexperienced and when the dose is low, such as those used in pediatric patients. Dosing errors involving CP pharmaceutically active agents therefore become critical in pediatric populations, particularly given the fact that pharmaceutical CP active agents are administered at low doses (eg, less than 100 mg or less than 50 mg per unit dose). These dosing errors become critical in pediatric patients who have a low threshold for dose deviation.

[0015] Accordingly, there is a need for stable biologically active pharmaceutical compositions of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide useful for treatment of patients, for example, patients with CF who have problems swallowing adult tablets, including, but not limited to, pediatric patients, and methods for their manufacture and administration.

[0016] There is a need for stable biologically active pharmaceutical compositions of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide useful for treating a specific populations with unmet medical needs, such as children under 6 years of age, children or infants who cannot swallow adult tablets.

[0017] There is a need for stable biologically active pharmaceutical compositions of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide that can be administered into combination with some generally accepted baby food products for the treatment of infants.

[0018] There is a need for stable biologically active pharmaceutical compositions of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide that accurately and Flexibly dose in pediatric patients, including, but not limited to, infants, by varying the number of mini-tablets in a single dose, pack, packet or capsule.

[0019] Compound 1 (N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) was awarded Breakthrough Therapy Recognition by the Office Food and Drug Administration (FDA) for the treatment of cystic fibrosis, one of only two such approvals at the time of this application. This demonstrates a significant unmet need for effective treatment of the cause of cystic fibrosis compared with symptomatic treatments.

SUMMARY OF THE INVENTION

[0020] The present invention relates to pharmaceutical compositions containing a solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, and methods for preparing and administering pharmaceutical compositions containing N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. Pharmaceutical compositions containing a solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (hereinafter Compound 1) may also include one or more of the following excipients: one or more excipients, a sweetener, a disintegrant, a humectant, a glidant and a lubricant.

[0021] The pharmaceutical compositions of the present invention relate to a free-flowing powder composition that can be formulated into tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. Powdered forms of a pharmaceutical composition such as tablets, mini-tablets, granules, granule-filled capsules, pellets, pellets, particles, microparticles, lozenges and other dosage forms containing powdered forms of a pharmaceutical composition may be contained in capsules, packets, packs, sachets, bottles or blister packs. Tablets, mini-tablets, granules, granule-filled capsules, pellets, beads, microparticles, or particles can also be compressed into other solid forms. In one embodiment, the pharmaceutical composition may include powder compositions described in the present invention, containing: a solid dispersion containing substantially amorphous or amorphous Compound 1 and an excipient (for example, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant substance) and formulated in a capsule or packet, capsule or packet containing a specified amount of substantially amorphous or amorphous Compound 1 ranging from at least 1 mg to at least 250 mg. Tablets, mini-tablets, granules, granule-filled capsules, pellets, beads, microparticles or particles, and other dosage forms may contain granular particles or other powder forms of substantially amorphous or amorphous Compound 1.

[0022] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains up to about 1 mg of amorphous Compound 1. In another embodiment, the present invention provides a pharmaceutical composition containing a solid dispersion of amorphous Compound 1 wherein the solid dispersion contains up to about 5 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains up to about 5 mg of substantially amorphous Compound 1. For example, the solid dispersion contains 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of amorphous or substantially amorphous Compound 1.

[0023] In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains up to about 1 mg of substantially amorphous Compound 1. In some embodiments, the solid dispersion contains up to about 1 mg of amorphous or essentially amorphous Compound 1. For example, the solid dispersion contains 0.25 mg, 0.5 mg, 0.75 mg or 1 mg of amorphous or substantially amorphous Compound 1.

[0024] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 5 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 5 mg of substantially amorphous Compound 1.

[0025] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 10 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 10 mg of substantially amorphous Compound 1.

[0026] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 12.5 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 12.5 mg of substantially amorphous Compound 1.

[0027] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 15 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 15 mg of substantially amorphous Compound 1.

[0028] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 20 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 20 mg of substantially amorphous Compound 1.

[0029] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 25 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 25 mg of substantially amorphous Compound 1.

[0030] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 30 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 30 mg of substantially amorphous Compound 1.

[0031] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 35 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 35 mg of substantially amorphous Compound 1.

[0032] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 37.5 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 37.5 mg of substantially amorphous Compound 1.

[0033] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 40 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 40 mg of substantially amorphous Compound 1.

[0034] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 45 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 45 mg of substantially amorphous Compound 1.

[0035] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 50 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 50 mg of substantially amorphous Compound 1.

[0036] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 62.5 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 62.5 mg of substantially amorphous Compound 1.

[0037] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 75 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 75 mg of substantially amorphous Compound 1.

[0038] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 100 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 100 mg of substantially amorphous Compound 1.

[0039] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 125 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 125 mg of substantially amorphous Compound 1.

[0040] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 150 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 150 mg of substantially amorphous Compound 1.

[0041] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 175 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 175 mg of substantially amorphous Compound 1.

[0042] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 200 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 200 mg of substantially amorphous Compound 1.

[0043] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 225 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 225 mg of substantially amorphous Compound 1.

[0044] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 250 mg of amorphous Compound 1. In some embodiments, the solid dispersion contains approximately 250 mg of substantially amorphous Compound 1.

[0045] In one aspect, the solid form of Compound 1 in the pharmaceutical composition is a solid dispersion containing substantially amorphous or amorphous Compound 1 and a polymer such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/ VA), polyvinylpyrrolidone (PVP), methacrylic acid/methacrylate copolymers, hydroxypropylcellulose (HPC), or any combination thereof. Embodiments of this aspect include one or more of the following: the solid dispersion is a powder having an average particle diameter greater than about 5 microns, or the solid dispersion has a bulk density of about 0.10 g/cc or greater.

[0046] In some cases, the solid dispersion has a concentration of at least 20 wt.% Compound 1 by weight of the solid dispersion. In other cases, the solid dispersion contains 80 wt.% or less HPMCAS. Some solid dispersions contain from about 40 wt.% to about 60 wt.% substantially amorphous or amorphous Compound 1 by weight of the solid dispersion and from about 60 wt.% to about 40 wt.% polymer by weight of the solid dispersion. Other solid dispersions contain from about 60 wt% to about 95 wt% substantially amorphous or amorphous Compound 1 by weight of the solid dispersion and from about 40 wt% to about 5 wt% polymer by weight of the solid dispersion.

[0047] Solid dispersions may also optionally contain additives, such as a humectant (eg, sodium lauryl sulfate (SLS)), which may be present at a concentration of less than 10 wt.% humectant by weight of the solid dispersion.

[0048] Other solid dispersions contain from about 45 wt% to about 85 wt% substantially amorphous or amorphous Compound 1, from about 0.45 wt% to about 0.55 wt% SLS, and from about 14.45 wt.% to approximately 55.55 wt.% HPMCAS by weight of the solid dispersion.

[0049] In other additional embodiments, the pharmaceutical compositions also contain one or more excipients (e.g., mannitol, celluloses, calcium carbonate, starches, sugars (e.g., dextrose, lactose, or the like)) in concentrations of at least about 10% by weight weight of the composition; a sweetener (eg, sucralose, sorbitol, saccharin, fructose, aspartame, or combinations thereof) at a concentration of about 10% or less by weight of the composition; a disintegrant (eg, croscarmellose, sodium starch glycolate, or combinations thereof) in concentrations of about 10% by weight or less by weight of the composition; optionally a humectant (eg, sodium lauryl sulfate, SLS) in concentrations of about 10 wt.% or less by weight of the composition; a glidant (eg, colloidal silica, talc, or combinations thereof) in concentrations of about 2 wt.% or less by weight of the composition; and a lubricant (eg, magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof) in concentrations of about 5 wt.% or less by weight of the composition.

[0050] Such pharmaceutical compositions may optionally contain one or more colors, flavors and/or flavoring agents to improve their visual appeal, taste and aroma.

[0051] In other embodiments, the present invention provides a pharmaceutical composition in the form of a powder composition as described above, which may also be formulated in solid unit dosage forms for the treatment of various diseases associated with wild-type and mutant forms of human CFTR (including eg ΔF508, R117H and G551D). The present invention therefore also contemplates new dosage forms, such as granules, pellets, mini-tablets and other solid dosage forms, which overcome the problems described above regarding dosing errors, particularly for pediatric patients. These stable solid unit dosage forms can have any shape, including oval, spherical, cylindrical, elliptical, cubic, square or triangular, among others. Tablets or mini-tablets may have flat, flattened, standard deep convex or deep biconvex surfaces, or combinations thereof.

[0052] In one aspect, the pharmaceutical composition can be formulated into a unit dosage form, such as a capsule, sachet, and the like, containing at least one or more mini-tablets to facilitate administration of the pharmaceutical composition. In some embodiments, a unit dose may include a capsule or pack containing at least one mini-tablet or a plurality of mini-tablets, as described above and in the description provided below. In another embodiment, a unit dose may include a pouch, pack or sachet containing a specific dose of substantially amorphous or amorphous Compound 1 in powder form.

[0053] Such pharmaceutical compositions as described herein may be in the form of a mini-tablet and/or a plurality of mini-tablets consisting of any number of mini-tablets (e.g., at least 2, at least 3, at least at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60 or any amount greater than 60). Pharmaceutical compositions as described herein may also be in the form of a mini-tablet and/or a plurality of mini-tablets (e.g., at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24, at least 26, at least 28, at least 29, at least 30, at least 32, at least 34, at least 36, at least 38, at least 39 or at least 60 mini-tablets, including all intervals between them). In one embodiment, the pharmaceutical composition is in the form of 10, 19, 29 or 58 mini-tablets. In another embodiment, the pharmaceutical composition is in the form of 13, 26, 39 or 77 mini-tablets. In yet another embodiment, the pharmaceutical composition is in the form of 30, 60, 90 or 179 mini-tablets. In another embodiment, the pharmaceutical composition is in the form of 1, 2, 3, 4 or 5 mini-tablets. In another embodiment, the pharmaceutical composition is in the form of 13, 21, 26, 39, 52, 65, 78, 91, 104, 117, 130, or 336 mini-tablets. In yet another further embodiment, the pharmaceutical composition is in the form of 5 mini-tablets. In another embodiment, the pharmaceutical composition is in the form of 10 mini-tablets. In one embodiment, the pharmaceutical composition is in the form of 13 mini-tablets. In yet another further embodiment, the pharmaceutical composition is in the form of 15 mini-tablets. In another embodiment, the pharmaceutical composition is in the form of 21 mini-tablets. In one embodiment, the pharmaceutical composition is in the form of 26 mini-tablets. In another embodiment, the pharmaceutical composition is in the form of 39 mini-tablets. In one embodiment, the pharmaceutical composition is in the form of 52 mini-tablets. Another aspect of the present invention relates to a pharmaceutical composition consisting of at least one mini-tablet, said mini-tablet containing a solid dispersion, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the solubility of said mini-tablet is tablet is at least about 50% in about 30 minutes, and the solid dispersion contains amorphous Compound 1. As noted below, dissolution can be measured using a standard USP Type II instrument containing a dissolution medium of 0.5 or 0.7% sodium lauryl sulfate , dissolved in 900 ml of 50 mM sodium phosphate buffer, pH 6.8, at approximately 37°C. The solubility of the mini-tablets is determined by recording the solubility of a plurality of mini-tablets containing, in aggregate, 75 mg (using 0.5% sodium lauryl sulfate) or 150 mg (using 0.7% sodium lauryl sulfate) of Compound 1 in the dissolution medium. Individual mini-tablets may exhibit a solubility that is lower than, equal to, or higher than the solubility of the plurality, with the average solubility of each individual mini-tablet being similar to the average solubility of the plurality.

[0054] Another aspect of the present invention relates to a pharmaceutical composition consisting of a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a solid dispersion containing amorphous or substantially amorphous Compound 1 and HPMCAS; and one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the mini-tablet has an average tensile strength of between about 0.5 MPa and about 4 MPa. In some embodiments, the mini-tablet has an average tensile strength of at least 0.5 MPa, at least 1.0 MPa, at least 1.5 MPa, at least 2.0 MPa, or at least 2.5 MPa. In yet another aspect, the mini-tablets described in the present invention are optionally coated.

[0055] In another aspect, the coated mini-tablets described in the present invention are colored, for example, by incorporating a dye into the mini-tablet or by coloring the surface of the mini-tablet.

[0056] In another aspect, the present invention relates to new manufacturing methods that provide the formulation of miniaturized versions of adult dosage forms and other solid unit dosage forms described above, the size range of which is from about 1 mm to about 5 mm (for example, 2 mm or 4 mm) in any one or more dimensions. These miniaturized solid unit dosage forms may further be enclosed in capsules, bottles or sachets. In other embodiments, the pharmaceutical composition comprising a mini-tablet or multiple mini-tablets may be in pouches, sachets, packs, bottles or blister packs, or optionally further compressed into other solid unit dosage forms that can be easily administered to patients who have difficulty swallowing adult-sized tablet formulations. In this regard, these new powder pharmaceutical compositions and unit dosage forms containing these pharmaceutical compositions are acceptable in organoleptic properties for these patients, are injected into liquids or light foods and disintegrate or disperse in these various liquids and light foods or foods. compositions such as milk (including breast milk), infant or infant formula, applesauce, water, plain yogurt, ice cream, baby food, ensuring that the entire prescribed dose is disintegrated or dispersed and it could be administered to patients who had difficulty swallowing adult tablets. Baby food includes, but is not limited to, carrots or carrot puree. The pharmaceutical composition can also be incorporated into strawberry jam, rice pudding, chocolate pudding and the like. In one embodiment, the unit dosage form is sprayed into a light meal and administered. In another embodiment, the unit dosage form is injected into a liquid and administered. In one embodiment, the unit dosage form is sprayed into a light meal, mixed and administered. In another embodiment, the unit dosage form is injected into a liquid, mixed, and administered. Liquids may include, but are not limited to, infant formula, infant formula, milk or breast milk. In some cases, mini-tablets or smaller granules, the contents of packets, packets, capsules, bottles or sachets may be administered directly into the mouth followed by breast milk or formula. The administration methods of the present invention may also optionally include, for mini-tablets or smaller granules, administering the contents of packets, packets, capsules, bottles or sachets directly into the oral cavity followed by administration of a liquid or beverage. In some embodiments, any routes of administration of the present invention may optionally include oral administration with a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. In other embodiments, any routes of administration of the present invention may optionally include oral administration concomitantly with, before or after a meal containing fat, such as a standard CF high-calorie, high-fat meal or snack. In one embodiment, the pharmaceutical compositions of the present invention and solid dosage unit forms thereof are typically used in the treatment of CFTR-mediated disease in a pediatric patient population.

[0057] Another aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising the steps of preparing a mixture of a solid dispersion of amorphous Compound 1, a sweetener, one or more excipients, a disintegrant, optionally a humectant, a glidant and a lubricant, and compressing this mixture into a solid dosage form , for example, granule, pellet or mini-tablet, solid dosage form having a solubility of at least about 50% in about 30 minutes. In one example, the mixture is compressed into a solid dosage form, such as a mini-tablet, having an average tensile strength between about 0.5 MPa and about 4 MPa. Another aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising the steps of preparing a mixture of a solid dispersion of amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, and compressing this mixture into a solid dosage form, e.g. one or more mini-tablets, wherein the solid dosage form is capable of dissolving at least about 70% in about 30 minutes.

[0058] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, of a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein the unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the unit dose contains at least about 10 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to the patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily or every 12 hours.

[0059] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 12.5 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0060] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or mini-tablets or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 15 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0061] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or mini-tablets or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 20 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0062] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or mini-tablets or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 25 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0063] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of the pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 30 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0064] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 37.5 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0065] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of the pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 40 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0066] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 50 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0067] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 62.5 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0068] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of the pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 75 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily, or every 12 hours.

[0069] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of the pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 100 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0070] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of the pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 125 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0071] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 150 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is orally administered to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0072] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 175 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0073] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 200 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0074] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of a pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 225 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0075] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a patient, for example, a human pediatric patient, at least once daily, in a unit dose (via capsule, sachet, blister pack, pouch, pack, bottle or other container) containing a powder form of the pharmaceutical composition and/or a mini-tablet or a plurality of mini-tablets, wherein said unit dose contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant a substance and a lubricant, wherein said unit dose contains at least about 250 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the unit dose is administered orally to a patient once daily. In some other embodiments, a single dose is administered orally to a patient twice daily.

[0076] The unit dosage forms used in this method contain a solid dispersion containing at least about 5 mg of substantially amorphous or amorphous Compound 1, at least about 10 mg of substantially amorphous or amorphous Compound 1, at least 12, 5 mg of essentially amorphous or amorphous Compound 1, at least 15 mg of essentially amorphous or amorphous Compound 1, at least about 20 mg of essentially amorphous or amorphous Compound 1, at least 25 mg of essentially amorphous or amorphous Compound 1, at least about 30 mg of essentially amorphous or amorphous Compound 1, at least 37.5 mg of essentially amorphous or amorphous Compound 1, at least about 40 mg of essentially amorphous or amorphous Compound 1, at least 50 mg of essentially amorphous or amorphous Compound 1, at least 62.5 mg of essentially amorphous or amorphous Compound 1, at least 75 mg of essentially amorphous or amorphous Compound 1, at least 100 mg of essentially amorphous or amorphous Compound 1, at least 125 mg of essentially amorphous or amorphous Compound 1, at least 150 mg of essentially amorphous or amorphous Compound 1, at least 175 mg of essentially amorphous or amorphous Compound 1, at least 200 mg of essentially amorphous or amorphous Compound 1, by at least 225 mg of substantially amorphous or amorphous Compound 1, or at least 250 mg of substantially amorphous or amorphous Compound 1. Some unit dosage forms used in this method contain a solid dispersion containing at least about 1 mg to about 250 mg of substantially amorphous or amorphous Compound 1 (including all values and ranges contained within this range) in mixture with one or more excipients.

[0077] In another aspect, the present invention relates to a method for producing a unit dosage form containing a mini-tablet or a plurality of mini-tablets comprising a pharmaceutical composition described herein. This method includes the stages

a) mixing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1 and a polymer, a polymer containing HPMCAS, with a lubricant, a sweetener and optionally a humectant to form a first mixture;

b) sifting the first mixture;

c) mixing the screened first mixture with 20% screened lubricant to form a first mixed mixture;

d) mixing the sifted filler and the sieved baking powder in the first blended mixture to form a second blended mixture;

e) distributing the second mixed mixture to obtain a homogeneous mixture;

f) mixing 80% of the sifted lubricant with a homogeneous mixture to obtain a pressing mixture; And

g) pressing the compression mixture to obtain mini-tablets. In other embodiments, the mini-tablets of the present invention can be prepared according to the following steps:

i) mixing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1 and a polymer, a polymer containing HPMCAS, PVP/VA, or combinations thereof with a lubricant and a sweetener to produce a first mixture;

ii) sifting the first mixture;

iii) mixing the sieved first mixture;

iv) mixing the sifted litter and sieved disintegrant with the first blended mixture to form a second blended mixture;

v) distributing the second mixed mixture to obtain a homogeneous mixture;

vi) mixing the sifted lubricant with a homogeneous mixture to obtain a pressing mixture; And

vii) compressing the compression mixture to obtain a mini-tablet.

[0078] Administration includes orally administering to a patient at least once daily at least one unit dosage form containing a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant. a substance wherein at least one dosage form contains at least about 75 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the at least one dosage form contains at least about 75 mg of substantially amorphous or amorphous Compound 1.

[0079] In various embodiments, the pharmaceutical composition is in the form of a powder and optionally in a capsule or packet. In other embodiments, the pharmaceutical composition is contained in a solid dosage form, such as one or more mini-tablets or granules or pellets, and optionally enclosed in capsules, sachets, blister packs, pouches, packs, bottles, or other container. The solid dosage form of the pharmaceutical composition or the contents of the capsules or packets can then be administered orally to the patient once daily. For example, a pharmaceutical composition powder or mini-tablet is removed from a capsule or packet, added to food, and then given to a patient. Alternatively, the powdered pharmaceutical composition or mini-tablets are removed from the capsule or packet, added to food, mixed, and then given to the patient. Additionally, the powder composition or mini-tablets are removed from the capsule or pack and then given to the patient if the patient is capable of directly ingesting the powder pharmaceutical composition or mini-tablets.

[0080] In one aspect, the present invention includes a pharmaceutical composition comprising a solid dispersion of amorphous or substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, and optionally a humectant.

[0081] In one embodiment of this aspect, the pharmaceutical composition contains from about 30 to about 50 percent solid dispersion by weight of the composition.

[0082] In one embodiment, the pharmaceutical composition contains approximately 35 percent solid dispersion by weight of the composition.

[0083] In another embodiment, the pharmaceutical composition contains approximately 47 percent solid dispersion by weight of the composition.

[0084] In one embodiment, the pharmaceutical composition contains approximately 46.9 percent solid dispersion by weight of the composition.

[0085] In one embodiment, the filler contains:

mannitol, lactose, sucrose, dextrose, maltodextrin, sorbitol, xylitol, powdered cellulose, polyhydric alcohols, microcrystalline cellulose, silicated microcrystalline cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, talc, starch, pregelatinized starch, dibasic phosphate calcium, sulfate calcium, calcium carbonate or combinations thereof.

[0086] In another embodiment, the excipient contains mannitol, which is present in an amount of from about 30 to about 80 percent by weight of the composition.

[0087] In a further embodiment, the excipient contains mannitol, which is present in an amount of from about 42 to about 57.5 percent by weight of the composition.

[0088] In one embodiment, the sweetener contains:

glucose, sucrose, maltose, mannose, dextrose, fructose, lactose, trehalose, maltitol, lactitol, xylitol, sorbitol, mannitol, tagatose, glycerin, erythritol, isomalt, maltose, sucralose, aspartame, neotame, alitame, neohesperidin dihydrochalcone, cyclamate, thaumatin , acesulfame potassium, saccharin, sodium saccharin or combinations thereof.

[0089] In another embodiment, the sweetener contains sucralose, which is present in an amount of from about 0.1 to about 5 percent by weight of the composition.

[0090] In one embodiment, the disintegrant contains: croscarmellose sodium, sodium alginate, calcium alginate, alginic acid, starch, pregelatinized starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpyrrolidone copolymers, crospovidone, calcium carboxymethylcellulose, cellulose and its derivatives, sodium carboxymethylcellulose, soy polysaccharide , clays, gums and ion exchange resin, an effervescent system based on food acids and an alkali carbonate component, sodium bicarbonate or combinations thereof.

[0091] In a further embodiment, the disintegrant contains croscarmellose sodium, which is present in an amount of from about 1.5 to about 8 percent by weight of the composition.

[0092] In one embodiment, the humectant contains: sodium lauryl sulfate, cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, sodium docusate, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, polyoxyethylene sorbitan fatty acid esters, acacia gum, cholesterol, tragacanth, polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, PEGylated hydrogenated castor oils, sorbitan fatty acid esters, vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters, lecithin, phospholipids and their derivatives, poloxamers, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, mono- and diglycerides, propylene glycol fatty acid esters, glycerol fatty acid esters, ethylene glycol palmitostearate, polyoxyglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkylaryl polyether alcohols and polyglyceryl oleate or combinations thereof .

[0093] In another embodiment, the humectant contains sodium lauryl sulfate, which is present in an amount of about 2 percent or less by weight of the composition.

[0094] In one embodiment, the glidant comprises talc, fumed silica, precipitated silica, magnesium oxide, magnesium silicate, leucine and starch.

[0095] In a further embodiment, the glidant comprises colloidal silica, which is present in an amount of from about 0.1 to about 5 percent by weight of the composition.

[0096] In one embodiment, the lubricant contains: talc, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, stearic acid, glyceryl monostearate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated oils, polyethylene glycol, fatty alcohol, ester fatty acid, glyceryl behenate, mineral oil, vegetable oil, leucine, sodium benzoate, or combinations thereof.

[0097] In a further embodiment, the lubricant contains magnesium stearate, which is present in an amount of from about 0.1 to about 7 percent by weight of the composition.

[0098] In one embodiment, the solid dispersion contains approximately 80 percent amorphous Compound 1 by weight of the solid dispersion and approximately 19.5 percent HPMCAS by weight of the solid dispersion, and approximately 0.5 percent SLS by weight of the dispersion.

[0099] In another aspect, the present invention includes a pharmaceutical composition containing:

a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of from about 15 to about 47 percent by weight of the pharmaceutical composition;

sucralose in an amount of approximately 2 percent by weight of the pharmaceutical composition;

croscarmellose sodium in an amount of from about 3 to about 6 percent by weight of the pharmaceutical composition;

SLS in an amount of from about 0 to about 0.5 percent by weight of the pharmaceutical composition;

colloidal silicon dioxide in an amount of approximately 1 percent by weight of the pharmaceutical composition;

magnesium stearate in an amount of approximately 1.5 percent by weight of the pharmaceutical composition; And

mannitol in an amount of from about 42 to about 77.5 percent by weight of the pharmaceutical composition.

[00100] In another aspect, the present invention includes a pharmaceutical composition containing:

a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of from about 35 to about 47 percent by weight of the pharmaceutical composition;

sucralose in an amount of approximately 2 percent by weight of the pharmaceutical composition;

croscarmellose sodium in an amount of from about 3 to about 6 percent by weight of the pharmaceutical composition;

SLS in an amount of from about 0 to about 0.5 percent by weight of the pharmaceutical composition;

colloidal silicon dioxide in an amount of approximately 1 percent by weight of the pharmaceutical composition;

magnesium stearate in an amount of approximately 1.5 percent by weight of the pharmaceutical composition; And

mannitol in an amount of from about 42 to about 57.5 percent by weight of the pharmaceutical composition.

[00101] In one embodiment of this aspect, croscarmellose sodium is present in an amount of approximately 5 percent by weight of the pharmaceutical composition.

[00102] In another embodiment, SLS is present in an amount of approximately 0.5 percent by weight of the pharmaceutical composition.

[00103] In one embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition.

[00104] In another embodiment, the solid dispersion is present in an amount of approximately 47 percent by weight of the pharmaceutical composition.

[00105] In another aspect, the present invention includes a pharmaceutical composition containing:

a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of approximately 35 percent by weight of the pharmaceutical composition;

sucralose in an amount of approximately 2 percent by weight of the pharmaceutical composition;

croscarmellose sodium in an amount of approximately 6 percent by weight of the pharmaceutical composition;

colloidal silicon dioxide in an amount of approximately 1 percent by weight of the pharmaceutical composition;

magnesium stearate in an amount of approximately 1.5 percent by weight of the pharmaceutical composition;

mannitol in an amount of approximately 13.5 percent by weight of the pharmaceutical composition; And

lactose in an amount of approximately 41 percent by weight of the pharmaceutical composition.

[00106] In one embodiment, the pharmaceutical composition is a unit dosage form containing one or a plurality of granules, pellets, particles, or mini-tablets, and wherein the unit dosage form contains from about 1 mg to about 250 mg of a substantially amorphous or amorphous Compound 1.

[00107] In a further embodiment, the unit dosage form contains from about 50 mg of substantially amorphous or amorphous Compound 1.

[00108] In another embodiment, the unit dosage form contains from about 75 mg of substantially amorphous or amorphous Compound 1.

[00109] In a further embodiment, the unit dosage form contains from about 25 to about 40 mini-tablets.

[00110] In a further embodiment, the unit dosage form contains from about 1, 2, 3, 4 or 5 mini-tablets.

[00111] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains 1, 2, 3, 4, or 5 mini-tablets.

[00112] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains 1 mini-tablet.

[00113] In a further embodiment, the unit dosage form contains from about 21 to about 52 mini-tablets.

[00114] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains 5 mini-tablets.

[00115] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains 13 mini-tablets.

[00116] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains approximately 21 mini-tablets.

[00117] In one embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains approximately 26 mini-tablets.

[00118] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains approximately 39 mini-tablets.

[00119] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains approximately 52 mini-tablets.

[00120] In one embodiment, the pharmaceutical composition is a unit dosage form containing a granule, pellet, or mini-tablet, and wherein the unit dosage form contains approximately 10 mg of substantially amorphous or amorphous Compound 1.

[00121] In a further embodiment, the solid dispersion is present in an amount of approximately 47 percent by weight of the pharmaceutical composition, and the unit dosage form is a mini-tablet having a shape that is a shape such as a cylinder, oval, cone, sphere, ellipse, polygon, or combinations thereof, wherein the mini-tablet has a largest size or diameter of approximately 4 mm in length.

[00122] In another embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form is a mini-tablet having a shape that is a shape such as a cylinder, oval, cone, sphere, ellipse, polygon, or combinations thereof, wherein the mini-tablet has a largest size or diameter of approximately 4 mm in length.

[00123] In a further embodiment, the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition, and the unit dosage form is a mini-tablet having a shape that is a shape such as a cylinder, oval, cone, sphere, ellipse, polygon, or combinations thereof, wherein the mini-tablet has a largest size or diameter of approximately 2 mm in length.

[00124] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily at least one unit dosage form comprising a powder pharmaceutical composition and/or a solid dosage form of the pharmaceutical composition (e.g., a mini-tablet or a plurality of mini-tablets) containing a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the powder pharmaceutical composition and/or solid dosage form of the pharmaceutical composition contains up to approximately 5 mg of substantially amorphous or amorphous Compound 1. For example, the solid dispersion contains 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg of substantially amorphous or amorphous Compounds 1. In some embodiments, a powder pharmaceutical composition and/or a solid dosage form of a pharmaceutical composition is administered orally to a patient once daily. For example, a powdered pharmaceutical composition or mini-tablets are removed from a capsule or packet, added to food, mixed, and then fed to the patient.

[00125] In yet another aspect, the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily at least one unit dosage form containing a powder pharmaceutical composition and/or a solid dosage form of a pharmaceutical composition (e.g. mini-tablet or plurality of mini-tablets) containing a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the powder pharmaceutical composition and/or the solid pharmaceutical dosage form composition contains up to about 1 mg of substantially amorphous or amorphous Compound 1. In another embodiment, the solid dispersion contains from about 0.1 mg to about 1 mg of substantially amorphous or amorphous Compound 1. In another embodiment, the solid dispersion contains from about 0. 1 mg to approximately 5 mg (including all values and ranges within this range). In a specific embodiment, the solid dispersion contains 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the present invention provides a method for oral administration of the pharmaceutical compositions described herein , at least once a day. In other embodiments, the present invention relates to a method of orally administering a pharmaceutical composition described herein once daily. In some embodiments, the present invention relates to a method of orally administering the pharmaceutical compositions described herein at least once daily. In some embodiments, the present invention relates to a method of orally administering a pharmaceutical composition described herein twice daily or more times daily.

[00126] In one aspect, the present invention also provides a method of treating or reducing the severity of a disease in a patient, comprising administering to said patient one of the compositions described herein, and said disease is selected from cystic fibrosis, smoke-induced asthma COPD, chronic bronchitis, Rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility due to congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation disorders -fibrinolysis such as protein C deficiency, hereditary angioedema type 1, lipid processing disorders such as familial hypercholesterolemia, cheilomicronemia type 1, abetalipoproteinemia, lysosomal storage diseases such as inclusion cell/pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff/Tay disease -Sachs, Crigler-Najjar disease type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laronon type dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG glycogenosis type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, AST deficiency, diabetes insipidus (DI) ), neurohypophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some neurological disorders characterized by the deposition of polyglutamine- containing proteins [in the nuclei of neurons], such as Huntington's disease, spinocerebellar ataxia type I, spinal bulbar muscular atrophy, dentatorubro-pallidoluis atrophy and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (due to impaired processing prion protein), Fabry disease, Gerstmann-Straussler-Scheinker syndrome, COPD, dry eye disease, Sjögren's disease, osteoporosis, osteopenia, Gorham's disease, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Barter syndrome type III, disease Denta, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome and primary ciliary dyskinesia (PCD), a term for inherited disorders of the structure and/or function of the ciliary epithelium, including PCD with complete splanchnic inversion (also known as Kartagener syndrome), PCD without complete inversion inversion of internal organs and ciliary aplasia.

BRIEF DESCRIPTION OF THE DRAWINGS

[00127] In FIG. 1 is a schematic representation of the production and process steps used to produce certain exemplary mini-tablets in accordance with various embodiments of the present invention.

[00128] In FIG. 2 is a schematic representation of the production and process steps used to produce other exemplary mini-tablets in accordance with various embodiments of the present invention.

[00129] These figures are presented by way of example and are not intended to limit the invention.

DETAILED DESCRIPTION

[00130] The present invention relates to a pharmaceutical composition containing a solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, a method for producing a pharmaceutical composition containing N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, and a method of administering a pharmaceutical composition containing the solid form of N -[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.

I. DEFINITIONS

[00131] In the context of the present invention, the term "active pharmaceutical ingredient" or "API" refers to a biologically active compound. Exemplary APIs include CF potentiator (eg, N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide).

[00132] In the context of the present invention, the term "Compound 1" is used interchangeably with "N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide ", which has the following structure:

[00133] "Compound 1" also means tautomeric forms such as:

[00134] In the context of the present invention, the term “amorphous” refers to a solid that does not have long-range order in the position of its molecules. Amorphous solids are typically supercooled liquids in which the molecules are arranged randomly so that there is no well-defined arrangement, such as molecular packing, and there is no long-range order. Amorphous solids are usually isotropic, meaning they exhibit similar properties in all directions and do not have specific melting points. For example, an amorphous substance is a solid that does not have distinct characteristic crystalline peaks in its X-ray powder diffraction (XRPD) diffraction patterns (ie, is not crystalline by XRPD definition). Instead, one or more broad peaks (eg, halos) appear in their XRPD patterns. Broad peaks are characteristic of an amorphous solid. See US 2004/0006237 for a comparison of XRPD of amorphous material and crystalline material.

[00135] In the context of the present invention, the term “substantially amorphous” refers to a solid having little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than about 15% crystallinity (eg, less than about 10% crystallinity or less than about 5% crystallinity). It should also be noted that the term “substantially amorphous” includes the characteristic “amorphous”, which refers to substances that have no crystallinity (0%).

[00136] In the context of the present invention, the term “dispersion” refers to a dispersion system in which one substance, the disperse phase, is distributed in discrete units throughout a second substance (the dispersant phase or carrier). The size of the dispersed phase can vary significantly (for example, single molecules, nanometer-sized colloidal particles, up to many microns in size). In general, the dispersed phases may be solids, liquids or gases. In the case of a solid dispersion, both the dispersed and dispersive phases are solids. In pharmaceutical applications, the solid dispersion may include: an amorphous drug in an amorphous polymer; amorphous drug in a crystalline polymer; crystalline drug in an amorphous polymer; or a crystalline drug in a crystalline polymer. In the present invention, the solid dispersion may include an amorphous drug in an amorphous polymer or an amorphous drug in a crystalline polymer. In some embodiments, the solid dispersion includes a polymer constituting the disperse phase and the drug constituting the dispersing phase. Or, the solid dispersion includes the drug constituting the dispersed phase and the polymer constituting the dispersing phase.

[00137] In the context of the present invention, the term "solid dispersion" generally refers to a solid dispersion of two or more components, typically one or more drugs (for example, one drug (for example, Compound 1)) and a polymer, but may contain other components , such as surfactants or other pharmaceutical excipients, wherein the drug(s) (e.g., Compound 1) is substantially amorphous (e.g., having about 15% or less (e.g., about 10% or less, or about 5 % or less)) crystalline drug (for example, N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) or amorphous (t ie, a non-crystalline drug), and the physical stability and/or dissolution and/or solubility of the substantially amorphous or amorphous drug is enhanced by other components. Solid dispersions typically comprise the compound dispersed in a suitable carrier medium, such as a solid phase carrier. For example, the carrier contains a polymer (eg, a water-soluble polymer or a partially water-soluble polymer) and may include optional excipients, such as functional excipients (eg, one or more surfactants) or non-functional excipients (eg, one or more fillers). Another exemplary solid dispersion is a coprecipitate or co-melt of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide with at least one polymer.

[00138] "Coprecipitate" is the product after dissolving the drug and polymer in a solvent or mixture of solvents and then removing the solvent or mixture of solvents. Sometimes the polymer may be suspended in a solvent or mixture of solvents. The solvent or mixture of solvents includes organic solvents and supercritical fluids. A "comelt" is the product after heating the drug and polymer to melt, optionally in the presence of a solvent or mixture of solvents, followed by mixing, removing at least a portion of the solvent if possible, and cooling to room temperature at a selected rate.

[00139] In the context of the present invention, “crystallinity” refers to the degree of structural order in a solid. For example, Compound 1, which is substantially amorphous, has less than about 15% crystallinity, or its solid state structure is less than about 15% crystalline. In another example, Compound 1, which is amorphous, has zero (0%) crystallinity.

[00140] As used herein, "CF potentiating agent" refers to a compound that exhibits biological activity characterized by increasing the functionality of the cell surface mutant CFTR protein gating mechanism to approximately wild-type levels (i.e., a compound that increases or induces the activity of CFTR protein channels located on the cell surface, resulting in increased functional activity).

[00141] As used herein, the term “CFTR corrector” refers to a compound that increases or induces the amount of functionally active CFTR protein on the cell surface, resulting in increased functional activity.

[00142] In the context of the present invention, "solid dosage form" includes capsules, packets, sachets, packets containing a pharmaceutical composition either in powder form or in compressed form, such as granules, pellets, particles, mini-tablets and the like, solid dosage form contains a certain amount of Compound 1.

[00143] In the context of the present invention, an "excipient" is an inactive ingredient in a pharmaceutical composition. Examples of excipients include filler, sweetener, disintegrant, glidant, lubricant and the like.

[00144] In the context of the present invention, a "disintegrant" is an excipient that hydrates the pharmaceutical composition and helps disperse the tablet. Examples of disintegrants include croscarmellose sodium and/or sodium starch glycolate.

[00145] In the context of the present invention, a "diluent" or "excipient" is an excipient that helps impart a desired volume to a pharmaceutical composition. Examples of excipients include mannitol, cellulose, ethylcellulose, cellulose acetate, calcium carbonate, potato starch, sorbitol, polyhydric alcohols, dextrose, or combinations thereof.

[00146] In the context of the present invention, a “humectant” is an excipient that imparts increased solubility and/or wettability to pharmaceutical compositions. Examples of humectants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan monooleate (eg, Tween™), or any combination thereof.

[00147] In the context of the present invention, a “sweetener” is an excipient that imparts a sweet taste to pharmaceutical compositions and/or masks other unpleasant taste sensations. Examples of sweeteners include sucralose, sorbitol, xylitol, and combinations thereof.

[00148] In the context of the present invention, a "glidant" is an excipient that imparts improved flow properties to pharmaceutical compositions. Examples of glidants include colloidal silica, precipitated silica and/or talc.

[00149] In the context of the present invention, a “dye” is an excipient that imparts the desired color to pharmaceutical compositions. Examples of colorants include commercially available pigments such as FD&C Blue #1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.

[00150] In the context of the present invention, a “lubricant” is an excipient that is added to pharmaceutical compositions to minimize adhesion to surfaces, particularly for pharmaceutical compositions that are to be compressed into tablets. The lubricant facilitates ejection of the tablet of the pharmaceutical composition from the mold. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[00151] In the context of the present invention, "average particle diameter" is the average particle diameter measured using methods such as laser light scattering, image analysis or particle size analysis.

[00152] In the context of the present invention, "bulk density" is the mass of particles of a material divided by the total volume that the particles occupy. The total volume includes the volume of particles, the volume of voids between particles and the internal volume of pores. Bulk density is not an intrinsic property of the material; it may vary depending on how the material is processed.

[00153] In the context of the present invention, the term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for use in contact with tissues of humans and lower animals without exhibiting non-specific toxicity, irritation, allergic reaction, or the like. ., and meet a reasonable benefit/risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt or ester salt of a compound of this invention which, when administered to a recipient, is capable of providing, either directly or indirectly, the compound of this invention or its inhibitory active metabolite or residue.

[00154] In the context of the present invention, the term "mini-tablet" is equivalent to the term "pellet".

[00155] As used herein, "CFTR" or "CFTR protein" means the cystic fibrosis transmembrane conductance regulator protein.

[00156] In the context of the present invention, "CFTR" or "CFTR gene" means the cystic fibrosis transmembrane conductance regulator gene.

[00157] In the context of the present invention, "mutations" may refer to mutations in the CFTR gene or CFTR protein. "CFTR mutation" refers to a mutation in the CFTR gene, and "CFTR mutation" refers to a mutation in the CFTR protein. A genetic defect or mutation, or change in nucleotides in a gene, usually results in a mutation in the CFTR protein translated from that gene. For example, the G551D CFTR mutation is a mutation or change in the nucleotides of the CFTR gene that results in the G551D CFTR mutation in the translated CFTR protein, where the amino acid at position 551 of the CFTR protein is changed from glycine (G) to aspartic acid (D) due to the mutation or changes in the nucleotides of the CFTR gene. Likewise, ΔF508 or F508del is a specific mutation in the CFTR protein. The ΔF508 or F508del CFTR mutation is a deletion of three nucleotides in the CFTR gene that contains a codon for the amino acid phenylalanine at position 508 of the CFTR protein, resulting in a ΔF508 or F508del CFTR mutation or a CFTR protein that lacks that particular phenylalanine.

[00158] The term “CFTR gating mutation” as used in the context of the present invention means a mutation in CFTR that results in the production of a CFTR protein whose predominant defect is a low channel opening ability compared to normal CFTR (Van Goor, F ., Hadida S. and Grootenhuis P., “Pharmacological Rescue of Mutant CFTR function for the Treatment of Cystic Fibrosis,” Top Med Chem 3:91-120 (2008). Gate mutations include, but are not limited to, G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

[00159] The term “residual function phenotype” as used herein refers to the presence of residual function in CFTR. In other words, an individual who exhibits a residual function phenotype has residual CFTR function. Individuals who have CFTR with residual function, such as the R117H mutation (due to either a defect in gating, conduction, or amounts of functionally active CFTR protein), tend to have a late onset of clinical symptoms and a mild course of the disease. Many of these individuals have evidence of either sufficient pancreatic function or late onset of partial pancreatic insufficiency. Such individuals also tend to have slow progression of sinopulmonary disease, delayed diagnosis, and sweat chloride levels that are intermediate between normal and severe mutations (McKone E.F., et al., “CFTR Genotype as a Predictor as a Predictor of Prognosis in Cystic Fibrosis ", Chest., 130:1441-7 (2006); Kristidis, P., et al, "Genetic Determination of Exocrine Pancreatic Function in Cystic Fibrosis", Am. J. Hum. Genet., 50: 1178-84 (1992 ); Kerem, E. and Kerem B, “Genotype-Phenotype Correlations in Cystic Fibrosis,” Pediatr. Pulmonol., 22:387-95 (1996); Green, D. M., et al., “Mutations that Permit Residual CFTR Function Delay Acquisition of Multiple Respiratory Pathogens in CF Patients,” Respir. Res., 11:140-(2010)).

[00160] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include pharmaceutically acceptable salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange.

[00161] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, edisylate (ethane disulfonate), ethanesulfate onate, formate , fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodides, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate , palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl) ₄ salts. In addition, this invention provides for the quaternization of any of the basic nitrogen-containing groups of compounds disclosed herein. With this quaternization it is possible to obtain products that are soluble or dispersible in water or oil. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations produced using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

II. PHARMACEUTICAL COMPOSITION

[00162] In one aspect, the present invention relates to a pharmaceutical composition containing a powder mixture including an API, CF potentiator (eg, a solid dispersion of Compound 1). As illustrated herein, the pharmaceutical composition of the present invention may be a powder mixture of an API, a CF potentiator (eg, a solid dispersion of Compound 1), and one or more of the excipients described herein. Alternatively, the pharmaceutical composition may be provided as a unit dosage form containing a powder mixture, or a unit dosage form prepared such that it contains a compressed solid dosage form of a powder mixture in addition to one or more additional functional excipients, for example, optionally a humectant and/or lubricant for compressing the powder mixture into granules, pellets, particles or one or more mini-tablets, the pharmaceutical composition and/or unit dosage form contains certain ingredients in predetermined quantities. The pharmaceutical composition can be prepared in unit dosage form, for example, tablets, capsules, sachets, lozenges, blister packs and the like, containing powder and/or compressed form of the pharmaceutical composition of the present invention.

[00163] In one embodiment, the present invention relates to a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1, wherein the pharmaceutical composition contains up to about 1 mg of substantially amorphous Compound 1. For example, the solid dispersion contains about 0.25 mg, about 0 .5 mg, about 0.75 mg, or about 1 mg of substantially amorphous Compound 1.

[00164] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the pharmaceutical composition contains up to about 5 mg of substantially amorphous Compound 1. For example, the pharmaceutical composition contains about 0.25 mg, 0. 5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of substantially amorphous Compound 1.

[00165] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the pharmaceutical composition contains approximately 10 mg of substantially amorphous Compound 1.

[00166] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the pharmaceutical composition contains approximately 12.5 mg of substantially amorphous Compound 1.

[00167] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 15 mg of substantially amorphous Compound 1.

[00168] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 20 mg of substantially amorphous Compound 1.

[00169] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 25 mg of substantially amorphous Compound 1.

[00170] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 30 mg of substantially amorphous Compound 1.

[00171] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 37.5 mg of substantially amorphous Compound 1.

[00172] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 40 mg of substantially amorphous Compound 1.

[00173] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 50 mg of substantially amorphous Compound 1.

[00174] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 62.5 mg of substantially amorphous Compound 1.

[00175] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 75 mg of substantially amorphous Compound 1.

[00176] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the pharmaceutical composition contains approximately 100 mg of substantially amorphous Compound 1.

[00177] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 125 mg of substantially amorphous Compound 1.

[00178] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion is approximately 150 mg of substantially amorphous Compound 1.

[00179] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 175 mg of substantially amorphous Compound 1.

[00180] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 200 mg of substantially amorphous Compound 1.

[00181] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 225 mg of substantially amorphous Compound 1.

[00182] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains approximately 250 mg of substantially amorphous Compound 1.

[00183] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains up to about 1 mg of amorphous Compound 1. For example, the solid dispersion contains about 0.25 mg, about 0.5 mg, approximately 0.75 mg or approximately 1 mg of amorphous Compound 1.

[00184] In one embodiment, the present invention provides a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1, wherein the solid dispersion contains up to about 5 mg of amorphous Compound 1. For example, the solid dispersion contains about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of amorphous Compound 1.

[00185] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 10 mg of amorphous Compound 1.

[00186] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 12.5 mg of amorphous Compound 1.

[00187] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 15 mg of amorphous Compound 1.

[00188] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 20 mg of amorphous Compound 1.

[00189] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 25 mg of amorphous Compound 1.

[00190] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 30 mg of amorphous Compound 1.

[00191] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 37.5 mg of amorphous Compound 1.

[00192] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 40 mg of amorphous Compound 1.

[00193] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 50 mg of amorphous Compound 1.

[00194] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 62.5 mg of amorphous Compound 1.

[00195] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 75 mg of amorphous Compound 1.

[00196] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 100 mg of amorphous Compound 1.

[00197] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 125 mg of amorphous Compound 1.

[00198] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 150 mg of amorphous Compound 1.

[00199] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 175 mg of amorphous Compound 1.

[00200] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 200 mg of amorphous Compound 1.

[00201] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 225 mg of amorphous Compound 1.

[00202] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1, wherein the solid dispersion contains approximately 250 mg of amorphous Compound 1.

[00203] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains up to about 1 mg of substantially amorphous Compound 1. For example, the solid dispersion contains approximately 0.5 mg, about 0.75 mg or about 1 mg of substantially amorphous Compound 1.

[00204] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the solid dispersion contains from about 0.1 mg to about 5 mg of substantially amorphous Compound 1. For example, the solid dispersion contains about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of substantially amorphous Compound 1.

[00205] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 10 mg of substantially amorphous Compound 1.

[00206] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 12.5 mg of substantially amorphous Compound 1.

[00207] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 15 mg of substantially amorphous Compound 1.

[00208] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 20 mg of substantially amorphous Compound 1.

[00209] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 25 mg of substantially amorphous Compound 1.

[00210] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 30 mg of substantially amorphous Compound 1.

[00211] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 35 mg of substantially amorphous Compound 1.

[00212] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 37.5 mg of substantially amorphous Compound 1.

[00213] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 40 mg of substantially amorphous Compound 1.

[00214] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 45 mg of substantially amorphous Compound 1.

[00215] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 50 mg of substantially amorphous Compound 1.

[00216] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 62.5 mg of substantially amorphous Compound 1.

[00217] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 75 mg of substantially amorphous Compound 1.

[00218] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 100 mg of substantially amorphous Compound 1.

[00219] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 125 mg of substantially amorphous Compound 1.

[00220] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 150 mg of substantially amorphous Compound 1.

[00221] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 175 mg of substantially amorphous Compound 1.

[00222] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 200 mg of substantially amorphous Compound 1.

[00223] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 225 mg of substantially amorphous Compound 1.

[00224] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of substantially amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 250 mg of substantially amorphous Compound 1.

[00225] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the solid dispersion contains up to about 5 mg of amorphous Compound 1. For example, the solid dispersion contains about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of amorphous Compound 1.

[00226] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 10 mg of amorphous Compound 1.

[00227] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 12.5 mg of amorphous Compound 1.

[00228] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 15 mg of amorphous Compound 1.

[00229] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 20 mg of amorphous Compound 1.

[00230] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 25 mg of amorphous Compound 1.

[00231] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 30 mg of amorphous Compound 1.

[00232] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 35 mg of amorphous Compound 1.

[00233] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 37.5 mg of amorphous Compound 1.

[00234] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 40 mg of amorphous Compound 1.

[00235] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 45 mg of amorphous Compound 1.

[00236] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 50 mg of amorphous Compound 1.

[00237] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 62.5 mg of amorphous Compound 1.

[00238] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 75 mg of amorphous Compound 1.

[00239] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 100 mg of amorphous Compound 1.

[00240] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 125 mg of amorphous Compound 1.

[00241] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 150 mg of amorphous Compound 1.

[00242] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 175 mg of amorphous Compound 1.

[00243] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 200 mg of amorphous Compound 1.

[00244] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 225 mg of amorphous Compound 1.

[00245] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains approximately 250 mg of amorphous Compound 1.

[00246] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of amorphous Compound 1 and HPMCAS, wherein the pharmaceutical composition contains from about 5 mg to about 250 mg of Compound 1.

[00247] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to about 1 mg of substantially amorphous Compound 1.

[00248] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to about 5 mg of substantially amorphous Compound 1.

[00249] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 5 mg of substantially amorphous Compound 1.

[00250] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 10 mg of essentially amorphous Compound 1.

[00251] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 12.5 mg of substantially amorphous Compound 1.

[00252] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 15 mg of substantially amorphous Compound 1.

[00253] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 20 mg of substantially amorphous Compound 1.

[00254] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 25 mg of substantially amorphous Compound 1.

[00255] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 30 mg of substantially amorphous Compound 1.

[00256] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 35 mg of substantially amorphous Compound 1.

[00257] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 37.5 mg of substantially amorphous Compound 1.

[00258] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 40 mg of substantially amorphous Compound 1.

[00259] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 45 mg of substantially amorphous Compound 1.

[00260] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 50 mg of substantially amorphous Compound 1.

[00261] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 62.5 mg of substantially amorphous Compound 1.

[00262] In another embodiment, the present invention relates to a pharmaceutical composition containing:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 75 mg of essentially amorphous Compound 1.

[00263] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 100 mg of substantially amorphous Compound 1.

[00264] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 125 mg of substantially amorphous Compound 1.

[00265] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 150 mg of substantially amorphous Compound 1.

[00266] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 175 mg of substantially amorphous Compound 1.

[00267] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 200 mg of substantially amorphous Compound 1.

[00268] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 225 mg of substantially amorphous Compound 1.

[00269] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 250 mg of substantially amorphous Compound 1.

[00270] In a further embodiment, the one or more fillers is a two-component filler containing a mixture of 2 fillers. In another additional embodiment, the two-component filler is a mixture of mannitol and another filler. In another further embodiment, the two-component filler is a mixture of lactose and another filler. In another further embodiment, the two-component filler is a mixture of mannitol and lactose.

[00271] In another further embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to about 100 wt.% of the two-component excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose in an amount of up to about 100% by weight of the bicomponent excipient. In yet another further embodiment, the pharmaceutical composition contains a bicomponent excipient, wherein the bicomponent excipient contains mannitol in an amount of up to about 100 wt.% of the bicomponent excipient and lactose in such an amount that the sum of the amounts of mannitol and lactose is equal to 100 wt.%.

[00272] In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient comprises mannitol and another excipient in a ratio of mannitol to other excipient of about 3:1, in a ratio of about 1:1 mannitol to other excipient, or in a ratio of about 1:3 mannitol to another filler. In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose and another excipient in a ratio of lactose to other excipient of about 3:1, in a ratio of lactose to other excipient of about 1:1, or in a ratio of lactose to other excipient of about 1: 3. In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and lactose in a ratio of about 3:1 mannitol to lactose, in a ratio of about 1:1 mannitol to lactose, or in a ratio of about 1:3 mannitol to lactose.

[00273] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to approximately 1 mg of amorphous Compound 1.

[00274] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to approximately 5 mg of amorphous Compound 1.

[00275] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 10 mg of amorphous Compound 1.

[00276] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 12.5 mg of amorphous Compound 1.

[00277] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 15 mg of amorphous Compound 1.

[00278] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 20 mg of amorphous Compound 1.

[00279] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 25 mg of amorphous Compound 1.

[00280] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 30 mg of amorphous Compound 1.

[00281] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 35 mg of amorphous Compound 1.

[00282] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 37.5 mg of amorphous Compound 1.

[00283] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 40 mg of amorphous Compound 1.

[00284] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 45 mg of amorphous Compound 1.

[00285] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 50 mg of amorphous Compound 1.

[00286] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 62.5 mg of amorphous Compound 1.

[00287] In another embodiment, the present invention relates to a pharmaceutical composition containing:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 75 mg of amorphous Compound 1.

[00288] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 100 mg of amorphous Compound 1.

[00289] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 125 mg of amorphous Compound 1.

[00290] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 150 mg of amorphous Compound 1.

[00291] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 175 mg of amorphous Compound 1.

[00292] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 200 mg of amorphous Compound 1.

[00293] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 225 mg of amorphous Compound 1.

[00294] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and a polymer;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 250 mg of amorphous Compound 1.

[00295] In a further embodiment, the one or more fillers is a two-component filler containing a mixture of 2 fillers. In another additional embodiment, the two-component filler is a mixture of mannitol and another filler. In another further embodiment, the two-component filler is a mixture of lactose and another filler. In another further embodiment, the two-component filler is a mixture of mannitol and lactose.

[00296] In another further embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to about 100 wt.% of the two-component excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose in an amount of up to about 100% by weight of the bicomponent excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains mannitol in an amount of up to about 100 wt.% of the bicomponent excipient and lactose in such an amount that the sum of the amounts of mannitol and lactose is equal to 100 wt.%.

[00297] In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and another excipient in a ratio of mannitol to another excipient of approximately 3:1, in a ratio of mannitol to other excipient of approximately 1:1, or in a ratio of mannitol to other excipient approximately 1:3. In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose and another excipient in a ratio of lactose to other excipient of about 3:1, in a ratio of lactose to other excipient of about 1:1, or in a ratio of lactose to other excipient of about 1: 3. In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and lactose in a ratio of about 3:1 mannitol to lactose, in a ratio of about 1:1 mannitol to lactose, or in a ratio of about 1:3 mannitol to lactose.

[00298] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to about 1 mg of substantially amorphous Compound 1.

[00299] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to about 5 mg of substantially amorphous Compound 1.

[00300] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 5 mg of substantially amorphous Compound 1.

[00301] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 10 mg of substantially amorphous Compound 1.

[00302] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 12.5 mg of substantially amorphous Compound 1.

[00303] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 15 mg of substantially amorphous Compound 1.

[00304] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 20 mg of substantially amorphous Compound 1.

[00305] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 25 mg of substantially amorphous Compound 1.

[00306] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 30 mg of substantially amorphous Compound 1.

[00307] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 35 mg of substantially amorphous Compound 1.

[00308] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 37.5 mg of substantially amorphous Compound 1.

[00309] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 40 mg of substantially amorphous Compound 1.

[00310] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 45 mg of substantially amorphous Compound 1.

[00311] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 50 mg of substantially amorphous Compound 1.

[00312] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 62.5 mg of substantially amorphous Compound 1.

[00313] In another embodiment, the present invention relates to a pharmaceutical composition containing:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 75 mg of essentially amorphous Compound 1.

[00314] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 100 mg of substantially amorphous Compound 1.

[00315] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 125 mg of substantially amorphous Compound 1.

[00316] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 150 mg of substantially amorphous Compound 1.

[00317] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 175 mg of substantially amorphous Compound 1.

[00318] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 200 mg of substantially amorphous Compound 1.

[00319] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 225 mg of substantially amorphous Compound 1.

[00320] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of substantially amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 250 mg of substantially amorphous Compound 1.

[00321] In a further embodiment, the one or more fillers is a two-component filler containing a mixture of 2 fillers. In another additional embodiment, the two-component filler is a mixture of mannitol and another filler. In another further embodiment, the two-component filler is a mixture of lactose and another filler. In another further embodiment, the two-component filler is a mixture of mannitol and lactose.

[00322] In another further embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to about 100 wt.% of the two-component excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose in an amount of up to about 100% by weight of the bicomponent excipient. In yet another further embodiment, the pharmaceutical composition contains a bicomponent excipient, wherein the bicomponent excipient contains mannitol in an amount of up to about 100 wt.% of the bicomponent excipient and lactose in such an amount that the sum of the amounts of mannitol and lactose is equal to 100 wt.%.

[00323] In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and another excipient in a ratio of mannitol to another excipient of approximately 3:1, in a ratio of mannitol to other excipient of approximately 1:1, or in a ratio of mannitol to other excipient approximately 1:3. In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose and another excipient in a ratio of lactose to other excipient of about 3:1, in a ratio of lactose to other excipient of about 1:1, or in a ratio of lactose to other excipient of about 1: 3. In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and lactose in a ratio of about 3:1 mannitol to lactose, in a ratio of about 1:1 mannitol to lactose, or in a ratio of about 1:3 mannitol to lactose.

[00324] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to approximately 1 mg of amorphous Compound 1.

[00325] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the solid dispersion contains up to approximately 5 mg of amorphous Compound 1.

[00326] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 5 mg of amorphous Compound 1.

[00327] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 10 mg of amorphous Compound 1.

[00328] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 12.5 mg of amorphous Compound 1.

[00329] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 15 mg of amorphous Compound 1.

[00330] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 20 mg of amorphous Compound 1.

[00331] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 25 mg of amorphous Compound 1.

[00332] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 30 mg of amorphous Compound 1.

[00333] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 35 mg of amorphous Compound 1.

[00334] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 37.5 mg of amorphous Compound 1

[00335] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 40 mg of amorphous Compound 1.

[00336] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 45 mg of amorphous Compound 1.

[00337] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 50 mg of amorphous Compound 1.

[00338] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 62.5 mg of amorphous Compound 1.

[00339] In another embodiment, the present invention relates to a pharmaceutical composition containing:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 75 mg of amorphous Compound 1.

[00340] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 100 mg of amorphous Compound 1.

[00341] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 125 mg of amorphous Compound 1.

[00342] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 150 mg of amorphous Compound 1.

[00343] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 175 mg of amorphous Compound 1.

[00344] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 200 mg of amorphous Compound 1.

[00345] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

wherein the pharmaceutical composition contains approximately 225 mg of amorphous Compound 1.

[00346] In one embodiment, the present invention provides a pharmaceutical composition comprising:

a. a solid dispersion of amorphous Compound 1 and HPMCAS;

b. one or more fillers;

c. sweetener;

d. glidant; And

e. lubricant,

where the pharmaceutical composition contains approximately 250 mg of amorphous Compound 1.

[00347] In a further embodiment, the one or more fillers is a two-component filler containing a mixture of 2 fillers. In another additional embodiment, the two-component filler is a mixture of mannitol and another filler. In another further embodiment, the two-component filler is a mixture of lactose and another filler. In another further embodiment, the two-component filler is a mixture of mannitol and lactose.

[00348] In another further embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to about 100 wt.% of the two-component excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose in an amount of up to about 100% by weight of the bicomponent excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains mannitol in an amount of up to about 100 wt.% of the bicomponent excipient and lactose in such an amount that the sum of the amounts of mannitol and lactose is equal to 100 wt.%.

[00349] In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and another excipient in a ratio of mannitol to another excipient of approximately 3:1, in a ratio of mannitol to other excipient of approximately 1:1, or in a ratio of mannitol to other excipient approximately 1:3. In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose and another excipient in a ratio of lactose to other excipient of about 3:1, in a ratio of lactose to other excipient of about 1:1, or in a ratio of lactose to other excipient of about 1: 3. In some embodiments, the pharmaceutical composition contains a bicomponent excipient, wherein the bicomponent excipient contains mannitol and lactose in a ratio of about 3:1 mannitol to lactose, in a ratio of about 1:1 mannitol to lactose, or in a ratio of about 1:3 mannitol to lactose.

[00350] Suitable solid dispersions of Compound 1, i.e., N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, include, but are not limited to, dispersions described in PCT publications WO 2007/079139, WO 2010/019239, WO 2011/019413, US 2010/0074949, US 2010/0256184 and US 2011/0064811, which are hereby incorporated by reference in their entirety.

[00351] In one embodiment, the pharmaceutical composition of the present invention contains a solid dispersion of Compound 1. For example, the solid dispersion contains substantially amorphous Compound 1, wherein Compound 1 is less than about 15% crystalline (e.g., less than about 10% or less than about 5% ), and at least one polymer. In another example, the solid dispersion contains amorphous Compound 1, that is, Compound 1 has approximately 0% crystallinity. The concentration of Compound 1 in the solid dispersion depends on several factors, such as the amount of pharmaceutical composition needed to provide the desired amount of Compound 1 and the desired dissolution profile of the pharmaceutical composition.

[00352] The polymers used in such solid dispersions are inert, pharmaceutically acceptable polymers that are at least partially soluble in water or body fluids. Polymers may include homopolymers (eg, polysaccharides) or copolymers (eg, block copolymers). In one example, the solid dispersion contains substantially amorphous or amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and at least one a polymer independently selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer, polyvinylpyrrolidone (PVP), methacrylic acid/methacrylate copolymers, hydroxypropylcellulose (HPC), or any combination thereof. In another example, the solid dispersion contains substantially amorphous or amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and HPMCAS or PVP/ V.A.

[00353] In another embodiment, the pharmaceutical composition contains a solid dispersion that contains substantially amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter measured by light scattering (for example, using a Malvern Mastersizer, available from Malvern Instruments in England) , greater than about 5 microns (eg, greater than about 6 microns, greater than about 7 microns, greater than about 8 microns, or greater than about 10 microns). For example, the pharmaceutical composition contains a solid dispersion that contains amorphous Compound 1 and HPMCAS, wherein the solid dispersion has an average particle diameter, as measured by light scattering, of greater than about 5 μm (e.g., greater than about 6 μm, greater than about 7 μm, greater than about 8 μm or approximately more than 10 µm). In another example, the pharmaceutical composition contains a solid dispersion containing substantially amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 7 μm to about 25 μm. For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 7 μm to about 25 μm. In yet another example, the pharmaceutical composition contains a solid dispersion containing substantially amorphous Compound 1 and HPMCAS, wherein the solid dispersion has an average particle diameter, as measured by light scattering, from about 10 μm to about 35 μm. For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 10 μm to about 35 μm.

[00354] For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 10 μm to about 100 μm.

[00355] For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 50 μm to about 150 μm.

[00356] For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 100 μm to about 200 μm.

[00357] For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has an average particle diameter, measured by light scattering, from about 150 μm to about 300 μm.

[00358] In another example, the pharmaceutical composition contains a solid dispersion containing substantially amorphous Compound 1 and HPMCAS, where the solid dispersion has a bulk density of approximately 0.10 g/cc or more (for example, 0.15 g/cc or more than 0.17 g/cc or more). For example, the pharmaceutical composition contains a solid dispersion containing amorphous Compound 1 and HPMCAS, where the solid dispersion has a bulk density of about 0.10 g/cc or more (e.g., 0.15 g/cc or more, 0.17 g /cc.cm or more). In another example, the pharmaceutical composition comprises a solid dispersion that contains substantially amorphous Compound 1 and HPMCAS, wherein the solid dispersion has a bulk density of from about 0.10 g/cc to about 0.45 g/cc (e.g., from about 0.15 g/cc to about 0.42 g/cc, or about 0.17 g/cc to about 0.40 g/cc). In yet another example, the pharmaceutical composition contains a solid dispersion that includes amorphous Compound 1 and HPMCAS, where the solid dispersion has a bulk density of from about 0.10 g/cc to about 0.45 g/cc (e.g., from about 0. 15 g/cc to about 0.42 g/cc, or about 0.17 g/cc to about 0.40 g/cc). In another example, the pharmaceutical composition comprises a solid dispersion that contains substantially amorphous Compound 1 and HPMCAS, wherein the solid dispersion has a bulk density of from about 0.10 g/cc to about 0.45 g/cc (e.g., from about 0.15 g/cc to about 0.42 g/cc, or about 0.17 g/cc to about 0.40 g/cc). For example, the pharmaceutical composition includes a solid dispersion that contains amorphous Compound 1 and HPMCAS, where the solid dispersion has a bulk density of from about 0.10 g/cc to about 0.45 g/cc (e.g., from about 0.15 g/cc to about 0.42 g/cc, or from about 0.17 g/cc to about 0.40 g/cc).

[00359] Alternative solid dispersions contain substantially amorphous or amorphous Compound 1 and HPMCAS, wherein the substantially amorphous Compound 1 or amorphous Compound 1 is present in an amount of at least 20 wt.% (e.g., at least 40 wt.%, at least at least 45 wt.%, at least 49 wt.% or at least 50 wt.%) by weight of the solid dispersion. In some embodiments, the solid dispersion comprises HPMCAS and from about 20 wt% to about 99 wt%, including all values and ranges contained within this range (e.g., from about 40 wt% to about 90 wt%, from about 42 wt% to about 88 wt%, about 45 wt% to about 85 wt%, or about 50 wt% to about 80 wt%) essentially amorphous or amorphous Compound 1 by weight of the solid dispersion. For example, the solid dispersion contains HPMCAS and from about 40 wt.% to about 60 wt.%, including all values and ranges contained within this range, (for example, from about 42 wt.% to about 57 wt.%, from about 45 wt.% to about 55 wt.% or from about 47 wt.% to about 53 wt.%) essentially amorphous or amorphous Compound 1 by weight of the solid dispersion. In another example, the solid dispersion contains HPMCAS and from about 65 wt.% to about 95 wt.%, including all values and ranges contained within this range (for example, from about 67 wt.% to about 92 wt.%, from about 70 wt.% to about 90 wt.% or from about 72 wt.% to about 88 wt.%) essentially amorphous Compound 1 or amorphous Compound 1 by weight of the solid dispersion.

[00360] In other embodiments, the solid dispersion contains 80 wt% or less (e.g., 60 wt% or less, 55 wt% or less, or 50 wt% or less) polymer (e.g., HPMCAS) by weight of the solid variances. In some cases, the solid dispersion contains from about 1 wt.% to about 80 wt.%, including all values and ranges contained within this range, (for example, from about 10 wt.% to about 60 wt.%) polymer (e.g. HPMCAS).

[00361] Some solid dispersions contain from about 40 wt.% to about 60 wt.%, including all values and ranges contained within this range, (for example, from about 42 wt.% to about 57 wt.%, from about 45 wt% to about 55 wt% or about 47 wt% to about 53 wt%) substantially amorphous Compound 1 by weight of the solid dispersion and from about 60 wt% to about 40 wt% polymer (e.g., HPMCAS ). Alternative solid dispersions contain from about 40 wt.% to about 60 wt.%, including all values and ranges contained within this range, (for example, from about 42 wt.% to about 57 wt.%, from about 45 wt.% to about 55 wt.% or from about 47 wt.% to about 53 wt.%) amorphous Compound 1 by weight of the solid dispersion and from about 60 wt.% to about 40 wt.% polymer (eg, HPMCAS).

[00362] Other solid dispersions contain from about 65 wt.% to about 95 wt.%, including all values and ranges contained within this range (for example, from about 67 wt.% to about 92 wt.%, from about 70 wt. .% to about 90 wt.% or from about 72 wt.% to about 88 wt.%), substantially amorphous Compound 1 by weight of the solid dispersion and from about 45 wt.% to about 5 wt.% polymer (e.g., HPMCAS ). For example, the solid dispersion contains from about 65 wt.% to about 95 wt.%, including all values and ranges contained within this range, (for example, from about 67 wt.% to about 92 wt.%, from about 70 wt. % to about 90 wt.% or about 72 wt.% to about 88 wt.%) amorphous Compound 1 by weight of the solid dispersion and from about 45 wt.% to about 5 wt.% polymer (eg, HPMCAS).

[00363] In alternative embodiments, the solid dispersion contains from about 45 wt% to about 85 wt% substantially amorphous or amorphous Compound 1, from about 0.45 wt% to about 0.55 wt% SLS, and from about 14.45 wt.% to approximately 55.55 wt.% HPMCAS by weight of solid dispersion. One exemplary solid dispersion contains approximately 50 wt% substantially amorphous or amorphous Compound 1, approximately 49.5 wt% HPMCAS, and approximately 0.5 wt% SLS by weight of the solid dispersion. Another exemplary solid dispersion contains about 72.4 wt% substantially amorphous or amorphous Compound 1, about 27.1 wt% HPMCAS, and about 0.5 wt% SLS.

[00364] Another exemplary solid dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1, about 19.5 wt% HPMCAS, and about 0.5 wt% SLS.

[00365] In addition to the solid dispersion of Compound 1, the pharmaceutical compositions of the present invention also contain one or more excipients such as fillers, sweeteners, disintegrants, humectants, lubricants, lubricants, colors, flavors, or combinations thereof. It should be noted that some excipients may serve more than one function, for example, some excipients may also be sweeteners and some disintegrants may also be humectants (eg, mannitol is a bulking agent and sweetener, SLS is a humectant and lubricant).

[00366] Excipients suitable for the present invention are compatible with the ingredients of the pharmaceutical composition, that is, they do not significantly reduce the solubility, chemical stability, physical stability or biological activity of the pharmaceutical composition. Examples of excipient may include, but are not limited to, mannitol, lactose, sucrose, dextrose, maltodextrin, sorbitol, xylitol, powdered cellulose, polyhydric alcohols, microcrystalline cellulose, silicated microcrystalline cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, talc , starch (ie, potato starch), pregelatinized starch, dibasic calcium phosphate, calcium sulfate and calcium carbonate. In one embodiment, the pharmaceutical composition contains at least one excipient in an amount of at least about 10% by weight (e.g., at least about 20% by weight, at least about 25% by weight, or at least about 27% by weight). %) by weight of the composition. For example, the pharmaceutical composition contains from about 10 wt.% to about 90 wt.% (for example, from about 10 wt.% to about 60 wt.%, from about 20 wt.% to about 55 wt.%, from about 25 wt. .% to about 50% by weight or from about 27% by weight to about 45% by weight of filler by weight of the composition. In another example, the pharmaceutical composition contains at least about 20 wt% (eg, at least 25 wt% or at least 27 wt%) mannitol, by weight of the composition. In yet another example, the pharmaceutical composition contains from about 30 wt.% to about 90 wt.% (for example, from about 30 wt.% to about 80 wt.%, from about 30 wt.% to about 60 wt.%, from about 35 wt.% to about 55 wt.% or from about 40 wt.% to about 50 wt.%) mannitol, by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 45.1% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 80.37% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 82.5% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 82% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 79% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 79.5% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 75% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 59.28% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 43.1% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 55% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 42% (ie, approximately 42.0% or approximately 42.1%) mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 57% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 57.5% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 45.5% mannitol by weight of the composition. In another example, the pharmaceutical composition contains approximately 45.1% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 45% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 54.5% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 54% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 42.5% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 49.75% mannitol by weight of the composition. In one embodiment, the pharmaceutical composition contains at least 10 wt.% mannitol by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 13.5% mannitol by weight of the composition. In one embodiment, the pharmaceutical composition contains at least 10 wt.% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 57% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 57.5% lactose by weight of the composition. In another example, the pharmaceutical composition contains approximately 45.5% lactose by weight of the composition. In another example, the pharmaceutical composition contains approximately 45.1% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 45% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 54.5% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 54% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 42.5% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 49.75% lactose by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 13.5% lactose by weight of the composition.

[00367] In another embodiment, the pharmaceutical composition contains a number of excipients. In one embodiment, the pharmaceutical composition contains a number of excipients, where the total amount of excipient is at least about 10 wt.% (for example, at least about 20 wt.%, at least about 25 wt.%, or at least about 27 wt.% .%) by weight of the composition. For example, the pharmaceutical composition contains from about 10 wt.% to about 90 wt.% (for example, from about 20 wt.% to about 70 wt.%, from about 30 wt.% to about 60 wt.%, from about 40 wt. .% to about 55 wt%, from about 40 wt% to about 45 wt%, from about 45 wt% to about 50 wt%, or from about 50 wt% to about 55 wt%; or about 54.5 wt%, about 48.5 wt%, or about 42.5 wt%) filler, by weight of the composition. In some embodiments, the pharmaceutical composition contains one to three excipients. In some embodiments, the pharmaceutical composition contains two excipients (bicomponent excipient). In a further embodiment, the excipients are selected from mannitol and lactose. In one embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to 100 wt.% of the bicomponent excipient and lactose in such an amount that the amount of mannitol plus lactose is equal to 100 wt.%. In one embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol and lactose in a ratio of approximately 3:1 mannitol to lactose. In one embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol and lactose in a ratio of approximately 1:1 mannitol to lactose. In one embodiment, the pharmaceutical composition contains a bicomponent excipient, wherein the bicomponent excipient contains mannitol and lactose in a ratio of approximately 1:3 mannitol to lactose. In one embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of from about 0 wt.% to about 70 wt.% (for example, from about 10 wt.% to about 60 wt.%, from about 10 wt. % to about 15 wt%, about 20 wt% to about 30 wt%, or about 40 wt% to about 60 wt%, or about 13.5 wt%, about 21.25 wt% , about 24.25 wt.%, about 27.25 wt.%, about 41 wt.%, about 42.5 wt.% or about 54.5 wt.%) of the composition and lactose in an amount of from about 0 wt.% to about 70% by weight (e.g., from about 10% by weight to about 60% by weight, from about 10% by weight to about 15% by weight, from about 20% by weight to about 30% by weight, or from about 40 wt% to about 60 wt%, or about 13.5 wt%, about 21.25 wt%, about 24.25 wt%, about 27.25 wt%, about 41 wt%, about 42.5 wt.% or about 54.5 wt.%) of the composition. In a further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains approximately 13.5 wt% mannitol and approximately 41 wt% lactose, by weight of the composition. In another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains approximately 41 wt% mannitol and approximately 13.5 wt% lactose, by weight of the composition. In another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains approximately 27.25 wt% mannitol and approximately 27.25 wt% lactose, by weight of the composition. In another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains approximately 24.25 wt% mannitol and approximately 24.25 wt% lactose, by weight of the composition. In another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains approximately 21.25 wt% mannitol and approximately 21.25 wt% lactose, by weight of the composition.

[00368] The pharmaceutical composition also contains a sweetener to mask and enhance the taste of the composition. In some embodiments, the one or more sweeteners include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of suitable sweeteners include both natural and artificial sweeteners. Examples may include, but are not limited to, glucose, sucrose, maltose, mannose, dextrose, fructose, lactose, trehalose, maltitol, lactitol, xylitol, sorbitol, mannitol, tagatose, glycerin, erythritol, isomalt, maltose, sucralose, aspartame, neotame , alitame, neohesperidin dihydrochalcone, cyclamate (i.e., sodium cyclamate), thaumatin, acesulfame potassium, saccharin, and sodium saccharin. The sweetener concentration in the compositions of the present invention may range from about 0.1 wt% to about 5 wt% (e.g., about 1 wt% to about 5 wt%, about 1 wt% to about 3 wt% .%, from about 1.5 wt.% to about 2.5 wt.%) of the pharmaceutical composition. In one embodiment, the sweetener is sucralose. In another embodiment, the pharmaceutical composition contains sucralose at a concentration of about 0.1 wt% to about 5 wt% (e.g., about 1 wt% to about 5 wt%, about 1 wt% to about 3 wt% .%, from about 1.5 wt.% to about 2.5 wt.%). In a further embodiment, the pharmaceutical composition contains sucralose at a concentration of approximately 2 wt%.

[00369] Disintegrants suitable for the present invention enhance the dispersibility of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, that is, they do not significantly reduce the chemical stability, physical stability or biological activity of the pharmaceutical composition. Exemplary disintegrants include: croscarmellose sodium (e.g., AcDiSol), sodium alginate, calcium alginate, alginic acid, starch, pregelatinized starch, sodium starch glycolate, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone, crospovidone, calcium carboxymethylcellulose, cellulose and its derivatives, sodium carboxymethylcellulose, soybean polysaccharide, clay, gum (i.e. guar gum), ion exchange resin, effervescent system based on food acids and alkali carbonate component and sodium bicarbonate. In one embodiment, the pharmaceutical composition contains a disintegrant in an amount of about 10 wt% or less (e.g., about 8 wt% or less, about 7 wt% or less, about 6 wt% or less, or about 5 wt% or less) by weight of the composition. For example, the pharmaceutical composition contains from about 1 wt.% to about 10 wt.% (for example, from about 1.5 wt.% to about 7.5 wt.% or from about 2.5 wt.% to about 6 wt. %) baking powder by weight of the composition. In another example, the pharmaceutical composition contains about 10 wt% or less (eg, 7 wt% or less, 6 wt% or less, or 5 wt% or less) croscarmellose sodium by weight of the composition. In some examples, the pharmaceutical composition contains from about 0.1% to about 10% by weight (e.g., from about 0.5% by weight to about 7.5% by weight or from about 1.5% by weight to about 6% by weight .%) baking powder by weight of the composition. In other examples, the pharmaceutical composition contains from about 0.5% to about 10% by weight (e.g., from about 1.5% by weight to about 7.5% by weight, from about 3% by weight to about 6% by weight or from about 2 wt.% to about 5 wt.%) disintegrant, by weight of the composition. In yet another example, the pharmaceutical composition contains from about 0.1 wt% to about 10 wt% (e.g., from about 1.5 wt% to about 7.5 wt%, from about 1 wt% to about 6 wt%). wt.%, from about 3 wt.% to about 6 wt.%, or from about 2 wt.% to about 5 wt.%) croscarmellose sodium by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 3 wt.% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition contains approximately 4 wt.% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition contains approximately 4.5 wt.% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition contains approximately 5 wt.% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition contains approximately 6 wt.% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition contains approximately 7 wt.% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition contains approximately 8 wt.% croscarmellose sodium by weight of the composition.

[00370] Humectants and/or surfactants suitable for the present invention can increase the solubility or wettability of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, that is, they do not significantly reduce the chemical stability, physical stability or biological activity of the pharmaceutical composition. In some embodiments, one or more humectants include one or more surfactants. Examples of humectants/surfactants may include, but are not limited to, the following: sodium lauryl sulfate (also called sodium dodecyl sulfate (SDS)), cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, sodium docusate, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, polyoxyethylene sorbitan fatty acid esters (e.g. Polysorbate 80, Polysorbate 20), acacia gum, cholesterol, tragacanth, polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, PEGylated hydrogenated castor oils, sorbitan fatty acid esters , vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters, lecithin, phospholipids and their derivatives, poloxamers, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, mono- and diglycerides, propylene glycol fatty acid esters, esters glycerol and fatty acids (i.e., glycerol monostearate), ethylene glycol palmitostearate, polyoxylglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkylaryl polyether alcohols (Triton®) and polyglyceryl oleate. In one embodiment, the pharmaceutical composition contains a humectant in an amount of about 10 wt% or less (e.g., about 5 wt% or less, about 2 wt% or less, about 1 wt% or less, about 0.8 wt. % or less, or about 0.6 wt.% or less) by weight of the composition. For example, the pharmaceutical composition includes from about 10 wt.% to about 0.01 wt.% (for example, from about 5 wt.% to about 0.05 wt.% or from about 2 wt.% to about 0.1 wt. %) humidifier by weight of the composition. In another example, the pharmaceutical composition contains 10 wt% or less (e.g., about 5 wt% or less, about 2 wt% or less, about 1 wt% or less, about 0.8 wt% or less, or approximately 0.6 wt.% or less) sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains from about 10 wt.% to about 0.01 wt.% (for example, from about 3 wt.% to about 0.01 wt.% or from about 2 wt.% to about 0.05 wt.%) sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.5 wt.% sodium lauryl sulfate by weight of the composition. In another example, the pharmaceutical composition contains approximately 0 wt.% sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.175 wt.% sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.205 wt.% sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.235 wt.% sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.675 wt.% sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.705 wt.% sodium lauryl sulfate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 0.735 wt.% sodium lauryl sulfate by weight of the composition.

[00371] Glidants suitable for the present invention improve the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, that is, they do not substantially reduce the solubility, chemical stability, physical stability or biological activity of the pharmaceutical composition. A "glidant" is a substance that promotes the sliding of a powder by reducing the friction between particles and the adhesion of particles to each other due to their interaction. In some embodiments, one or more excipients may include one or more glidants. Examples of glidants may include, but are not limited to, talc, colloidal silica (eg, Cabosil M-5P), precipitated silica, magnesium oxide, magnesium silicate, leucine, and starch. In one embodiment, the pharmaceutical composition contains a lubricant in an amount of 5 wt% or less (eg, 1.75 wt%, 1.25 wt% or less, or 1.00 wt% or less) by weight of the composition. For example, the pharmaceutical composition contains from about 5 wt.% to about 0.1 wt.% (for example, from about 4 wt.% to about 0.02 wt.% or from about 3 wt.% to about 0.5 wt. %) of the sliding substance by weight of the composition. In another example, the pharmaceutical composition contains 5 wt% or less (eg, 1.75 wt%, 1.25 wt% or less, or 1.00 wt% or less) colloidal silica by weight of the composition. In yet another example, the pharmaceutical composition contains from about 5 wt.% to about 0.1 wt.% (for example, from about 4 wt.% to about 0.2 wt.% or from about 3 wt.% to about 0.5 wt.% wt.%) colloidal silicon dioxide by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 1 wt.% colloidal silicon dioxide by weight of the composition.

[00372] Lubricants suitable for the present invention facilitate pressing and ejection of compressed pharmaceutical compositions from the mold. Lubricants may additionally have anti-stick or anti-adhesive properties and minimize sticking in various processing steps of the present invention, including steps such as encapsulation, and are compatible with the ingredients of the pharmaceutical composition, that is, they do not substantially reduce the solubility or biological activity of the pharmaceutical composition. Examples of lubricants may include, but are not limited to, talc, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, stearic acid, glyceryl monostearate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated oils (i.e., hydrogenated vegetable oil), polyethylene glycol, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, leucine, sodium benzoate or combinations thereof. In one embodiment, the pharmaceutical composition contains a lubricant in an amount of 10 wt% or less (e.g., 2.5 wt%, 2.0 wt%, 1.75 wt%, 1.5 wt% or less, 1.25 wt.% or less, or 1.00 wt.% or less) by weight of the composition. For example, the pharmaceutical composition contains from about 7 wt% to about 0.10 wt% (for example, from about 6 wt% to about 0.15 wt% or from about 5 wt% to about 0.30 wt%) lubricant by weight of the composition. In another example, the pharmaceutical composition contains 10 wt% or less (e.g., 2.5 wt% or less, 1.75 wt% or less, 1.5 wt% or less, 1.25 wt% or less , or 1.00 wt.% or less) magnesium stearate by weight of the composition. In yet another example, the pharmaceutical composition contains from about 10 wt.% to about 0.10 wt.% (for example, from about 7 wt.% to about 0.1 wt.% or from about 5 wt.% to about 0.30 wt.% wt.%) magnesium stearate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 1.5 wt.% magnesium stearate by weight of the composition. In yet another example, the pharmaceutical composition contains approximately 1.0 wt.% magnesium stearate by weight of the composition.

[00373] The pharmaceutical compositions of the present invention may optionally contain one or more colors, flavors and/or fragrances to improve the appearance, taste and/or odor of the composition. Suitable colors, flavors or fragrances are compatible with the ingredients of the pharmaceutical composition, that is, they do not substantially reduce the solubility, chemical stability, physical stability or biological activity of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains a colorant, flavoring agent and/or flavoring agent. For example, the pharmaceutical composition contains less than about 1% by weight (e.g., less than about 0.75% by weight or less than about 0.5% by weight) of each optional ingredient, i.e., color, flavor, and/or flavoring agent, by weight of the composition . In another example, the pharmaceutical composition contains less than about 1 wt% (eg, less than about 0.75 wt% or about less than 0.5 wt%) dye. In yet another example, the pharmaceutical composition contains less than about 1 wt% (e.g., less than about 0.75 wt% or less than about 0.5 wt%) blue dye (e.g., FD&C Blue #1 and/or FD&C Blue #2 Aluminum Lake, commercially available from Colorcon, Inc. West Point, PA.).

[00374] Suitable flavors may include, for example, flavors that are known to those skilled in the art, such as natural flavors, artificial flavors, and combinations thereof. Flavoring agents are compatible with the ingredients of the pharmaceutical composition, that is, they do not significantly reduce the chemical stability, physical stability or biological activity of the pharmaceutical composition. Flavoring agents may be selected, for example, from synthetic flavor oils and flavoring compounds and/or oils, oleoresins, extracts derived from plants, leaves, flowers, fruits, and the like, and combinations thereof. Non-limiting examples of flavoring oils include spearmint oil, cinnamon oil, wintergreen oil (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, clove oil, sage oil, dried nutmeg oil, bitter almond oil and cassia oil. Suitable flavors further include, for example, artificial, natural and synthetic microgranular powders derived from fruit flavors such as vanilla, ethylvanillin, citrus oils (eg lemon, orange, tangerine, lime and grapefruit), and fruit essences ( for example, natural and/or artificial flavorings of apple, pear, peach, orange, grape, strawberry, raspberry, cherry, plum, pineapple and apricot), and the like, and combinations thereof. Flavoring agents may be used in liquid or solid form and, as stated above, may be used individually or in mixtures. Other flavoring agents may include, for example, certain aldehydes and esters, for example, cinnamyl acetate, cinnamaldehyde, citraldiethyl acetal, dihydrocarvylacetate, eugenyl formate, p-methylamizole, and the like, and combinations thereof.

[00375] A. POWDER DOSAGE FORMS OF PHARMACEUTICAL COMPOSITION

[00376] In some embodiments, the present invention provides a pharmaceutical composition that can be used to treat a patient having mutant forms of human CFTR. In some embodiments, the pharmaceutical composition may include a powder mixture of the ingredients of the pharmaceutical composition described above, enclosed in a capsule, packet, pouch, sachet, or some other container designed to provide a unit dose of the powder pharmaceutical composition to a patient in need thereof.

[00377] In some embodiments, a powder pharmaceutical composition or "powder mixture" dosage form is prepared by administering it to a food or liquid intended for consumption by a patient. Such powder dosage forms are primarily, although not exclusively, useful for patients who are unable to swallow an adult-sized tablet or who have difficulty swallowing such adult-sized tablets or pieces thereof.

[00378] In one embodiment, the powder pharmaceutical composition contains a solid dispersion and an excipient, for example: one or more excipients, a sweetener, a glidant, a lubricant, and combinations thereof, where the solid dispersion contains from about 30 wt.% to about 95 wt. % Compound 1 by weight of dispersion and polymer.

[00379] In some embodiments, the solid dispersion contains from about 45 wt.% to about 85 wt.% including all values and ranges within the specified range (for example, about 50 wt.%, about 72.4 wt.%, about 78. 8 wt.% or approximately 80 wt.%) Compounds 1 by weight dispersion and polymer.

[00380] One exemplary pharmaceutical composition contains from about 5 wt.% to about 70 wt.% (for example, from about 5 wt.% to about 65 wt.%, from about 5 wt.% to about 50 wt.% wt.%, from about 10 wt.% to about 20 wt.%, from about 30 wt.% to about 40 wt.%, or from about 40 wt.% to about 50 wt.%) solid dispersion by weight of a composition containing from about 30 wt.% to about 90 wt.% essentially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 25 wt.% to about 90 wt.% one or more fillers; from about 0.1 wt.% to about 5 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant. Or the powder pharmaceutical composition contains from about 5 wt.% to about 65 wt.% (for example, from about 5 wt.% to about 25 wt.%, from about 15 wt.% to about 40 wt.%, or from about 30 wt.% .% to about 50 wt.%) solid dispersion by weight of a composition containing from about 30 wt.% to about 90 wt.% amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 20 wt.% polymer , by mass of dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 0.1 wt.% to about 5 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant.

[00381] Another exemplary pharmaceutical composition contains from about 5 wt.% to about 60 wt.% (for example, from about 5 wt.% to about 55 wt.%, from about 15 wt.% to about 50 wt.% wt.% or from about 30 wt.% to about 50 wt.%) solid dispersion, by weight of the composition containing from about 30 wt.% to about 90 wt.% substantially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 0.1 wt.% to about 5 wt.% sweetener, from about 7 wt.% to about 0.1 wt.% lubricant; and from about 5 wt.% to about 0.1 wt.% glidant. Or the pharmaceutical composition contains from about 5 wt.% to about 55 wt.% (for example, from about 5 wt.% to about 50 wt.%, from about 5 wt.% to about 45 wt.%, or from about 5 wt.% .% to about 40 wt.%) solid dispersion by weight of a composition containing from about 30 wt.% to about 90 wt.% amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer , by mass of dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 5 wt.% to about 0.1 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant.

[00382] One pharmaceutical composition in powder form in accordance with the present invention contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19 .5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition. Or, the powder pharmaceutical composition of the present invention contains about 15 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0. 5 wt.% SLS by weight of dispersion; approximately 81 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition. Or, the powder pharmaceutical composition of the present invention contains about 36.8 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of dispersion; approximately 59.2 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition.

[00383] Another pharmaceutical composition in powder form in accordance with the present invention contains approximately 24.6 wt.% (equivalent to 24.6 mg of active substance in a 200 mg unit dose) solid dispersion by weight of the composition, where the said dispersion contains approximately 50 wt. % substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 49.5 wt % HPMCAS by weight of the dispersion, and approximately 0.5 wt % SLS by weight of the dispersion; approximately 71.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition. Or, the pharmaceutical composition of the present invention contains approximately 34 wt.% (equivalent to 49.2 mg of active ingredient per 200 mg dose) solid dispersion by weight of the composition, wherein said dispersion contains approximately 72.4 wt.% substantially amorphous or amorphous Compound 1 according to by weight of the dispersion, approximately 27.1 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 62 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition.

[00384] Another pharmaceutical composition in powder form in accordance with the present invention contains approximately 61.6 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19 .5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 34.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; approximately 1 wt.% magnesium stearate by weight of the composition. Or, the powder pharmaceutical composition of the present invention contains about 68.7 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 27.3 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; approximately 1 wt.% magnesium stearate by weight of the composition. Optionally, the above pharmaceutical compositions may also include approximately 0.4 wt.% colorant by weight of the composition.

[00385] One powder pharmaceutical composition of the present invention contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% essentially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt. % HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains about 75 mg of Compound 1. Or the powder pharmaceutical composition of the present invention contains about 15 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt.% amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; approximately 81 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains about 50 mg of Compound 1.

[00386] Another exemplary pharmaceutical composition contains from about 30 wt% to about 50 wt% solid dispersion by weight of the composition containing from about 30 wt% to about 90 wt% substantially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 30 wt.% to about 60 wt.% two fillers; from about 0.1 wt.% to about 5 wt.% sweetener, from about 7 wt.% to about 0.1 wt.% lubricant; from about 8 wt.% to about 0.1 wt.% disintegrant, and from about 5 wt.% to about 0.1 wt.% glidant. In some embodiments, each of the two fillers may be independently present in an amount of up to about 60% by weight.

[00387] In one aspect, the present invention provides a pharmaceutical composition containing from about 30 wt% to about 50 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight dispersions, about 19.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00388] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains about 10 mg of Compound 1.

[00389] Another pharmaceutical composition in powder form in accordance with the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 12.5 mg of Compound 1.

[00390] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 20 mg of Compound 1.

[00391] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 25 mg of Compound 1.

[00392] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 30 mg of Compound 1.

[00393] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 37.5 mg of Compound 1.

[00394] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 40 mg of Compound 1.

[00395] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains about 50 mg of Compound 1.

[00396] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 62.5 mg of Compound 1.

[00397] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 75 mg of Compound 1.

[00398] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; about 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains about 100 mg of Compound 1.

[00399] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 125 mg of Compound 1.

[00400] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 150 mg of Compound 1.

[00401] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 175 mg of Compound 1.

[00402] One powder pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains about 200 mg of Compound 1.

[00403] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and about 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 225 mg of Compound 1.

[00404] One powder pharmaceutical composition of the present invention contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1 wt.% magnesium stearate by weight of the composition, wherein said composition contains approximately 250 mg of Compound 1.

[00405] B. COMPRESSED DOSAGE FORMS OF PHARMACEUTICAL COMPOSITION

[00406] Another aspect of the present invention relates to solid dosage forms and unit dosage forms containing a pharmaceutical composition in the form of granules, pellets, particles, mini-tablets, coating particles and the like, or compressed into these dosage forms. Solid dosage forms and unit dosage forms contain compressed powder pharmaceutical compositions described above, with the addition of one or more functional excipients, for example, a disintegrant, glidant, lubricant, excipient and/or humectant to facilitate compression of the powder pharmaceutical composition into a compressed pharmaceutical composition, and to facilitate disintegration and dissolution of the pressed powder. Compressed pharmaceutical composition (solid dosage forms) such as granules, pellets, particles, mini-tablets and the like can be included in unit dosage forms such as tablets, capsules, pouches, packs, sachets, vials and blister packs containing one or a number of such solid dosage forms. The amount of solid dosage forms required for each unit dosage form will depend on the concentration of Compound 1 in each solid dosage form (e.g., each granule, pellet, or mini-tablet), and the required final amount of Compound 1 provided by the unit dosage form. For purposes of illustration only, if a unit dosage form (e.g., capsule, packet, pack, sachet, vial, or blister pack containing a mini-tablet or multiple mini-tablets) requires a final dose of approximately 75 mg and the weight of each mini-tablet is approximately 7 mg, and each mini-tablet contains approximately 2.6 mg of Compound 1, then each capsule or pack may contain approximately 29 mini-tablets. If a unit dosage form requires a final dose of approximately 40 mg and each mini-tablet weighs approximately 6.9 mg, then each capsule, packet, pack, sachet, vial or blister pack may contain approximately 21 mini-tablets. If a unit dosage form requires a final dose of approximately 50 mg and each mini-tablet weighs approximately 6.9 mg, then each capsule, packet, pack, sachet, vial or blister pack may contain approximately 26 mini-tablets. If the unit dosage form requires a final dose of approximately 75 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2 mg of Compound 1, then each capsule, packet, pack, sachet, vial or blister pack may contains approximately 39 mini-tablets. Also, if a unit dosage form requires a final dose of approximately 75 mg and each mini-tablet weighs approximately 6.9 mg, then each capsule, packet, pack, sachet, vial or blister pack may contain approximately 39 mini-tablets. If a unit dosage form requires a final dose of approximately 100 mg and each mini-tablet weighs approximately 6.9 mg, then each capsule, packet, pack, sachet, vial or blister pack may contain approximately 52 mini-tablets. If the unit dosage form requires a final dose of approximately 75 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 0.84 mg of Compound 1, then each capsule, packet, pack, sachet, vial, or blister pack the package may contain approximately 90 mini-tablets. If the unit dosage form requires a final dose of approximately 150 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2.6 mg of Compound 1, then each capsule, packet, pack, sachet, vial, or blister pack the package may contain approximately 58 mini-tablets. If a unit dosage form requires a final dose of approximately 150 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2 mg of Compound 1, then each capsule, packet, pack, sachet, vial or blister pack may contain approximately 75 mini-tablets. If the unit dosage form requires a final dose of approximately 150 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 0.84 mg of Compound 1, then each capsule, packet, pack, sachet, vial or blister pack the package may contain approximately 179 mini-tablets. If the unit dosage form requires a final dose of approximately 25 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2.6 mg of Compound 1, then each capsule, packet, pack, sachet, vial, or blister pack the package may contain approximately 10 mini-tablets. If the unit dosage form requires a final dose of approximately 25 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2 mg of Compound 1, then each capsule, packet, pack, sachet, vial or blister pack may contains approximately 13 mini-tablets. If a unit dosage form requires a final dose of approximately 25 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 0.84 mg of Compound 1, then each capsule, packet, pack, sachet, vial, or blister pack the package may contain approximately 30 mini-tablets. If a unit dosage form requires a final dose of approximately 50 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2.6 mg of Compound 1, then each capsule, packet, pack, sachet, vial, or blister pack the package may contain approximately 19 mini-tablets. If a unit dosage form requires a final dose of approximately 50 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 2 mg of Compound 1, then each capsule, packet, pack, sachet, vial or blister pack may contain approximately 25 mini-tablets. If the unit dosage form requires a final dose of approximately 50 mg, and each mini-tablet weighs approximately 7 mg, and each mini-tablet contains approximately 0.84 mg of Compound 1, then each capsule, packet, pack, sachet, vial or blister pack the package may contain approximately 60 mini-tablets. If a unit dosage form requires a final dose of approximately 10 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain 1 mini-tablet. If a unit dosage form requires a final dose of approximately 20 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 2 mini-tablets. If a unit dosage form requires a final dose of approximately 30 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 3 mini-tablets. If a unit dosage form requires a final dose of approximately 40 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 4 mini-tablets. If a unit dosage form requires a final dose of approximately 50 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 5 mini-tablets. If a unit dosage form requires a final dose of approximately 70 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 7 mini-tablets. If a unit dosage form requires a final dose of approximately 80 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 8 mini-tablets. If a unit dosage form requires a final dose of approximately 100 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 10 mini-tablets. If a unit dosage form requires a final dose of approximately 150 mg, and each mini-tablet contains approximately 10 mg of Compound 1, and each mini-tablet weighs approximately 26.7 mg or 35.7 mg, then each capsule, packet, pack, A sachet, bottle or blister pack may contain approximately 15 mini-tablets. If a unit dosage form requires a final dose of approximately 12.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, a packet, pack, sachet, bottle or blister pack may contain approximately 1 mini-tablet. If a unit dosage form requires a final dose of approximately 25 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, packet, a pack, sachet, bottle or blister pack may contain approximately 2 mini-tablets. If the unit dosage form requires a final dose of approximately 37.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, a packet, pack, sachet, bottle or blister pack may contain approximately 3 mini-tablets. If a unit dosage form requires a final dose of approximately 50 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, packet, a pack, sachet, bottle or blister pack may contain approximately 4 mini-tablets. If the unit dosage form requires a final dose of approximately 62.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, a pack, bag, sachet, bottle or blister pack may contain approximately 5 mini-tablets. If the unit dosage form requires a final dose of approximately 75 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, packet, a pack, sachet, bottle or blister pack may contain approximately 6 mini-tablets. If the unit dosage form requires a final dose of approximately 87.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, a packet, pack, sachet, bottle or blister pack may contain approximately 7 mini-tablets. If a unit dosage form requires a final dose of approximately 100 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, packet, a pack, sachet, bottle or blister pack may contain approximately 8 mini-tablets. If a unit dosage form requires a final dose of approximately 125 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, packet, a pack, sachet, vial or blister pack may contain approximately 10 mini-tablets. Where a unit dosage form requires a final dose of approximately 150 mg and each mini-tablet contains approximately 12.5 mg of Compound 1 and each mini-tablet weighs approximately 33.2 mg or 44.6 mg, then each capsule, packet, pack, sachet, bottle or blister pack may contain approximately 12 mini-tablets.

[00407] If the unit dosage form requires a final dose of approximately 12.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, a pack, sachet, bottle or blister pack may contain approximately 1 mini-tablet. If the unit dosage form requires a final dose of approximately 25 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet, vial or a blister pack may contain approximately 2 mini-tablets. If the unit dosage form requires a final dose of approximately 37.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet , bottle or blister pack may contain approximately 3 mini-tablets. If the unit dosage form requires a final dose of approximately 50 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet, vial or a blister pack may contain approximately 4 mini-tablets. If the unit dosage form requires a final dose of approximately 62.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet , a bottle or blister pack may contain approximately 5 mini-tablets. If the unit dosage form requires a final dose of approximately 75 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet, vial or a blister pack may contain approximately 6 mini-tablets. If the unit dosage form requires a final dose of approximately 87.5 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet , a bottle or blister pack may contain approximately 7 mini-tablets. If the unit dosage form requires a final dose of approximately 100 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet, vial or a blister pack may contain approximately 8 mini-tablets. If the unit dosage form requires a final dose of approximately 125 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, sachet, pack, vial or a blister pack may contain approximately 10 mini-tablets. If the unit dosage form requires a final dose of approximately 150 mg, and each mini-tablet contains approximately 12.5 mg of Compound 1, and each mini-tablet weighs approximately 44.7 mg, then each capsule, packet, packet, sachet, vial or a blister pack may contain approximately 12 mini-tablets.

[00408] The final dose depends on the amount of Compound 1 in the solid dispersion, the amount of solid dispersion in the mini-tablet, the weight of the mini-tablet, and the number of mini-tablet(s). Although the examples illustrate 2 mm and 4 mm mini-tablets weighing 6.9 mg, 7 mg, 35.7 mg, 44.7 mg, one skilled in the art would appreciate that for a particular dosage form formulation, any desired dose can be achieved by adjusting the mini-tablet weight and then introducing the appropriate number of mini-tablets into the desired dose delivery vehicle. For example, 100 mini-tablets, in which each mini-tablet weighs 5 mg and includes 35 wt% of the dispersion described in the examples as Intermediate 1, will result in a final dose of 140 mg of Compound 1.

[00409] In some embodiments, the compressed finished dosage forms have a size from about 1 mm to about 5 mm (for example, 2 mm or 4 mm) in all dimensions. In some embodiments, the compressed dosage forms include beads of any shape, including irregular shapes, that have a size of from about 1 mm to about 5 mm (eg, 2 mm or 4 mm) in all dimensions. For example, a spherical granule has a diameter ranging from about 1 mm to about 5 mm (eg, 2 mm or 4 mm). The elliptical-shaped granule has a length ranging from about 1 mm to about 5 mm (eg, 2 mm or 4 mm), and a diameter ranging from about 1 mm to about 5 mm (eg, 2 mm or 4 mm). The mini-tablet may be cylindrical in shape and have a diameter ranging from about 1 mm to about 5 mm (for example, 2 mm or 4 mm), and a length or thickness ranging from about 1 mm to about 5 mm (for example, 2 mm mm or 4 mm). There are no restrictions on the geometry of the compressed dosage form, and it is limited only by the geometry of the tooling equipment (ie, molds and punches) used to compress the powder mixture of the pharmaceutical composition of the present invention into various compressed solid dosage forms.

[00410] For purposes of illustration only, embodiments of the present invention will provide examples of the use of a mini-tablet having a diameter of approximately 2 mm and a length of approximately 2 mm. A batch of mini-tablets containing a single pharmaceutical composition is formulated into a capsule, pouch, pack, sachet, vial or blister pack (unit dose), said capsule, pouch, pack, sachet, vial or blister pack containing from about 1 mg to about 250 mg of Compound 1, or from about 10 mg to about 250 mg, or from about 15 mg to about 250 mg of Compound 1. The number of mini-tablets used to form a capsule, packet, pack, sachet, vial or blister pack may vary from 1 to 350 (for example: 1-336, 1-150, 1-100, 1-50, 1-30) mini-tablets per capsule, packet, pack, sachet, bottle or blister pack. Each batch of mini-tablets illustrated in the Examples below contains a compressed powder pharmaceutical composition, said composition containing a solid dispersion of Compound 1, wherein the solid dispersion contains a polymer, and one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant. substance. Different batches of compressed pharmaceutical compositions may contain the same or different amounts of Compound 1 and/or different amounts of excipients.

[00411] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains an amount of substantially amorphous Compound 1 or amorphous Compound 1 ranging from about 1 mg to about 250 mg.

[00412] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00413] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 10 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00414] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 12.5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00415] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 15 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00416] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 20 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00417] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 25 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00418] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 30 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00419] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 35 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00420] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 37.5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00421] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 40 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00422] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 45 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00423] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 50 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00424] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 62.5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00425] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 75 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00426] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 100 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00427] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 125 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00428] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 150 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00429] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 175 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00430] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 200 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00431] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 225 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00432] In some embodiments, the present invention provides a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets in a unit dosage form, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein said mini-tablet or plurality of mini-tablets contains approximately 250 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00433] In a further embodiment, the one or more fillers is a two-component filler containing a mixture of 2 fillers. In another additional embodiment, the two-component filler is a mixture of mannitol and another filler. In another further embodiment, the two-component filler is a mixture of lactose and another filler. In another further embodiment, the two-component filler is a mixture of mannitol and lactose.

[00434] In another further embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to about 100 wt.% of the two-component excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose in an amount of up to about 100% by weight of the bicomponent excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains mannitol in an amount up to about 100% by weight of the bicomponent excipient and lactose in an amount such that the sum of the amounts of mannitol and lactose is equal to 100% by weight.

[00435] In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient comprises mannitol and another excipient in a ratio of about 3:1 mannitol to other excipient, in a ratio of about 1:1 mannitol to other excipient, or in a ratio of about 1:3 mannitol to another filler. In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient comprises lactose and another excipient in a ratio of about 3:1 lactose to other excipient, about 1:1 lactose to other excipient, or about 1:3 lactose to other excipient. filler. In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and lactose in a ratio of about 3:1 mannitol to lactose, in a ratio of about 1:1 mannitol to lactose, or in a ratio of about 1:3 mannitol to lactose.

[00436] One exemplary compressed pharmaceutical composition contains from about 5 wt% to about 70 wt% (e.g., from about 5 wt% to about 65 wt%, from about 5 wt% to about 50 wt.% or from about 30 wt.% to about 40 wt.%) solid dispersion by weight of the composition containing from about 30 wt.% to about 90 wt.% substantially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 1 wt.% to about 10 wt.% disintegrant; optionally from about 3 wt.% to about 0.01 wt.% humectant; from about 0.1 wt.% to about 5 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant. Or the compressed pharmaceutical composition contains from about 5 wt.% to about 65 wt.% (for example, from about 5 wt.% to about 25 wt.%, from about 15 wt.% to about 40 wt.%, or from about 30 wt.% .% to about 50 wt.%) solid dispersion by weight of a composition containing from about 30 wt.% to about 90 wt.% amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer , by mass of dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 1 wt.% to about 10 wt.% disintegrant; optionally from about 3 wt.% to about 0.01 wt.% humectant; from about 0.1 wt.% to about 5 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant.

[00437] Another exemplary pharmaceutical composition contains from about 5 wt.% to about 60 wt.% (for example, from about 5 wt.% to about 55 wt.%, from about 15 wt.% to about 50 wt.% wt.% or from about 30 wt.% to about 50 wt.%) solid dispersion, by weight of the composition containing from about 30 wt.% to about 90 wt.% substantially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 1 wt.% to about 10 wt.% disintegrant; from about 0.1 wt.% to about 5 wt.% sweetener, from about 7 wt.% to about 0.1 wt.% lubricant; optionally from about 0.01 wt.% to about 3 wt.% humectant; from about 5 wt.% to about 0.1 wt.% glidant. Or the pharmaceutical composition contains from about 5 wt.% to about 70 wt.% (for example, from about 5 wt.% to about 65 wt.%, from about 5 wt.% to about 50 wt.%, or from about 30 wt.%). % to about 50 wt.%) solid dispersion by weight of a composition containing from about 40 wt.% to about 90 wt.% amorphous Compound 1, by weight of the dispersion, and from about 60 wt.% to about 10 wt.% polymer, by mass of dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 1 wt.% to about 10 wt.% disintegrant; from about 5 wt.% to about 0.1 wt.% sweetener; optionally from about 3 wt.% to about 0.01 wt.% humectant; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant.

[00438] One pharmaceutical composition of the present invention contains approximately 46.9 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 45.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00439] Another compressed pharmaceutical composition of the present invention contains approximately 24.6 wt.% (equivalent to 24.6 mg of active ingredient for a 200 mg unit) solid dispersion by weight of the composition, wherein said dispersion contains approximately 50 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 49.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; approximately 67.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00440] In another embodiment, the compressed pharmaceutical composition of the present invention contains approximately 35 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 72.4 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 27. 1 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 54 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00441] In some embodiments, the compressed pharmaceutical composition of the present invention contains approximately 61.6 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19. 5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 30.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00442] In some embodiments, the compressed pharmaceutical composition of the present invention contains approximately 68.7 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19. 5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 23.3 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; approximately 1.5 wt.% magnesium stearate by weight of the composition. Optionally, the above compressed pharmaceutical compositions may also include approximately 0.4 wt.% colorant by weight of the composition.

[00443] In yet another further compressed pharmaceutical composition of the present invention, the pharmaceutical composition contains approximately 34 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19 .5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 58 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00444] In one aspect, the present invention provides a pharmaceutical composition containing from about 30 wt% to about 50 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight dispersions, about 19.5 wt.% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00445] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00446] In some embodiments, the compressed pharmaceutical composition contains 25-40 mini-tablets, said mini-tablets collectively containing 75 mg of Compound 1 may additionally be contained in a unit dose, such as a capsule, packet, pack, sachet, vial or blister packaging. In other embodiments, a unit dose comprising a capsule, packet, pack, sachet, vial or blister pack containing 25-40 mini-tablets may contain about 50 mg, about 40 mg, about 30 mg, about 25 mg, about 20 mg , about 15 mg, about 10 mg, or about 5 mg of Compound 1.

[00447] In some embodiments, the compressed pharmaceutical composition contains 5-30 mini-tablets, said mini-tablets collectively containing 75 mg of Compound 1 may additionally be contained in a unit dose, such as a capsule, packet, sachet, vial or blister pack packaging. In other embodiments, a unit dose comprising a capsule, packet, pack, sachet, vial or blister pack containing 5-30 mini-tablets may contain about 50 mg, about 40 mg, about 30 mg, about 25 mg, about 20 mg , about 15 mg, about 10 mg, or about 5 mg of Compound 1.

[00448] In some embodiments, the compressed pharmaceutical composition contains 1-30 mini-tablets, said mini-tablets collectively containing 50 mg of Compound 1 may further be formulated in a unit dose, such as a capsule, packet, sachet, vial or blister pack . In other embodiments, a unit dose comprising a capsule, packet, pack, sachet, vial or blister pack containing 1-30 mini-tablets may contain about 75 mg, about 50 mg, about 40 mg, about 30 mg, about 25 mg , about 20 mg, about 15 mg, about 10 mg, or about 5 mg of Compound 1.

[00449] In some embodiments, the compressed pharmaceutical composition contains about 1-50 mini-tablets (e.g., about 27 to about 32 or about 35 to about 42), said mini-tablets collectively containing 75 mg of Compound 1, additionally may be contained in a unit dose, for example a capsule, packet, pack, sachet, bottle or blister pack. In other embodiments, a unit dose comprising a capsule, packet, pack, sachet, vial, or blister pack containing 1-30 mini-tablets (e.g., about 25, about 20, about 19, about 15, about 12, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2 or about 1), may contain about 50 mg, about 40 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, approximately 10 mg, or approximately 5 mg of Compound 1.

[00450] In yet another additional pharmaceutical composition of the present invention, the mini-tablet compressed pharmaceutical composition has an average tensile strength of from about 0.5 MPa to about 4 MPa and contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 45.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some embodiments, the compressed pharmaceutical composition comprising a mini-tablet or plurality of mini-tablets contains 75 mg of Compound 1. In some embodiments, the compressed pharmaceutical composition contains 75 mg of Compound 1 in a unit dose.

[00451] In yet another pharmaceutical composition of the present invention, the pharmaceutical composition, compressed into a mini-tablet having an initial average tensile strength of 3.14 MPa, contains approximately 49.3 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 50 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 49.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 42.7 wt.% mannitol by weight of the composition; approximately 2% wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some embodiments, the capsule, pouch, pack, sachet, vial, or blister pack is filled with a mini-tablet or a plurality of mini-tablets containing 50 mg of Compound 1.

[00452] In yet another compressed pharmaceutical composition of the present invention, the mini-tablet pharmaceutical composition having an initial average tensile strength of 3.1 MPa contains approximately 24.6 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 50 wt% substantially amorphous Compound 1 by weight of the dispersion, about 49.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 67.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some aspects, a unit dose containing a capsule or pack filled with a mini-tablet or a plurality of mini-tablets contains 25 mg of Compound 1.

[00453] In other aspects, the mini-tablet pharmaceutical composition of the present invention optionally includes a color coating. In some embodiments of this aspect, said mini-tablet in solid dosage form contains a blue OPADRY® II coating. In some embodiments, the capsule or pack containing the pharmaceutical composition in the form of a mini-tablet or multiple mini-tablets contains 25 mg of Compound 1.

[00454] In some embodiments, a capsule or pack containing 20-40 mini-tablets contains approximately 75 mg of Compound 1. In some aspects, said mini-tablet pharmaceutical composition may optionally further comprise a color coating and/or a wax coating. In some aspects, a pharmaceutical composition containing 20-60 mini-tablets contained in a capsule or pack contains 100 mg of Compound 1.

[00455] In another compressed pharmaceutical composition of the present invention, the mini-tablet obtained in the methods described in the present invention has an initial average tensile strength between 2.1 and 4.0 MPa and contains approximately 61.6 wt.% solid a dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 30.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.1 wt.% SLS by weight of the composition; approximately 1.5 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some aspects, a capsule or pack containing a mini-tablet or a plurality of mini-tablets contains 100 mg of Compound 1. In some aspects, a unit dosage form (e.g., a capsule or pack) contains a mini-tablet or a plurality of mini-tablets, for example, from about 20 to approximately 50 mini-tablets. In some embodiments, a capsule or pack containing 39 mini-tablets contains 150 mg of Compound 1.

[00456] In another pharmaceutical composition of the present invention, the pharmaceutical composition contains approximately 34.1 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 57.9 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical mini-tablet contains 1.91 mg of Compound 1. In other embodiments, the pharmaceutical composition comprising the mini-tablet contains 1.72 mg of Compound 1.

[00457] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical mini-tablet contains 1.93 mg of Compound 1. In other embodiments, the pharmaceutical composition comprising the mini-tablet contains 1.96 mg of Compound 1. In some aspects, the pharmaceutical mini-tablet contains 10 mg of Compound 1. In others In embodiments, the pharmaceutical composition comprising the mini-tablet contains 12.5 mg of Compound 1. In some aspects, the pharmaceutical mini-tablet contains 1.92 mg of Compound 1.

[00458] It is also noted that pharmaceutical compositions containing one or more mini-tablets of the present invention may be formulated into a capsule or packaged in a sachet or pack for oral administration, or may be reconstituted in an aqueous vehicle (e.g., deionized water or saline) for oral or intravenous administration. Preferably, said pharmaceutical compositions in the form of mini-tablets described in this application are prepared and enclosed in capsules, bottles or sachets. In other embodiments, the pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets may be in pouches, packs, sachets, vials or blister packs. In one embodiment, the pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets may be contained in packs.

[00459] Another aspect of the present invention relates to a pharmaceutical composition consisting of 1-200 mini-tablets, each mini-tablet including a CF potentiating agent API (e.g., a solid dispersion of N-[2,4-bis(1,1-dimethylethyl )-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) and other excipients (for example, one or more excipients, disintegrant, sweetener, humectant, glidant, lubricant, or any combination thereof), each of which are described above and in the examples below, wherein said mini-tablet or plurality of mini-tablets has a solubility of at least about 50% (e.g., at least about 60%, at least about 70%, or at least about 80 %) in approximately 30 minutes. In one example, the pharmaceutical composition consists of a capsule or pack containing approximately 29 mini-tablets that includes a CF potentiating agent API (e.g., a solid dispersion of Compound 1) and other excipients (e.g., one or more excipients, a sweetener, a disintegrant, a humectant, a lubricant substance and lubricant, or any combination thereof), each of which is described above and in the examples below, wherein in some embodiments, said mini-tablet has a solubility of from about 50% to about 100% (for example, from about 55% to about 95%, about 60% to about 90%, or about 70% to about 80%) in about 30 minutes. In another example, the pharmaceutical composition consists of a capsule or pack containing approximately 29 mini-tablets, each mini-tablet containing a solid dispersion containing substantially amorphous or amorphous Compound 1 and HPMCAS; and one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, wherein the contents of the capsule or packet have a solubility of at least about 50% (e.g., at least about 60%, at least about 70%, according to at least about 80%, at least about 90%) in about 30 minutes. In yet another example, the pharmaceutical composition consists of a capsule or pack containing approximately 29 mini-tablets, each mini-tablet containing a solid dispersion containing substantially amorphous or amorphous Compound 1 and HPMCAS; and one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, wherein the contents of the capsule or packet have a solubility of from about 50% to about 100% (e.g., from about 55% to about 95%, from about 60% to about 90% or from about 70% to about 80%) in about 30 minutes.

[00460] In one embodiment, the capsule or pack contains a mini-tablet or a plurality of mini-tablets, wherein said mini-tablet or plurality of mini-tablets contains a solid dispersion containing at least about 15 mg (for example, at least about 20 mg , at least about 25 mg, at least about 30 mg, at least about 40 mg, or at least about 50 mg) of substantially amorphous or amorphous Compound 1, a polymer of HPMCAS and SLS. In another embodiment, the capsule or pack contains a mini-tablet or a plurality of mini-tablets, wherein said mini-tablet or plurality of mini-tablets contains a solid dispersion containing at least about 15 mg (e.g., at least 20 mg, at least 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, or at least 150 mg) of a substantially amorphous or amorphous Compound 1, and HPMCAS and SLS.

[00461] Solubility can be measured using a standard USP Type II instrument containing a solvent of 0.5 or 0.7% sodium lauryl sulfate dissolved in 900 ml of 50 mM sodium phosphate buffer at pH 6.8 at approximately 37°C. The dissolution of the mini-tablets was determined by recording the dissolution of a plurality of mini-tablets containing a total of 75 mg (using 0.5% sodium lauryl sulfate) or 150 mg (using 0.7% sodium lauryl sulfate) of Compound 1 in the solvent. Individual mini-tablets may exhibit a solubility that is lower than, equivalent to, or higher than the solubility of the plurality, with the average solubility of each individual mini-tablet being similar to the average solubility of the plurality.

[00462] Another aspect of the present invention relates to a pharmaceutical composition comprising a mini-tablet that contains a CF potentiating agent API (e.g., a solid dispersion of Compound 1) and other excipients (e.g., one or more excipients, a sweetener, a disintegrant, a humectant, a glidant and a lubricant, or any combination thereof), each of which is described above and in the examples below, wherein the mini-tablet has an average tensile strength ranging from about 0.5 MPa to about 4 MPa, for example, at least about 0 .5 MPa, at least about 1 MPa, or at least about 2 MPa. In one example, the pharmaceutical composition consists of a mini-tablet that contains a CF potentiating agent API (e.g., a solid dispersion of Compound 1) and other excipients (e.g., one or more excipients, a sweetener, a disintegrant, a humectant, a glidant and a lubricant, or any a combination thereof), each of which is described above and in the examples below, wherein the mini-tablet has an average tensile strength ranging from about 0.5 MPa to about 4 MPa, for example, at least about 0.5 MPa, at least at least about 1 MPa or at least about 2 MPa.

[00463] In yet another additional pharmaceutical composition of the present invention, the pharmaceutical composition is in the form of a mini-tablet having an average tensile strength in the range of from about 0.5 MPa to about 4.1 MPa (for example, from about 0.5 MPa to about 4 MPa, about 0.5 MPa to about 3 MPa, about 0.75 MPa to about 3 MPa, about 1 MPa to about 2 MPa, about 1 MPa to about 1.5 MPa, or about 2, 1 to about 4.05 MPa) and contains approximately 46.7 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 78.8 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 20.7 wt. .% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 45.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some embodiments, the pharmaceutical composition comprising one or more mini-tablets contains 75 mg of Compound 1.

[00464] In yet another pharmaceutical composition of the present invention, the pharmaceutical composition is in the form of a mini-tablet having an initial average tensile strength in the range of from about 0.5 MPa to about 4.1 MPa (for example, from about 0.5 MPa to about 4 MPa, about 0.5 MPa to about 3 MPa, about 0.75 MPa to about 3 MPa, about 1 MPa to about 2 MPa, about 1 MPa to about 1.5 MPa, or about 3.14 MPa ) and contains approximately 49.3 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 50 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 49.5 wt% HPMCAS by weight of the dispersion, and approximately 0 .5 wt.% SLS by weight of dispersion; approximately 42.7 wt.% mannitol by weight of the composition; approximately 2% wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some embodiments, a capsule or pack filled with a mini-tablet or multiple mini-tablets contains 50 mg of Compound 1.

[00465] In yet another pharmaceutical composition of the present invention, the pharmaceutical composition is in the form of a mini-tablet having an initial average tensile strength in the range of from about 0.5 MPa to about 4.1 MPa (for example, from about 0.5 MPa to about 4 MPa, about 0.5 MPa to about 3 MPa, about 0.75 MPa to about 3 MPa, about 1 MPa to about 2 MPa, about 1 MPa to about 1.5 MPa, or about 3.1 MPa ) and contains approximately 24.6 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 50 wt% substantially amorphous Compound 1 by weight of the dispersion, approximately 49.5 wt% HPMCAS by weight of the dispersion, and approximately 0.5 wt.% SLS by weight of dispersion; approximately 67.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some aspects, a pharmaceutical composition containing a capsule or pack filled with a mini-tablet or a plurality of mini-tablets contains 25 mg of Compound 1. In some embodiments, a capsule or pack containing a pharmaceutical composition in the form of a mini-tablet or a plurality of mini-tablets contains 25 mg Compound 1.

[00466] In another pharmaceutical composition of the present invention, a mini-tablet composition having an initial average tensile strength between 2.1 and 4.0 MPa contains approximately 61.6 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion, and approximately 0.5 wt% SLS by weight of the dispersion; approximately 30.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.1 wt.% SLS by weight of the composition; approximately 1.5 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some aspects, a capsule or pack containing a mini-tablet or a plurality of mini-tablets contains 100 mg of Compound 1. In some aspects, a compressed pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, for example, from about 20 to about 50 mini-tablets tablets, for example 43 mini-tablets, contains 150 mg of Compound 1.

[00467] In some embodiments, a capsule or pack containing 20-40 mini-tablets contains approximately 75 mg of Compound 1. In some aspects, a pharmaceutical composition containing 20-40 mini-tablets contained in a capsule or pack contains 100 mg of Compound 1.

[00468] In yet another additional pharmaceutical composition of the present invention, the compressed pharmaceutical composition contains approximately 34 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19. 5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 58 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some embodiments, a pharmaceutical composition containing a capsule or pack containing 25-30 (e.g., approximately 26) mini-tablets contains 50 mg of Compound 1. In other embodiments, a pharmaceutical composition containing a capsule or pack containing 20-30 mini-tablets tablets, contains 25, 15 or 10 mg of Compound 1.

[00469] In another pharmaceutical composition of the present invention, the pharmaceutical composition contains approximately 34.1 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 57.9 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In some embodiments, the compressed mini-tablet contains 1.91 mg of Compound 1. In other embodiments, said mini-tablet contains 1.72 mg of Compound 1.

[00470] In one aspect, the present invention provides a pharmaceutical composition containing from about 30 wt% to about 50 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight dispersions, about 19.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00471] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00472] In a further embodiment of this aspect, the pharmaceutical composition is in the form of a mini-tablet. In another embodiment, the size of said mini-tablet is approximately 2 mm. In another embodiment, the size of said mini-tablet is 4 mm. In a further embodiment, the plurality of 2 mm mini-tablets collectively form a dosage containing from about 20 mg to about 275 mg of Compound 1, e.g., the plurality of 2 mm mini-tablets collectively form a dosage containing about 25 mg to about 50 mg , approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, or approximately 250 mg. In another further embodiment, the plurality of 4 mm mini-tablets collectively form a dosage containing from about 5 mg to about 70 mg of Compound 1, e.g., the plurality of 4 mm mini-tablets collectively form a dosage containing about 10 mg, 12. 5 mg, approximately 20 mg, 25 mg, approximately 30 mg, approximately 37.5 mg, 40 mg, 50 mg, approximately 62.5 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, or approximately 250 mg.

[00473] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In one embodiment, the pharmaceutical composition contains a plurality of mini-tablets having approximately 50 mg of Compound 1 per 26 mini-tablets and 75 mg of Compound 1 per 39 mini-tablets. In a further embodiment, each mini-tablet is approximately 2 mm in diameter and approximately 2 mm in thickness. In a further embodiment, each mini-tablet weighs approximately 7 mg. In some embodiments, each mini-tablet weighs approximately 6.9 mg. In yet another further embodiment, the mini-tablets are cylindrical in shape. In one embodiment, the pharmaceutical composition includes a capsule or pack containing a plurality of mini-tablets. In one additional embodiment, the capsule or pack contains approximately 26 mini-tablets and approximately 50 mg of Compound 1. In another additional embodiment, the capsule or pack contains approximately 39 mini-tablets and approximately 75 mg of Compound 1.

[00474] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In one embodiment, the pharmaceutical composition contains a plurality of mini-tablets having approximately 40 mg of Compound 1 per 21 mini-tablets and 100 mg of Compound 1 per 52 mini-tablets. In a further embodiment, each mini-tablet has a diameter of approximately 2 mm and a thickness of approximately 2 mm. In a further embodiment, each mini-tablet weighs approximately 6.9 mg. In yet another embodiment, the mini-tablets are cylindrical in shape. In one embodiment, the pharmaceutical composition includes a capsule or pack containing a plurality of mini-tablets. In one additional embodiment, the capsule or pack contains approximately 21 mini-tablets and approximately 40 mg of Compound 1. In another additional embodiment, the capsule or pack contains approximately 52 mini-tablets and approximately 100 mg of Compound 1.

[00475] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In one embodiment, the pharmaceutical composition contains one or more tablets having approximately 10 mg of Compound 1 per tablet. In a further embodiment, the tablet diameter is approximately 4 mm and the tablet thickness is approximately 3 mm. In a further embodiment, the tablet weight is approximately 35.7 mg. In yet another further embodiment, the mini-tablets have a biconvex cylindrical shape. In other embodiments, the mini-tablets have any shape, including oval, spherical, cylindrical, elliptical, cubic, square, or triangular with flat, narrow, standard, highly convex, or double convex surfaces, or combinations thereof.

[00476] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In one embodiment, the pharmaceutical composition contains one or more tablets having approximately 12.5 mg of Compound 1 per tablet. In a further embodiment, the tablet diameter is approximately 4 mm and the thickness is approximately 3.7 mm. In a further embodiment, the tablet weight is approximately 44.7 mg. In yet another further embodiment, the mini-tablets have a convex cylindrical shape. In other embodiments, the mini-tablets have any shape, including oval, spherical, cylindrical, elliptical, cubic, square, or triangular with flat, narrow, standard, highly convex, or double convex surfaces, or combinations thereof.

[00477] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition. In one embodiment, the pharmaceutical composition contains a plurality of mini-tablets having approximately 50 mg of Compound 1 per 26 mini-tablets and 75 mg of Compound 1 per 39 mini-tablets. In a further embodiment, each mini-tablet has a diameter of approximately 2 mm and a thickness of approximately 2 mm. In a further embodiment, each mini-tablet weighs approximately 7 mg. In yet another further embodiment, the mini-tablets are cylindrical in shape. In one embodiment, the pharmaceutical composition includes a capsule or pack containing a plurality of mini-tablets. In one additional embodiment, the capsule or pack contains approximately 26 mini-tablets and approximately 50 mg of Compound 1. In another additional embodiment, the capsule or pack contains approximately 39 mini-tablets and approximately 75 mg of Compound 1.

[00478] It is also noted that unit dosage forms containing compressed pharmaceutical compositions containing one or more mini-tablets of the present invention can be processed into tablet form, capsule form or filled into sachets, bags, packs, vials and the like for oral administration administration, or can be reconstituted in an aqueous vehicle (eg, deionized water or saline) for oral or intravenous administration. Also, for oral administration, unit dosage forms can be added to light foods, for example, applesauce, plain yogurt, ice cream, baby food. Baby food may include, but is not limited to, carrots or carrot puree. Also for oral administration, the unit dosage forms may be administered in liquids such as milk (including breast milk), infant formula, or infant formula. Food items may also include strawberry jam, rice pudding or chocolate pudding. Liquids may also include water. In one embodiment, the unit dosage form is sprayed into a light meal and administered. In another embodiment, the unit dosage form is sprayed into a light food, mixed and administered. In one embodiment, the unit dosage form is squirted into a liquid, such as, but not limited to, infant formula, formula, milk, or breast milk, and administered. In another embodiment, the unit dosage form is injected into a liquid, such as, but not limited to, infant formula, formula, milk or breast milk, mixed and administered. Preferably, said compressed pharmaceutical compositions in the form of mini-tablets described in this application are prepared and enclosed in capsules, bottles or sachets. In other embodiments, the pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets may be in pouches, packs, sachets, vials or blister packs. In some cases, for mini-tablets or smaller granules, the contents of packs, bags, capsules, bottles or sachets can be administered directly into the mouth followed by breast milk or formula. The methods of administration of the present invention may also optionally include, for mini-tablets or smaller granules, administration of the contents of packets, pouches, capsules, bottles or sachets directly into the oral cavity followed by administration of a liquid or drink. In some embodiments, any routes of administration of the present invention may optionally include oral administration with a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. In one aspect, in accordance with the present invention, all modes of administration of the present invention may optionally involve oral administration simultaneously, before or after a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack.

[00479] Another aspect of the present invention relates to a compressed pharmaceutical composition containing 20-50 mini-tablets, each mini-tablet including a CF potentiating agent API (for example, a solid dispersion of N-[2,4-bis(1,1-dimethylethyl) -5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) and other excipients (for example, one or more excipients, disintegrant, sweetener, humectant, glidant, lubricant, or any combination thereof), each as described above and in the examples below, wherein said mini-tablet or plurality of mini-tablets has a solubility of at least about 50% (e.g., at least about 60%, at least about 70%, or at least about 80% ) in approximately 30 minutes. In one example, the pharmaceutical composition consists of a capsule or pack containing approximately 29 mini-tablets that include a CF potentiating agent API (e.g., a solid dispersion of Compound 1) and other excipients (e.g., one or more excipients, a sweetener, a disintegrant, a humectant, a lubricant substance and lubricant, or any combination thereof), each of which is described above and in the examples below, wherein in some embodiments, said mini-tablet has a solubility of from about 50% to about 100% (for example, from about 55% to about 95%, about 60% to about 90%, or about 70% to about 80%) in about 30 minutes. In another example, the pharmaceutical composition consists of a capsule or pack containing approximately 29 mini-tablets, each mini-tablet containing a solid dispersion containing substantially amorphous or amorphous Compound 1 and HPMCAS; and one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, wherein the contents of the capsule or packet have a solubility of at least about 50% (e.g., at least about 60%, at least about 70%, according to at least about 80%, at least about 90%) in about 30 minutes. In yet another example, the pharmaceutical composition consists of a capsule or pack containing approximately 29 mini-tablets, each mini-tablet containing a solid dispersion containing substantially amorphous or amorphous Compound 1 and HPMCAS; and one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, wherein the mini-tablets contained in the capsule or packet collectively have a solubility of from about 50% to about 100% (e.g., from about 55% to about 95 %, from about 60% to about 90%, or from about 70% to about 80%) in about 30 minutes.

[00480] In one embodiment, the unit dosage form contains a mini-tablet or a plurality of mini-tablets, said mini-tablet or plurality of mini-tablets contains a solid dispersion containing at least about 5 mg (for example, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, or at least about 50 mg) of substantially amorphous or amorphous Compound 1; HPMCAS and SLS. In another embodiment, the capsule or pack contains a mini-tablet or a plurality of mini-tablets, said mini-tablet or a plurality of mini-tablets containing a solid dispersion containing at least about 10 mg (e.g., at least about 15 mg, at least 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg or at least 150 mg) essentially amorphous or amorphous Compound 1; and HPMCAS and SLS.

[00481] Dissolution can be measured using a standard USP Type II device containing a dissolution medium of 0.5 or 0.7% sodium lauryl sulfate dissolved in 900 ml of 50 mM sodium phosphate buffer at pH 6.8 at approximately 37°C C. Mini-tablet dissolution was determined by recording the dissolution of multiple mini-tablets containing a total of 75 mg (using 0.5% sodium lauryl sulfate) or 150 mg (using 0.7% sodium lauryl sulfate) of Compound 1 in dissolution medium. Individual mini-tablets may exhibit a solubility lower, equivalent to, or higher than that of the plurality, with the average solubility of each individual mini-tablet being similar to the average solubility of the plurality.

[00482] Another aspect of the present invention relates to a pharmaceutical composition consisting of a mini-tablet that contains a CF potentiating agent API (e.g., a solid dispersion of Compound 1) and other excipients (e.g., one or more excipients, a sweetener, a disintegrant, a humectant, a lubricant substance and lubricant, or any combination thereof), each of which is described above and in the examples below, wherein the mini-tablet has an average tensile strength ranging from about 0.5 MPa to about 4 MPa, for example, at least about 0.5 MPa, at least about 1 MPa, or at least about 2 MPa. In one example, the pharmaceutical composition consists of a mini-tablet that contains a CF potentiating agent API (e.g., a solid dispersion of Compound 1) and other excipients (e.g., one or more excipients, a sweetener, a disintegrant, a humectant, a glidant and a lubricant, or any a combination thereof), each of which is described above and in the examples below, wherein the mini-tablet has an average tensile strength ranging from about 0.5 MPa to about 4 MPa, for example, at least about 0.5 MPa, at least at least about 1 MPa or at least about 2 MPa.

III. METHOD FOR OBTAINING PHARMACEUTICAL COMPOSITION

[00483] Another aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising preparing a mixture of a solid dispersion of substantially amorphous or amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro -4-oxoquinoline-3-carboxamide, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, and compressing the mixture into a mini-tablet. In some embodiments, said mini-tablet has a solubility of at least about 50% in about 30 minutes. In some further embodiments, a mini-tablet or a plurality of mini-tablets (e.g., at least 2, at least 4, at least 10, at least 15, at least 20, at least 25) collectively have solubility at least about 50% in about 30 minutes.

[00484] Each of the ingredients of this mixture is described above and in the following Examples. In addition, the mixture may include optional additives, such as one or more coloring agents, one or more flavoring agents , and/or one or more flavoring agents described above and in the following Examples. The relative concentrations (eg, % by weight) of each of these ingredients (and any optional additives) in the mixture are also presented above and in the Examples below. The ingredients making up the mixture may be provided sequentially or in any combination of additions; and the ingredients or combination of ingredients may be supplied in any order. In one embodiment, the lubricant, or parts of the lubricant, is the last component added to the mixture before pressing.

[00485] In another embodiment, a method for preparing a pharmaceutical composition includes preparing a mixture of a solid dispersion of substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant; mixing the mixture until the mixture becomes substantially homogeneous; and compressing the mixture into a solid dosage form as described above or in the Examples below. Or, a method for preparing a pharmaceutical composition includes preparing a mixture of a solid dispersion of amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant; mixing this mixture until it becomes substantially homogeneous, and compressing this mixture into a mini-tablet as described above or in the Examples below. For example, the mixture is mixed by stirring, kneading, shaking or the like, by hand mixing, a stirrer, a mixer, any combination thereof or the like. Where ingredients or combinations of ingredients are added sequentially, mixing may occur between successive additions, continuously throughout the addition of an ingredient, after all ingredients or combinations of ingredients have been added, or any combination thereof. In addition, before or after each mixing step, the mixed ingredients may further be sifted by passing the ingredients or mixture through a sieve of suitable mesh size or decompacted using a mill of appropriate mesh size. The mixture is stirred until it reaches a substantially homogeneous composition. This mixture/powder mixture can then be filled into a suitable dosage form or packaging, that is, it can be encapsulated or filled into bags, packs, sachets, vials, etc. for administration. The powder mixture can also be further processed into granules or pellets or mini-tablets and the like. This mixture or part of the mixture (some of the components of the composition) can be granulated, if necessary, using appropriate granulation methods, such as dry granulation (compaction by either clumping or rolling between counter-rotating rollers), wet granulation using granulators with high shear, twin screw extruder granulation, fluidized bed granulation, extrusion-spheronization, melt extrusion, spray drying and the like. The granules may be mixed with additional ingredients, if necessary, and compressed into tablets, mini-tablets, etc., or filled into capsules, packets, sachets, etc. Granules, pellets, mini-tablets and the like may also be filled into a suitable unit dosage form or packaging for administration, i.e. may be encapsulated or filled into pouches, packs, sachets, vials, etc., or they may be further processed with additional ingredients, if required, and compressed into tablets, lozenges and the like. It has been found that by adding a portion of the lubricant during the mixing stages of the solid dispersion, glidant, sweetener and humectant and before adding the filler and disintegrant, the result is a reduction in the loss of solid dispersion on surfaces during processing such as mixing, compacting and pharmaceutical compression. compositions in rotary tableting machines prepared for the production of mini-tablets. In one embodiment, a method for preparing a pharmaceutical composition of the present invention is shown schematically in FIG. 1. In other embodiments, the mini-tablets of the present invention can be prepared in accordance with the following steps:

a) mixing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1 and a polymer, said polymer comprising HPMCAS, PVP/VA or combinations thereof, with a lubricant, a sweetener and, optionally, a humectant to produce a first mixture;

b) sifting the first mixture;

c) mixing the screened first mixture with 20% of the screened lubricant until a first mixed mixture is formed;

d) mixing the sifted litter and sieved baking powder with the first blended mixture to form a second blended mixture;

e) distributing the second mixed mixture to obtain a homogeneous mixture;

f) mixing 80% of the screened lubricant with a homogeneous mixture to obtain a pressing mixture; And

g) pressing the compression mixture to obtain a mini-tablet. In other embodiments, the mini-tablets of the present invention can be prepared according to the following steps:

i) mixing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1 and a polymer, said polymer comprising HPMCAS, PVP/VA or combinations thereof, with a glidant and a sweetener to produce a first mixture;

ii) sifting the first mixture;

iii) mixing the sifted first mixture;

iv) mixing the sifted litter and sieved disintegrant with the first blended mixture to form a second blended mixture;

v) distributing the second mixed mixture to obtain a homogeneous mixture;

vi) mixing the sifted lubricant with a homogeneous mixture to obtain a pressing mixture; And

vii) compressing the compression mixture to obtain a mini-tablet.

[00486] In one embodiment, the mixture contains a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, where each of these ingredients is provided in powder form (e.g., provided in the form of particles having an average diameter, as measured by light scattering, of 250 μm or less (for example, 150 μm or less, 100 μm or less, 50 μm or less, 45 μm or less, 40 μm or less, or 35 μm or less )). For example, the mixture contains a solid dispersion of amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, where each of these ingredients is provided in powder form (e.g., presented as particles having an average diameter measured by light scattering, 250 µm or less (for example, 150 µm or less, 100 µm or less, 50 µm or less, 45 µm or less, 40 µm or less, or 35 µm or less)).

[00487] In another embodiment, the mixture contains a solid dispersion of substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant, and a lubricant, each of these ingredients being substantially free of water. Each of these ingredients contains less than 6 wt.% (for example, less than 2 wt.%, less than 1 wt.%, less than 0.75 wt.%, less than 0.5 wt.%, or less than 0.25 wt.%) water by weight of the ingredient. For example, this mixture contains a solid dispersion of amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, each of these ingredients being substantially free of water.

[00488] In another embodiment, compressing the mixture into a mini-tablet is accomplished by filling a mold (eg, a mold) with the compression mixture and applying pressure to the compression mixture. This operation can be performed using molds and suitably sized punches on a press or other similar equipment such as a rotary tableting machine. It is also noted that the application of pressure to the mold mixture can be done repeatedly, using the same applied pressure during each pressing or using different applied pressures during pressing. In another example, the compressible mixture may be compressed using sufficient pressure to produce a solid dosage form, such as granules, pellets, shaped particles, or mini-tablets, a solid dosage form. In some embodiments, a rotary tablet press, commercially available from Kikusui America (Model Virgo), having 19 press tool positions and operating to produce cylindrical mini-tablets measuring 2 mm (7 mg per mini tablet). In other embodiments, a rotary tableting machine commercially available from IMA KILIAN GMBH & CO., Cologne, Germany, can be used for the purposes of the present invention. For example, the compression mixture is compressed using suitable tooling (molds and punches on a pressing machine) to produce a 2 mm cylindrical shaped mini-tablet having an average tensile strength between about 0.5 MPa and about 4 MPa.

IV. INTRODUCTION OF PHARMACEUTICAL COMPOSITION

[00489] In another aspect, the present invention relates to a method of treating or reducing the severity of a disease in a patient, comprising administering to said patient one of the pharmaceutical compositions as defined herein, and said disease is selected from cystic fibrosis, smoking-induced asthma, 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 disorders such as protein C deficiency, hereditary angioedema type 1, lipid processing disorders such as familial hypercholesterolemia , cheilomicronemia type 1, abetalipoproteinemia, lysosomal storage diseases such as inclusion cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhoff/Tay-Sachs disease, Crigler-Nayjar disease type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, Laronon type dwarfism, myeloperoxidase deficiency , primary hypoparathyroidism, melanoma, CDG glycogenosis type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, AST deficiency, diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some neurological disorders characterized by the deposition of polyglutamine-containing proteins in the nuclei of neurons, such as Huntington's disease, spinocerebellar ataxia type I, spinal bulbar muscular atrophy , dentato-rubro-pallido-Lewis atrophy and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (due to impaired prion protein processing), Fabry disease, Gerstmann-Straussler-Scheinker syndrome, COPD, dry eye disease, Sjögren's, osteoporosis, osteopenia, bone fusion and bone formation (including bone repair, bone regeneration, decreased bone resorption and increased bone deposition), Gorham's disease, chloride channelopathies,such as myotonia congenita (Thomson and Becker forms), Barter syndrome type III, Dent's disease, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome and primary ciliary dyskinesia (PCD), a term for inherited disorders of the structure and/or function of the ciliary epithelium, including PCD with complete visceral inversion (also known as Kartagener's syndrome), PCD without complete visceral inversion, and ciliary aplasia.

[00490] Compound 1 (N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) was recognized as a new breakthrough therapy by the Government by the Food and Drug Administration (FDA) for the treatment of cystic fibrosis, only one of two at the time of filing this application. This demonstrates a significant unmet need for effective treatment of the causes of cystic fibrosis compared with symptomatic treatments.

[00491] In some embodiments, the method includes treating or reducing the severity of cystic fibrosis in a patient, for example, a pediatric patient, and the method includes administering to the patient one of the pharmaceutical compositions described in the present invention. Although the pharmaceutical compositions of this invention are not limited to their use in treating pediatric patients, the dosage forms provided herein are suitable for patients who have difficulty swallowing their required medications in tablet form or who are advised to take take their medications mixed with food or liquids. Some of these patients usually tolerate the pharmaceutical compositions required for them from the unit dosage form into food or liquid media intended for consumption.

[00492] In some embodiments, the patient has mutant forms of human CFTR. In other embodiments, the patient has one or more of the following ΔF508, R117H, and G551D human CFTR mutations. In some embodiments, the patient has a CFTR gate mutation. In some embodiments, the patient has a CFTR gate mutation, including, but not limited to, G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In some embodiments, the patient has one or more of the following human CFTR gate mutations: G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR ΔF508 mutation, comprising administering to said patient one of the pharmaceutical compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the G551D human CFTR mutation, comprising administering to said patient one of the pharmaceutical compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the R117H mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR ΔF508 mutation in at least one allele, comprising administering to said patient one of the compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR ΔF508 mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G551D mutation in at least one allele, comprising administering to the patient one of the compositions described in the present invention. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G551D mutation in both alleles, comprising administering to the patient one of the compositions described in the present invention. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR R117H mutation in at least one allele, comprising administering to said patient one of the compositions described in the present invention. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR R117H mutation in both alleles comprising administering to the patient one of the compositions described in the present invention.

[00493] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having a human CFTR gate mutation, comprising administering to said patient one of the pharmaceutical compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having a CFTR gate mutation in at least one allele, comprising administering to said patient one of the compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having a CFTR gate mutation in both alleles, comprising administering to the patient one of the compositions described in the present invention.

[00494] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the G178R mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G178R mutation in at least one allele, comprising administering to the patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G178R mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00495] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the G551S mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G551S mutation in at least one allele, comprising administering to said patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G551S mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00496] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the G970R mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G970R mutation in at least one allele, comprising administering to said patient one of the compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G970R mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00497] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the G1244E mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G1244E mutation in at least one allele, comprising administering to the patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G1244E mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00498] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the S1255P mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S1255P mutation in at least one allele, comprising administering to the patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S1255P mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00499] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the G1349D mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G1349D mutation in at least one allele, comprising administering to the patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR G1349D mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00500] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the S549N mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S549N mutation in at least one allele, comprising administering to said patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S549N mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00501] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the S549R mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S549R mutation in at least one allele, comprising administering to said patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S549R mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00502] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the S1251N mutation of human CFTR, comprising administering to said patient one of the pharmaceutical compositions described herein. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S1251N mutation in at least one allele, comprising administering to the patient one of the compositions described in the present invention. In another embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having the human CFTR S1251N mutation in both alleles, comprising administering to said patient one of the compositions described in the present invention.

[00503] In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having CFTR with residual function or a residual function phenotype, comprising administering to said patient one of the pharmaceutical compositions described herein.

[00504] In some embodiments, the method of administration of the present invention comprises orally administering a liquid or beverage, including, but not limited to, milk (including breast milk), infant formula or formula, or soft food, including including, but not limited to, applesauce, plain yogurt, ice cream, baby food products (including carrots and carrot puree). In some embodiments, the methods of administration of the present invention include oral administration of a liquid or beverage, including, but not limited to, milk (including breast milk), infant formula, or formula. In some embodiments, the administration methods of the present invention include oral administration of soft foods, including, but not limited to, applesauce, plain yogurt, ice cream, baby food (including carrots and carrot puree). In other embodiments, the methods of administration of the present invention include oral administration of a liquid, such as water. In one embodiment, the unit dosage form is squirted into a beverage or liquid, including, but not limited to, formula, formula, milk, or breast milk, and administered. In another embodiment, the unit dosage form is injected into a beverage or liquid, including, but not limited to, formula, formula, milk or breast milk, mixed and administered. In one embodiment, the unit dosage form is sprayed into soft foods, including, but not limited to, applesauce, plain yogurt, ice cream, baby food (including carrots and carrot puree), and administered. In another embodiment, the unit dosage form is injected into soft foods, including, but not limited to, applesauce, plain yogurt, ice cream, baby food (including carrots and carrot puree), mixed and administered. The administration methods of the present invention may also optionally include, for mini-tablets or reduced-size granules, administration of the contents of packets, pouches, capsules, bottles or sachets directly into the oral cavity, followed by the introduction of breast milk or formula. The administration methods of the present invention may also optionally include, for mini-tablets or reduced-size granules, administration of the contents of packets, pouches, capsules, bottles or sachets directly into the oral cavity followed by administration of a liquid or drink. It is noted that any of the routes of administration of the present invention may optionally involve oral administration with a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. In some embodiments, any of the routes of administration of the present invention may optionally include oral administration concomitantly with, before or after a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack.

[00505] It is also noted that the methods of administration of the present invention include administering the compositions of the present invention to a patient according to age or body weight. In some embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, where each mini-tablet contains a pharmaceutical composition described in the present invention, where the patient is younger six years of age, including, but not limited to, from 2 to 5 years of age, under 2, from zero (i.e. from birth) to 2 years of age, from 1 to 2 years, from 9 months to 2 years, from 6 months to 2 years, from 3 months to 2 years and from 2 months to 2 years of age. In some embodiments, birth means birth after a normal gestational age. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients, but not only them, whose body weight is greater than or equal to approximately 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients, but not only, whose body weight is less than 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight ranges from approximately 7.5 kilograms to less than 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight ranges from approximately 5 kilograms to less than 7.5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight ranges from approximately 2.5 kilograms to less than 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight is less than 7.5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight ranges from approximately 5 kilograms to more than 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight is less than 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight ranges from approximately 2.5 kilograms to more than 2.5 kilograms.

[00506] It is also noted that the methods of administration of the present invention include administering the compositions of the present invention to a patient in accordance with age or body weight. In some embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein age the patient is less than six years old, including, but not limited to, from 2 to 5 years of age, younger than 2, from zero (i.e., from birth) to 2 years of age, from 1 to 2 years, from 9 months to 2 years, from 6 months to 2 years, from 3 months to 2 years and from 2 months to 2 years of age. In some embodiments, birth means birth after a normal gestational age. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes, but is not limited to, those patients whose body weight is greater than or equal to approximately 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes, but is not limited to, those patients whose body weight is less than 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight ranges from approximately 7.5 kilograms to 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight ranges from approximately 5 kilograms to 7.5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight ranges from approximately 2.5 kilograms to 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight is less than 7.5 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is approximately 5 kilograms and above. In other embodiments, a method of administering a pharmaceutical composition includes orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described in the present invention, wherein the patient includes those patients whose body weight is less than 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is approximately 2.5 kilograms or more.

[00507] It is also noted that the methods of administration of the present invention include administering the compositions of the present invention to a patient according to age or body weight. In some embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein age the patient is less than six years old, including, but not limited to, from 2 to 5 years, younger than 2, from zero (i.e. from birth) to 2 years of age, from 1 to 2 years, from 9 months to 2 years, from 6 months to 2 years, from 3 months to 2 years and from 2 months to 2 years of age. In some embodiments, birth means birth after a normal gestational age. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes, but is not limited to, those patients whose body weight is greater than or equal to approximately 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes, but is not limited to, those patients whose body weight is less than 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight ranges from approximately 7.5 kilograms to 14 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is approximately 5 kilograms to 7.5 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is between approximately 2.5 kilograms and 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is less than 7.5 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is approximately 5 kilograms and above. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is less than 5 kilograms. In other embodiments, a method of administering a pharmaceutical composition comprises orally administering to a patient, twice daily, at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition described herein, wherein the patient includes those patients whose body weight is approximately 2.5 kilograms and above.

[00508] In some embodiments, the method comprises treating or reducing the severity of cystic fibrosis in a patient by administering to the patient a pharmaceutical composition comprising a powder composition or a compressed pharmaceutical composition. In one embodiment, a capsule or packet containing a powder pharmaceutical composition containing from 1 mg to about 250 mg of Compound 1 is administered to the patient.

[00509] In some embodiments, the composition may comprise a powder pharmaceutical composition containing a solid dispersion and an excipient, for example: one or more excipients, a sweetener, a glidant, a lubricant, and combinations thereof, wherein the solid dispersion contains from about 30 wt.% to approximately 95 wt.% Compound 1 by weight of the dispersion and polymer.

[00510] In some embodiments, the solid dispersion contains from about 45 wt.% to about 85 wt.%, including all values and ranges within the specified range (for example, about 50 wt.%, about 72.4 wt.%, about 78 .8 wt.% or approximately 80 wt.%) Compounds 1 by weight dispersion and polymer.

[00511] One exemplary pharmaceutical composition contains from about 5 wt.% to about 70 wt.% (for example, from about 5 wt.% to about 65 wt.%, from about 5 wt.% to about 50 wt.% wt.% or from about 30 wt.% to about 40 wt.%) solid dispersion, by weight of the composition containing from about 30 wt.% to about 90 wt.% substantially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 0.1 wt.% to about 5 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant. Or the powder pharmaceutical composition contains from about 5 wt.% to about 65 wt.% (for example, from about 5 wt.% to about 25 wt.%, from about 15 wt.% to about 40 wt.%, or from about 30 wt.% .% to about 50 wt.%) solid dispersion by weight of a composition containing from about 30 wt.% to about 90 wt.% amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 20 wt.% polymer , by mass of dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 0.1 wt.% to about 5 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant.

[00512] Another exemplary pharmaceutical composition contains from about 5 wt.% to about 60 wt.% (for example, from about 5 wt.% to about 55 wt.%, from about 15 wt.% to about 50 wt.% wt.% or from about 30 wt.% to about 50 wt.%) solid dispersion, by weight of the composition containing from about 30 wt.% to about 90 wt.% substantially amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by weight of the dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 0.1 wt.% to about 5 wt.% sweetener, from about 7 wt.% to about 0.1 wt.% lubricant; and from about 5 wt.% to about 0.1 wt.% glidant. Or the pharmaceutical composition contains from about 5 wt.% to about 55 wt.% (for example, from about 5 wt.% to about 50 wt.%, from about 5 wt.% to about 45 wt.%, or from about 5 wt.%). % to about 40 wt.%) solid dispersion by weight of a composition containing from about 30 wt.% to about 90 wt.% amorphous Compound 1, by weight of the dispersion, and from about 70 wt.% to about 10 wt.% polymer, by mass of dispersion; from about 10 wt.% to about 90 wt.% one or more fillers; from about 5 wt.% to about 0.1 wt.% sweetener; from about 5 wt.% to about 0.1 wt.% glidant; and from about 7 wt.% to about 0.1 wt.% lubricant.

[00513] One powder pharmaceutical composition of the present invention contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% essentially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt. % HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. Or, the powder pharmaceutical composition of the present invention contains about 15.6 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of dispersion; approximately 80.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition.

[00514] Another pharmaceutical composition in powder form in accordance with the present invention contains approximately 24.6 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 50 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 49 .5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 71.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. Or, the pharmaceutical composition of the present invention contains about 34 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 72.4 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 27.1 wt% HPMCAS by weight dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 62 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition.

[00515] Another pharmaceutical composition in powder form in accordance with the present invention contains approximately 61.6 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19 .5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 34.4 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; approximately 1.0 wt.% magnesium stearate by weight of the composition. Or, the powder pharmaceutical composition of the present invention contains about 68.7 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 27.3 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; approximately 1.0 wt.% magnesium stearate by weight of the composition. Optionally, the above pharmaceutical compositions may also include approximately 0.4 wt.% colorant by weight of the composition.

[00516] In one aspect, the present invention provides a pharmaceutical composition containing from about 30 wt% to about 50 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight dispersions, about 19.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00517] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00518] In other further embodiments, the pharmaceutical composition contains 1-200 mini-tablets (eg, about 1-50 or about 25-35 mini-tablets). Each mini-tablet of the pharmaceutical composition contains from about 20 wt% to about 70 wt% solid dispersion by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight dispersions, from about 70 wt.% to about 14 wt.% HPMCAS by weight of the dispersion and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 10 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, a pharmaceutical composition, such as a mini-tablet or multiple mini-tablets, is filled into a capsule or pack, where the capsule or pack contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. the composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. the composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical the composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00519] In some embodiments, a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets is filled into capsules, vials or sachets. In other embodiments, the pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets may be in pouches, packs, sachets, vials or blister packs.

[00520] In some embodiments, the method comprises reducing the severity of cystic fibrosis in a patient by administering to said patient one of the compositions described herein. In some embodiments, the patient has mutant forms of human CFTR. In other embodiments, the patient has one or more of the following mutations: ΔF508, R117H, and G551D in human CFTR. In one embodiment, the method comprises reducing the severity of cystic fibrosis in a patient having the ΔF508 human CFTR mutation by administering to said patient one of the compositions described herein. In one embodiment, the method includes reducing the severity of cystic fibrosis in a patient having the G551D mutation of human CFTR by administering to said patient one of the compositions described in the present invention. In one embodiment, the method includes reducing the severity of cystic fibrosis in a patient having the R117H mutation of human CFTR by administering to said patient one of the compositions described in the present invention. In one embodiment, the method comprises reducing the severity of cystic fibrosis in a patient having the human CFTR ΔF508 mutation in at least one allele by administering to the patient one of the compositions described herein. In one embodiment, the method comprises reducing the severity of cystic fibrosis in a patient having the human CFTR ΔF508 mutation in both alleles by administering to said patient one of the compositions described herein. In one embodiment, the method includes reducing the severity of cystic fibrosis in a patient having the human CFTR G551D mutation in at least one allele by administering to the patient one of the compositions described in the present invention. In one embodiment, the method comprises reducing the severity of cystic fibrosis in a patient having the human CFTR G551D mutation in both alleles by administering to the patient one of the compositions described herein. In one embodiment, the method includes reducing the severity of cystic fibrosis in a patient having the human CFTR R117H mutation in at least one allele by administering to the patient one of the compositions described in the present invention. In one embodiment, the method comprises reducing the severity of cystic fibrosis in a patient having the human CFTR R117H mutation in both alleles by administering to the patient one of the compositions described herein. In another embodiment, the method comprises reducing the severity of cystic fibrosis in a patient having CFTR with residual function or a residual function phenotype by administering to said patient one of the pharmaceutical compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having a human CFTR gate mutation by administering to said patient one of the pharmaceutical compositions described herein. In some embodiments, the patient has one or more of the following human CFTR gate mutations: G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In some embodiments, the patient has at least one of the human CFTR gate mutations, including, but not limited to, G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having a human CFTR gate mutation in at least one allele by administering to the patient one of the pharmaceutical compositions described herein. In one embodiment, the method includes treating or reducing the severity of cystic fibrosis in a patient having a human CFTR gate mutation in both alleles by administering to the patient one of the pharmaceutical compositions described herein.

[00521] In some embodiments, the method includes reducing the severity of cystic fibrosis in a patient by administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00522] In some embodiments, said method comprises administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt.% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00523] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00524] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, is filled into a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00525] In some additional aspects, the pharmaceutical composition comprises a mini-tablet or a plurality of mini-tablets. In some embodiments, the method comprises reducing the severity of cystic fibrosis in a patient, comprising administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets ranging from 1 to 40 mini-tablets, for example, about 5, about 10, about 22 , approximately 24, approximately 26, approximately 28, approximately 29, approximately 30, approximately 31, approximately 33, approximately 35, approximately 37 or approximately 39 mini-tablets, where each of the mini-tablets in said composition contains approximately 46.9 wt. % solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt % substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt % HPMCAS by weight of the dispersion, and approximately 0.5 wt % SLS by weight of the dispersion ; approximately 45.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 3 wt.% croscarmellose sodium by weight of the composition; about 0.5 wt.% SLS by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00526] In some aspects, the pharmaceutical composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition of the present invention contains 12.5 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition of the present invention contains 12.5 mg of Compound 1. a dose containing a pharmaceutical composition of the present invention contains 15 mg of Compound 1. In some aspects, the pharmaceutical composition contains 20 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition contains 25 mg of Compound 1. In some aspects, the pharmaceutical composition contains 30 mg Compounds 1. In some aspects, the pharmaceutical composition contains 35 mg of Compound 1. In some aspects, the pharmaceutical composition contains 37.5 mg of Compound 1. In some aspects, the pharmaceutical composition contains 40 mg of Compound 1. In some aspects, the pharmaceutical composition contains 45 mg of Compound 1. B In some aspects, the unit dose containing the pharmaceutical composition contains 50 mg of Compound 1. In some aspects, the pharmaceutical composition contains 62.5 mg of Compound 1. In some aspects, the unit dose containing the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the unit dose contains 75 mg of Compound 1. containing the pharmaceutical composition contains 100 mg of Compound 1. In some aspects, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition contains 150 mg of substantially amorphous or amorphous Compound 1. In some aspects, the pharmaceutical composition contains 175 mg of Compound 1. In some aspects, the pharmaceutical composition contains 200 mg of Compound 1. In some aspects, the pharmaceutical composition contains 225 mg of Compound 1. In some aspects, the pharmaceutical composition contains 250 mg of Compound 1.

[00527] In some aspects, the present invention provides a method of treating or reducing the severity of osteoporosis in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00528] In some embodiments, said method of treating or reducing the severity of osteoporosis in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00529] In other embodiments, said method of treating or reducing the severity of osteoporosis in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00530] In some embodiments, said method of treating or reducing the severity of osteoporosis in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets as described herein.

[00531] In some embodiments, the method includes reducing the severity of osteoporosis in a patient by administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture of the present invention contains 12.5 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in powder mixture of the present invention, contains 15 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention, contains 20 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in powder mixture, contains 25 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 30 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 35 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 40 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 45 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 45 mg of Compound 1. In some aspects, In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 75 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition in the form of powder mixture contains 100 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00532] In specific embodiments, said method of treating or reducing the severity of osteoporosis in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20 wt.% to about 70 wt.% solid dispersions by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion, and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, such as a mini-tablet or plurality of mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, such as a mini-tablet or plurality of mini-tablets , is prepared in the form of a capsule or packet, wherein the capsule or packet contains 10 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, is prepared in the form of a capsule or packet, wherein the capsule or packet contains 12.5 mg of Compound 1. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or pack, where the capsule or pack contains 15 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition , contains 50 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition, contains 150 mg of Compound 1.

[00533] In other embodiments, said method of treating or reducing the severity of osteoporosis in a patient comprises administering to the patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt.% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00534] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00535] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, such as a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00536] In some aspects, the present invention provides a method of treating or reducing the severity of osteopenia in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00537] In some embodiments, said method of treating or reducing the severity of osteopenia in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00538] In other embodiments, said method of treating or reducing the severity of osteopenia in a patient comprises administering amorphous Compound 1 to said patient.

[00539] In some embodiments, said method of treating or reducing the severity of osteopenia in a patient comprises administering to said patient a pharmaceutical composition described herein.

[00540] In specific embodiments, the method comprises reducing the severity of osteopenia in a patient by administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical powder mixture composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 10 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 12.5 mg of Compound 1. In some aspects a unit dose containing a pharmaceutical composition in powder form of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in powder form of the present invention contains 20 mg of Compound 1. In some aspects, a unit dose containing pharmaceutical composition in the form of a powder mixture, contains 25 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 30 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of of the present invention, contains 35 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 40 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 45 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition as a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition as a powder mixture contains 75 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition as a powder mixture contains 75 mg of Compound 1. a unit dose containing the pharmaceutical composition as a powder mixture contains 100 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition as a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00541] In specific embodiments, said method of treating or reducing the severity of osteopenia in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20 wt.% to about 70 wt.% solid dispersions by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion, and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In some additional aspects, the pharmaceutical composition contains one or more mini-tablets.

[00542] In specific embodiments, said method of treating or reducing the severity of osteopenia in a patient involves administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt. % substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00543] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; about 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00544] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00545] In some aspects, the present invention relates to a method of bone healing and/or bone tissue repair in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00546] In some embodiments, a method of healing bone and/or repairing bone tissue in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00547] In other embodiments, a method of healing bone and/or repairing bone tissue in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00548] In some embodiments, a method of healing bone and/or repairing bone tissue in a patient comprises administering to said patient a pharmaceutical composition described herein.

[00549] In some embodiments, a method of healing bone and/or repairing bone tissue in a patient comprises administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion, and approximately 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical powder mixture composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical powder mixture composition of the present invention contains 12. 5 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 20 mg of Compound 1 In some aspects, a unit dose containing a pharmaceutical composition as a powder mixture contains 25 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition as a powder mixture of the present invention contains 30 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition as a powder mixture of the present invention contains 30 mg of Compound 1. containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 35 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 40 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 40 mg of Compound 1. powder mixture of the present invention contains 45 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition as a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition as a powder mixture contains 75 mg Compounds 1. In other embodiments, the unit dose containing the pharmaceutical composition as a powder mixture contains 100 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition as a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00550] In specific embodiments, a method of healing bone and/or repairing bone tissue in a patient involves administering to said patient a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein the composition contains from about 20 wt.% to about 70 wt. % solid dispersion by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1.

[00551] In specific embodiments, a method of bone healing and/or bone repair in a patient comprises administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00552] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00553] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, such as a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00554] In some aspects, the present invention provides a method of reducing bone resorption in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00555] In some embodiments, said method of reducing bone resorption in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00556] In other embodiments, said method of reducing bone resorption in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00557] In some embodiments, said method of reducing bone resorption in a patient comprises administering to said patient a pharmaceutical composition described herein.

[00558] In some embodiments, said method of reducing bone resorption in a patient comprises administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical powder mixture composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical powder mixture composition of the present invention contains 12. 5 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 20 mg of Compound 1 In some aspects, a unit dose containing a pharmaceutical composition as a powder mixture contains 25 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition as a powder mixture of the present invention contains 30 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition as a powder mixture of the present invention contains 30 mg of Compound 1. containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 35 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 40 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 40 mg of Compound 1. powder mixture of the present invention contains 45 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition as a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition as a powder mixture contains 75 mg Compounds 1. In other embodiments, the unit dose containing the pharmaceutical composition as a powder mixture contains 100 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition as a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00559] In specific embodiments, said method of reducing bone resorption in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20 wt.% to about 70 wt.% solid dispersion by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion, and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1.

[00560] In some embodiments, said method of reducing bone resorption in a patient comprises administering to said patient a pharmaceutical composition containing from about 30% by weight to about 50% by weight of a solid dispersion by weight of the composition, wherein said dispersion contains about 80% by weight substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00561] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00562] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00563] In some aspects, the present invention provides a method of increasing bone mass and volume in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00564] In some embodiments, said method of increasing bone mass and volume in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00565] In other embodiments, said method of increasing bone mass and volume in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00566] In some embodiments, said method of increasing bone mass and volume in a patient involves administering to said patient a pharmaceutical composition described herein.

[00567] In some embodiments, said method of increasing bone mass and volume in a patient comprises administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical powder mixture composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical powder mixture composition of the present invention contains 12. 5 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical powder mixture composition of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a powder mixture of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 25 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 30 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 35 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of powder mixture contains 40 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 45 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 75 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition in the form of a powder mixture contains 100 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition in the form of a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00568] In specific embodiments, said method of increasing bone mass and volume in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20% by weight to about 70% by weight. a solid dispersion by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion, and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1.

[00569] In some embodiments, said method of increasing bone mass and volume in a patient comprises administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt.% .% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00570] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00571] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00572] In some aspects, the present invention provides a method of treating or reducing the severity of COPD in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient. In some embodiments, said method of treating or reducing the severity of COPD in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00573] In other embodiments, said method of treating or reducing the severity of COPD in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00574] In some embodiments, said method of treating or reducing the severity of COPD in a patient comprises administering to said patient a pharmaceutical composition described herein.

[00575] In some embodiments, said method of treating or reducing the severity of COPD in a patient comprises administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; about 2 wt.% sucralose by weight of the composition; about 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical powder mixture composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical powder mixture composition of the present invention contains 12. 5 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical powder mixture composition of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a powder mixture of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 25 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 30 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 40 mg of Compound 1. In some aspects, a unit dose containing pharmaceutical composition in the form of a powder mixture, contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 75 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 100 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00576] In specific embodiments, said method of treating or reducing the severity of COPD in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20 wt.% to about 70 wt.% solid dispersions by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion, and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1.

[00577] In some embodiments, said method of treating or reducing the severity of COPD in a patient comprises administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt. % substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00578] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00579] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00580] In some aspects, the present invention provides a method of treating or reducing the severity of smoke-induced COPD in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00581] In some embodiments, said method of treating or reducing the severity of smoke-induced COPD in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00582] In other embodiments, said method of treating or reducing the severity of smoke-induced COPD in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00583] In some embodiments, said method of treating or reducing the severity of smoke-induced COPD in a patient comprises administering to said patient a pharmaceutical composition described herein.

[00584] In some embodiments, said method of treating or reducing the severity of smoke-induced COPD in a patient comprises administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion, and approximately 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical powder mixture composition contains 5 mg of Compound 1. In some aspects, the pharmaceutical powder mixture composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical powder mixture composition of the present invention contains 12. 5 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical powder mixture composition of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a powder mixture of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 25 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 30 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 35 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of powder mixture contains 40 mg of Compound 1. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 45 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 75 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition in the form of a powder mixture contains 100 mg of Compound 1. In other embodiments, the unit dose containing the pharmaceutical composition in the form of a powder mixture contains 150 mg of substantially amorphous or amorphous Compound 1.

[00585] In specific embodiments, said method of treating or reducing the severity of smoke-induced COPD in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20 wt.% to about 70 wt. wt% solid dispersion by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1.

[00586] In some embodiments, said method of treating or reducing the severity of smoke-induced COPD in a patient comprises administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00587] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00588] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00589] In some aspects, the present invention provides a method of treating or reducing the severity of chronic bronchitis in a patient, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to said patient.

[00590] In some embodiments, said method of treating or reducing the severity of chronic bronchitis in a patient comprises administering to said patient a substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00591] In other embodiments, said method of treating or reducing the severity of chronic bronchitis in a patient comprises administering to said patient an amorphous Compound 1 or a pharmaceutically acceptable salt thereof.

[00592] In some embodiments, said method of treating or reducing the severity of chronic bronchitis in a patient comprises administering to said patient a pharmaceutical composition described herein.

[00593] In some embodiments, said method of treating or reducing the severity of chronic bronchitis in a patient comprises administering to said patient a pharmaceutical composition comprising a powder mixture, wherein the powder mixture composition contains approximately 46.9 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by weight of the dispersion; approximately 49.1 wt.% mannitol by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.0 wt.% magnesium stearate by weight of the composition. In some aspects, the pharmaceutical composition in the form of a powder mixture contains 5 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 10 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture mixture of the present invention contains 12.5 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 15 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of of the present invention, contains 20 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition contains 25 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 30 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 35 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 40 mg of Compound 1. In some aspects, a unit dose containing a powdered pharmaceutical composition of the present invention contains 40 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture of the present invention contains 45 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture contains 50 mg of Compound 1. In some aspects, a unit dose containing a pharmaceutical composition in the form of a powder mixture contains 50 mg of Compound 1. in the form of a powder mixture, contains 75 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 100 mg of Compound 1. In other embodiments, a unit dose containing the pharmaceutical composition in the form of a powder mixture contains 150 mg essentially amorphous or amorphous Compound 1.

[00594] In specific embodiments, said method of treating or reducing the severity of chronic bronchitis in a patient comprises administering to said patient a pharmaceutical composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains from about 20% by weight to about 70% by weight. a solid dispersion by weight of the composition, wherein said dispersion contains from about 30 wt% to about 85 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, from about 70 wt% to about 14 wt% HPMCAS by weight of the dispersion, and from about 0.45 wt.% to about 0.55 wt.% SLS by weight of the dispersion; from about 22 wt.% to about 70 wt.% mannitol by weight of the composition; from about 0.1 wt.% to about 5 wt.% sucralose by weight of the composition; from about 1 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.01 wt.% to about 3 wt.% SLS by weight of the composition; from about 0.1 wt.% to about 3 wt.% colloidal silicon dioxide by weight of the composition; and from about 0.1 wt% to about 7 wt% magnesium stearate, by weight of the composition. In some aspects, the pharmaceutical composition, e.g., a mini-tablet or multiple mini-tablets, is provided in the form of a capsule or packet, where the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1.

[00595] In some embodiments, said method of treating or reducing the severity of chronic bronchitis in a patient comprises administering to said patient a pharmaceutical composition containing from about 30 wt.% to about 50 wt.% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt.% .% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt.% HPMCAS by weight of the dispersion, and about 0.5 wt.% SLS by weight of the dispersion; from about 30 wt.% to about 60 wt.% two-component filler, where the two-component filler contains from about 0 wt.% to about 60 wt.% mannitol by weight of the composition and from about 0 wt.% to about 60 wt.% lactose by weight weight of the composition; from about 1.5 wt.% to about 2.5 wt.% sucralose by weight of the composition; from about 4 wt.% to about 8 wt.% croscarmellose sodium by weight of the composition; from about 0.5 wt.% to about 1.5 wt.% colloidal silica, by weight of the composition; and from about 1 wt.% to about 2 wt.% magnesium stearate, by weight of the composition.

[00596] In one embodiment, the pharmaceutical composition contains approximately 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains approximately 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, approximately 19.5 wt% HPMCAS by weight of the dispersion and approximately 0.5 wt.% SLS by weight of the dispersion; approximately 13.5 wt.% mannitol by weight of the composition; approximately 41 wt.% lactose by weight of the composition; approximately 2 wt.% sucralose by weight of the composition; approximately 6 wt.% croscarmellose sodium by weight of the composition; approximately 1 wt.% colloidal silicon dioxide by weight of the composition; and approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00597] In some aspects, the pharmaceutical composition contains 10 mg of Compound 1. In some aspects, a unit dose containing the pharmaceutical composition of the present invention contains 5 mg of Compound 1. In some aspects, the pharmaceutical composition, for example, a mini-tablet or a plurality of mini-tablets, placed in a capsule or packet, wherein the capsule or packet contains 5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 10 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 12.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 15 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 20 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 25 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 30 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 35 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 37.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 40 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 45 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 50 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 62.5 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 75 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 100 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 125 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 150 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 175 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 200 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 225 mg of Compound 1. In other embodiments, the pharmaceutical composition contains 250 mg of Compound 1.

[00598] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing one or more mini-tablets, wherein said composition contains up to about 1 mg of a substantially amorphous or amorphous Compound 1.

[00599] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 5 mg of substantially amorphous or amorphous Compound 1.

[00600] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 10 mg of substantially amorphous or amorphous Compound 1.

[00601] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 12.5 mg of essentially amorphous or amorphous Compound 1.

[00602] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 15 mg of substantially amorphous or amorphous Compound 1.

[00603] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 20 mg of substantially amorphous or amorphous Compound 1.

[00604] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 25 mg of substantially amorphous or amorphous Compound 1.

[00605] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 30 mg of substantially amorphous or amorphous Compound 1.

[00606] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 35 mg of substantially amorphous or amorphous Compound 1.

[00607] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition comprising a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 37.5 mg of essentially amorphous or amorphous Compound 1.

[00608] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 40 mg of substantially amorphous or amorphous Compound 1.

[00609] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 45 mg of substantially amorphous or amorphous Compound 1.

[00610] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 50 mg of substantially amorphous or amorphous Compound 1.

[00611] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 62.5 mg of essentially amorphous or amorphous Compound 1.

[00612] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 75 mg of substantially amorphous or amorphous Compound 1.

[00613] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 100 mg of substantially amorphous or amorphous Compound 1.

[00614] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 125 mg of substantially amorphous or amorphous Compound 1.

[00615] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 150 mg of substantially amorphous or amorphous Compound 1.

[00616] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 175 mg of substantially amorphous or amorphous Compound 1.

[00617] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 200 mg of substantially amorphous or amorphous Compound 1.

[00618] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 225 mg of substantially amorphous or amorphous Compound 1.

[00619] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 250 mg of substantially amorphous or amorphous Compound 1.

[00620] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing one or more mini-tablets, wherein said composition contains up to about 1 mg of substantially amorphous or amorphous Compound 1.

[00621] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 5 mg of substantially amorphous or amorphous Compound 1.

[00622] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 10 mg of substantially amorphous or amorphous Compound 1.

[00623] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 12.5 mg of a substantially amorphous or amorphous Compound 1.

[00624] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 15 mg of substantially amorphous or amorphous Compound 1.

[00625] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 20 mg of substantially amorphous or amorphous Compound 1.

[00626] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 25 mg of substantially amorphous or amorphous Compound 1.

[00627] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 30 mg of substantially amorphous or amorphous Compound 1.

[00628] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 35 mg of substantially amorphous or amorphous Compound 1.

[00629] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 37.5 mg of a substantially amorphous or amorphous Compound 1.

[00630] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 40 mg of substantially amorphous or amorphous Compound 1.

[00631] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 45 mg of substantially amorphous or amorphous Compound 1.

[00632] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 50 mg of substantially amorphous or amorphous Compound 1.

[00633] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 62.5 mg of a substantially amorphous or amorphous Compound 1.

[00634] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 75 mg of substantially amorphous or amorphous Compound 1.

[00635] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 100 mg of substantially amorphous or amorphous Compound 1.

[00636] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 125 mg of substantially amorphous or amorphous Compound 1.

[00637] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 150 mg of substantially amorphous or amorphous Compound 1.

[00638] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 175 mg of substantially amorphous or amorphous Compound 1.

[00639] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 200 mg of substantially amorphous or amorphous Compound 1.

[00640] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 225 mg of substantially amorphous or amorphous Compound 1.

[00641] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient twice daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 250 mg of substantially amorphous or amorphous Compound 1.

[00642] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a composition containing a mini-tablet or a plurality of mini-tablets, wherein the composition contains up to about 1 mg of substantially amorphous or amorphous Compound 1.

[00643] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a composition containing a mini-tablet or a plurality of mini-tablets, wherein the composition contains up to about 5 mg of substantially amorphous or amorphous Compound 1.

[00644] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 10 mg of substantially amorphous or amorphous Compound 1 .

[00645] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 12.5 mg of a substantially amorphous or amorphous Connections 1.

[00646] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 15 mg of substantially amorphous or amorphous Compound 1 .

[00647] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 20 mg of substantially amorphous or amorphous Compound 1 .

[00648] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 25 mg of substantially amorphous or amorphous Compound 1 .

[00649] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 30 mg of substantially amorphous or amorphous Compound 1 .

[00650] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 35 mg of substantially amorphous or amorphous Compound 1 .

[00651] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 37.5 mg of a substantially amorphous or amorphous Connections 1.

[00652] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 40 mg of substantially amorphous or amorphous Compound 1 .

[00653] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 45 mg of substantially amorphous or amorphous Compound 1 .

[00654] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 50 mg of substantially amorphous or amorphous Compound 1 .

[00655] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 62.5 mg of a substantially amorphous or amorphous Connections 1.

[00656] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 75 mg of substantially amorphous or amorphous Compound 1 .

[00657] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 100 mg of substantially amorphous or amorphous Compound 1 .

[00658] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 125 mg of substantially amorphous or amorphous Compound 1 .

[00659] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 150 mg of substantially amorphous or amorphous Compound 1 .

[00660] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 175 mg of substantially amorphous or amorphous Compound 1 .

[00661] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 200 mg of substantially amorphous or amorphous Compound 1 .

[00662] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 225 mg of substantially amorphous or amorphous Compound 1 .

[00663] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains up to about 250 mg of substantially amorphous or amorphous Compound 1 .

[00664] In other aspects of the present invention, the pharmaceutical composition described herein is administered orally to a patient once every 24 hours.

[00665] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 10 mg of a substantially amorphous or amorphous Connections 1.

[00666] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 12.5 mg of a substantially amorphous or amorphous Compound 1.

[00667] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 15 mg of a substantially amorphous or amorphous Connections 1.

[00668] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 20 mg of a substantially amorphous or amorphous Connections 1.

[00669] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 25 mg of a substantially amorphous or amorphous Connections 1.

[00670] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 30 mg of a substantially amorphous or amorphous Connections 1.

[00671] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 35 mg of a substantially amorphous or amorphous Connections 1.

[00672] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 37.5 mg of a substantially amorphous or amorphous Compound 1.

[00673] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 40 mg of a substantially amorphous or amorphous Connections 1.

[00674] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 45 mg of a substantially amorphous or amorphous Connections 1.

[00675] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 50 mg of a substantially amorphous or amorphous Connections 1.

[00676] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 62.5 mg of a substantially amorphous or amorphous Compound 1.

[00677] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 75 mg of a substantially amorphous or amorphous Connections 1.

[00678] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 100 mg of a substantially amorphous or amorphous Connections 1.

[00679] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 125 mg of a substantially amorphous or amorphous Connections 1.

[00680] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 150 mg of a substantially amorphous or amorphous Connections 1.

[00681] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 175 mg of a substantially amorphous or amorphous Connections 1.

[00682] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 200 mg of a substantially amorphous or amorphous Connections 1.

[00683] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 225 mg of a substantially amorphous or amorphous Connections 1.

[00684] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient once daily said composition containing a mini-tablet or a plurality of mini-tablets, wherein said composition contains at least about 250 mg of a substantially amorphous or amorphous Connections 1.

[00685] Another aspect of the present invention relates to a method of administering a pharmaceutical composition comprising orally administering to a patient at least once daily at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets (in one example, ranging from about 2 to 20; about 2 to 6; about 5 to 15; about 20 to 50, about 25 to about 35, or about 27 to about 32 mini-tablets, such as 6, 10, 29 or 48 mini-tablets -tablets per capsule or pack, and in a particular example, 29 mini-tablets per capsule or pack; in another example, in the range from about 1 to about 20; in another example, 1 mini-tablet per capsule or pack, or 2, 3, 4, 5, 7, 8, 10, 15 or 20 tablets per capsule, pack or plurality of capsules or packs), and where each mini-tablet contains a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant , optionally a humectant, a glidant, and a lubricant, each of which is described above and in the examples below, wherein the solid dispersion contains up to about 5 mg (e.g., about 0.25 mg, about 0.5 mg, about 0.75 mg, approximately 1 mg, approximately 1.25 mg, approximately 1.5 mg, approximately 1.75 mg, approximately 2 mg, approximately 2.25 mg, approximately 2.5 mg, approximately 2.75 mg, approximately 3 mg, approximately 3 .25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg or about 4.75 mg) of substantially amorphous or amorphous Compound 1.

[00686] Another aspect of the present invention relates to a method of administering a pharmaceutical composition comprising orally administering to a patient at least once daily at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets (in one example, ranging from about 2 to 20, about 2 to 6, about 5 to 15, about 20 to 50, about 25 to about 35, or about 27 to about 32 mini-tablets, such as 6, 10, 29 or 48 mini-tablets tablets per capsule or pack, and in a particular example, 29 mini-tablets per capsule or pack; in another example, in the range of about 1 to about 20; in another example, 1 mini-tablet per capsule or pack, or 2, 3, 4, 5, 7, 8, 10, 15 or 20 mini-tablets per capsule, pack or plurality of capsules or packs), and where each mini-tablet contains a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1, one or more excipients, a sweetener , disintegrant, glidant, and lubricant, each of which is described above and in the examples below, wherein the solid dispersion contains up to about 5 mg (e.g., about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, approximately 1.25 mg, approximately 1.5 mg, approximately 1.75 mg, approximately 2 mg, approximately 2.25 mg, approximately 2.5 mg, approximately 2.75 mg, approximately 3 mg, approximately 3, 25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg or about 4.75 mg) of substantially amorphous or amorphous Compound 1.

[00687] Another aspect of the present invention relates to a method of administering a pharmaceutical composition comprising orally administering to a patient at least once daily a mini-tablet or a plurality of mini-tablets (e.g., in the range of from about 20 to 40, from about 25 to about 35 or from about 27 to about 32 mini-tablets per capsule or pack, for example, 21, 26, 39 and 52 mini-tablets), and wherein each mini-tablet contains a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, each of which is described above and in the examples below, and wherein said mini-tablet or plurality of mini-tablets collectively contain up to about 250 mg (e.g., about 5 mg, approximately 10 mg, approximately 12.5 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 37.5 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 62.5 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 87.5 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 110 mg, approximately 112.5 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 137.5 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 162.5 mg, approximately 170 mg, about 175 mg, about 187.5 mg, about 200 mg, about 212.5 mg, about 225 mg, about 237.5 mg, or about 250 mg) of substantially amorphous or amorphous Compound 1.

[00688] Another aspect of the present invention relates to a method of administering a pharmaceutical composition comprising orally administering to a patient at least once daily a mini-tablet or a plurality of mini-tablets (e.g., ranging from about 1 to about 140, about 20 to about 100, from about 20 to about 80, from about 20 to about 60, from about 20 to about 40, from about 25 to about 35, or from about 27 to about 32 mini-tablets per capsule or pack), and wherein each mini- The tablet contains a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, each of which is described above and in the examples below, and wherein said mini-tablet or plurality of mini-tablets tablets contains up to about 250 mg (for example, about 5 mg, about 10 mg, 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 37.5 mg, about 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 62.5 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 87.5 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg approximately 110 mg, approximately 112.5 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 137.5 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg , about 162.5 mg, about 170 mg, about 175 mg, about 187.5 mg, about 200 mg, about 212.5 mg, about 225 mg, about 237.5 mg or about 250 mg) essentially amorphous or amorphous Connections 1.

[00689] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient between two and five years of age. In another embodiment, the pediatric patient's body weight is less than 14 kilograms.

[00690] One aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the patient is a child aged two to five years and whose body weight is less than 14 kilograms.

[00691] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 75 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient between two and five years of age. In another embodiment, the pediatric patient's body weight is 14 kilograms or greater than 14 kilograms.

[00692] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 75 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the patient is a child between two and five years of age and whose body weight is 14 kilograms or more than 14 kilograms.

[00693] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is between approximately 7.5 kilograms and 14 kilograms.

[00694] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is between approximately 7.5 kilograms and 14 kilograms.

[00695] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is between about 5 kilograms and about 7.5 kilograms.

[00696] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is between approximately 5 kilograms and 7.5 kilograms.

[00697] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is less than 7.5 kilograms.

[00698] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is less than 7.5 kilograms.

[00699] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is 5 kilograms or greater than 5 kilograms.

[00700] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is 5 kilograms or more than 5 kilograms.

[00701] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is between approximately 2.5 kilograms and 5 kilograms.

[00702] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is between approximately 2.5 kilograms and 5 kilograms.

[00703] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is less than 5 kilograms.

[00704] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is less than 5 kilograms.

[00705] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms. In one embodiment, the patient is a pediatric patient less than 2 years of age. In another embodiment, the pediatric patient's body weight is 2.5 kilograms or greater than 2.5 kilograms.

[00706] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the pediatric patient is less than two years old and whose body weight is 2.5 kilograms or more than 2.5 kilograms.

[00707] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the patient is a pediatric patient between two and five years of age and who has a CFTR gate mutation in at least one allele. Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein said composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the patient is a pediatric patient less than two years of age and who has a CFTR gate mutation in at least one allele.

[00708] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 75 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the patient is a pediatric patient between two and five years of age and who has a CFTR gate mutation in at least one allele. Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein said composition contains 75 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; where the patient is a pediatric patient less than two years of age and who has a CFTR gate mutation in at least one allele.

[00709] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein the composition contains 75 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; wherein the pediatric patient weighs 14 kilograms or more and has a CFTR gate mutation in at least one allele. Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein said composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; wherein the pediatric patient weighs less than 14 kilograms and has a CFTR gate mutation in at least one allele. Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein said composition contains 50 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; wherein the pediatric patient weighs between approximately 7.5 kilograms and 14 kilograms and has a CFTR gate mutation in at least one allele. Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein said composition contains 35 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; wherein the pediatric patient weighs between approximately 5 kilograms and 7.5 kilograms and has a CFTR gate mutation in at least one allele. Another aspect of the present invention relates to a method of administering a pharmaceutical composition by oral administration to a pediatric patient every 12 hours, wherein said composition contains 25 mg of substantially amorphous or amorphous Compound 1; wherein said composition may be in the form of tablets, mini-tablets, granules, pellets, lozenges and other dosage forms; wherein the pediatric patient weighs between approximately 2.5 kilograms and 5 kilograms and has a CFTR gate mutation in at least one allele.

[00710] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains an amount of substantially amorphous Compound 1 or amorphous Compound 1 ranging from about 1 mg to about 250 mg.

[00711] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 15 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00712] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00713] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 10 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00714] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 12.5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00715] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 20 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00716] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 25 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00717] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 30 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00718] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 35 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00719] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 37.5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00720] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 40 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00721] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 45 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00722] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 50 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00723] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 62.5 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00724] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 75 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00725] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 100 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00726] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 125 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00727] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 150 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00728] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 175 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00729] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 200 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00730] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 225 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00731] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient a unit dosage form comprising a mini-tablet or a plurality of mini-tablets, wherein each of the mini-tablets contains:

a) a solid dispersion of substantially amorphous or amorphous Compound 1 and a polymer, said polymer containing HPMCAS;

b) one or more fillers;

c) sweetener;

d) baking powder;

e) optionally a humidifier;

f) glidant; And

g) lubricant,

wherein the unit dosage form contains approximately 250 mg of substantially amorphous Compound 1 or amorphous Compound 1.

[00732] In a further embodiment, the one or more fillers is a two-component filler containing a mixture of 2 fillers. In another additional embodiment, the two-component filler is a mixture of mannitol and another filler. In another further embodiment, the two-component filler is a mixture of lactose and another filler. In another further embodiment, the two-component filler is a mixture of mannitol and lactose.

[00733] In another further embodiment, the pharmaceutical composition contains a two-component excipient, where the two-component excipient contains mannitol in an amount of up to about 100 wt.% of the two-component excipient. In yet another further embodiment, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient contains lactose in an amount of up to about 100% by weight of the bicomponent excipient. In yet another further embodiment, the pharmaceutical composition contains a bicomponent excipient, wherein the bicomponent excipient contains mannitol in an amount of up to about 100 wt.% of the bicomponent excipient and lactose in an amount such that the sum of the amounts of mannitol and lactose is equal to 100 wt.%.

[00734] In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient comprises mannitol and another excipient in a ratio of about 3:1 mannitol to other excipient, in a ratio of about 1:1 mannitol to other excipient, or in a ratio of about 1:3 mannitol to another filler. In some embodiments, the pharmaceutical composition comprises a bicomponent excipient, wherein the bicomponent excipient comprises lactose and another excipient in a ratio of about 3:1 lactose to other excipient, about 1:1 lactose to other excipient, or about 1:3 lactose to other excipient. filler. In some embodiments, the pharmaceutical composition contains a bicomponent excipient, where the bicomponent excipient contains mannitol and lactose in a ratio of about 3:1 mannitol to lactose, in a ratio of about 1:1 mannitol to lactose, or in a ratio of about 1:3 mannitol to lactose.

[00735] In some embodiments, the present invention provides a method of orally administering a pharmaceutical composition described herein once daily. In other embodiments, the present invention relates to a method of orally administering a pharmaceutical composition described herein twice daily.

[00736] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a mini-tablet or a plurality of mini-tablets, a mini-tablet containing a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more fillers, sweetener, leavening agent, optional humectant, glidant; and a lubricant, wherein the capsule or packet contains at least about 15 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the composition is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant. and a lubricant, wherein the capsule or packet contains at least about 5 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing mini-tablets. a tablet of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 10 mg of a substantially amorphous or amorphous Compound 1. In another route, administration comprises orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 15 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 12.5 mg of the substantially amorphous or amorphous Compound 1. In another route, administration involves oral administering to a patient once daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein capsule or pack contains at least about 25 mg of substantially amorphous or amorphous Compound 1. In another route of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrating agent, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 30 mg of the substantially amorphous or amorphous Compound 1. In another route, administration involves oral administration twice to the patient per day of a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 37.5 mg of a substantially amorphous or amorphous Compound 1. In another route of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 40 mg of substantially amorphous or amorphous Compound 1. In another route of administration, the administration involves oral administration to a patient twice daily mini-tablets or multiple mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least at least about 50 mg of substantially amorphous or amorphous Compound 1. In another route of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrating agent, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 62.5 mg of substantially amorphous or amorphous Compound 1. In another method of administration involves oral administration to the patient twice daily for mini- tablet or multiple mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 75 mg of substantially amorphous or amorphous Compound 1. Another route of administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients , a sweetener, a disintegrating agent, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 100 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering a mini-tablet or plurality of mini-tablets to the patient twice daily. -tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 125 mg of substantially amorphous or amorphous Compound 1. In another method, administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant , optionally a humectant, glidant and lubricant, wherein the capsule or pack contains at least about 150 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering to the patient twice daily a mini-tablet or a plurality of mini-tablets, mini -tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 175 mg of the substantially amorphous or amorphous Compound 1. Another method of administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 200 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrating agent, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 225 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, mini-tablets containing a mini-tablet of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant. and a lubricant, wherein the capsule or pack contains at least about 250 mg of substantially amorphous or amorphous Compound 1.

[00737] Another method of administration involves orally administering to a patient once daily a mini-tablet or a plurality of mini-tablets, a mini-tablet containing a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant. , a glidant and a lubricant, wherein the capsule or packet contains at least about 50 mg of substantially amorphous or amorphous Compound 1. In another method of administration, the administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, a mini-tablet, containing a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule or packet contains at least about 50 mg of a substantially amorphous or amorphous Compound 1. Certain pharmaceutical The compositions used in this method contain a mini-tablet or a plurality of mini-tablets containing a solid dispersion containing at least about 75 mg of substantially amorphous or amorphous Compound 1. In another method of administration involves oral administration to the patient once daily of mini-tablets. tablets or multiple mini-tablets, these mini-tablets contain a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the capsule or packet contains at least about 75 mg of substantially amorphous or amorphous Compound 1. In another method of administration involves orally administering to a patient twice daily a mini-tablet or a plurality of mini-tablets, said mini-tablets containing a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, glidant and lubricant, wherein the capsule or pack contains at least about 75 mg of substantially amorphous or amorphous Compound 1.

[00738] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 10 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 10 mg of substantially amorphous or amorphous Compound 1.

[00739] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 12.5 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 12.5 mg of substantially amorphous or amorphous Compound 1.

[00740] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 15 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 15 mg of substantially amorphous or amorphous Compound 1.

[00741] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 20 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 20 mg of substantially amorphous or amorphous Compound 1.

[00742] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 25 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 25 mg of substantially amorphous or amorphous Compound 1.

[00743] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 30 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 30 mg of substantially amorphous or amorphous Compound 1.

[00744] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 35 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 35 mg of substantially amorphous or amorphous Compound 1.

[00745] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 37.5 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 37.5 mg of substantially amorphous or amorphous Compound 1.

[00746] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 40 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 40 mg of substantially amorphous or amorphous Compound 1.

[00747] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 45 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 45 mg of substantially amorphous or amorphous Compound 1.

[00748] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 50 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 50 mg of substantially amorphous or amorphous Compound 1.

[00749] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 62.5 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 62.5 mg of substantially amorphous or amorphous Compound 1.

[00750] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 75 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 75 mg of substantially amorphous or amorphous Compound 1.

[00751] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 100 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 100 mg of substantially amorphous or amorphous Compound 1.

[00752] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant, and a lubricant, wherein the solid dispersion contains at least about 125 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 125 mg of substantially amorphous or amorphous Compound 1.

[00753] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 150 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 150 mg of substantially amorphous or amorphous Compound 1.

[00754] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant, and a lubricant, wherein the solid dispersion contains at least about 175 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 175 mg of substantially amorphous or amorphous Compound 1.

[00755] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 200 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 200 mg of substantially amorphous or amorphous Compound 1.

[00756] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 225 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 225 mg of substantially amorphous or amorphous Compound 1.

[00757] Another aspect of the present invention relates to a method of administering a pharmaceutical composition by orally administering to a patient at least once daily a solid dispersion of a substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least about 250 mg of substantially amorphous or amorphous Compound 1. In some embodiments, the solid dispersion is administered orally to a patient once daily. In another method of administration, the administration involves orally administering to a patient twice daily a solid dispersion, wherein the solid dispersion comprises a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, wherein the solid dispersion contains at least approximately 250 mg of substantially amorphous or amorphous Compound 1.

[00758] In one embodiment, a method of administering a pharmaceutical composition comprising orally administering to a patient at least once daily at least one capsule or the contents of a packet or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet including a pharmaceutical a composition containing a solid dispersion of amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, each of which is described above and in the examples below, wherein said capsule, pouch or packet containing said mini- tablet or multiple mini-tablets, contains at least 5 mg (for example, at least 10 mg, at least 12.5 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least at least 30 mg, at least 35 mg, at least 37.5 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least at least 62.5 mg, at least 65 mg, at least 70, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg or at least 250 mg) of essentially amorphous or amorphous Compound 1.

[00759] In one embodiment, a method of administering a pharmaceutical composition comprises orally administering to a patient, at least once daily, at least one capsule or the contents of a packet or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet comprising a pharmaceutical composition containing a solid dispersion of substantially amorphous or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein said capsule, pouch or pack containing said mini-tablet or plurality of mini-tablets contains from about 10 mg to about 300 mg (for example, from about 15 mg to about 280 mg, or from about 25 mg to about 260 mg, or from about 30 mg to about 200 mg, or from about 10 mg to about 150 mg, or about 10 mg to about 100 mg, or about 15 mg to about 75 mg) of substantially amorphous or amorphous Compound 1. Or, a method of administering the pharmaceutical composition comprises orally administering to a patient at least once daily at least one capsule or the contents of a packet or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition containing a solid dispersion of amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein specified capsule, packet or pack contains from about 10 mg to about 300 mg (for example, from about 15 mg to about 280 mg, or from about 25 mg to about 260 mg, or from about 30 mg to about 200 mg, or from about 10 mg to about 150 mg, or about 10 mg to about 100 mg, or about 15 mg to about 75 mg) of amorphous Compound 1.

[00760] In another embodiment, a method of administering a pharmaceutical composition comprises orally administering to a patient, once daily, at least one capsule or the contents of a packet or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition comprising a solid dispersion of Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, each of which is described above and in the examples below, wherein said capsule, packet or packet containing said mini-tablet or plurality of mini-tablets -tablets, contains at least 5 mg (for example, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 37.5 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 62.5 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least about 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, or at least about 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1. For example, a method of administering a pharmaceutical composition includes orally administering to a patient once daily at least one capsule or the contents of a packet or pack containing a pharmaceutical composition containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a solid dispersion of Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein said capsule, packet or packet containing said mini-tablet or plurality of mini-tablets -tablets, contains at least 75 mg (for example, at least 100 mg, at least 125 mg, at least 140 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least at least 225 mg, or at least 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1. In another example, a method of administering a pharmaceutical composition includes orally administering to a patient once daily a mini-tablet or a plurality of capsules or packets (e.g., two capsules, three capsules, four or five capsules), wherein each capsule or pack contains a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition containing a solid dispersion of a substantially amorphous Compound 1 or amorphous Compound 1, one or more excipients, a sweetener, a disintegrating agent, optionally a humectant, a glidant and a lubricant, wherein the capsule or pack containing said mini-tablet or plurality of mini-tablets contains at least 5 mg (e.g., at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 37.5 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 62.5 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least about 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, or at least about 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1.

[00761] In another embodiment, a method of administering a pharmaceutical composition comprises orally administering to a patient twice daily at least one capsule or the contents of a packet or pack containing a mini-tablet or a plurality of mini-tablets, wherein each mini-tablet contains a pharmaceutical composition comprising a solid dispersion of Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, each of which is described above and in the examples below, and wherein said capsule, packet or packet containing said mini-tablet or plurality of mini-tablets -tablets, contains at least 5 mg (for example, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 37.5 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 62.5 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least about 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, or at least about 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1. For example, a method of administering a pharmaceutical composition includes orally administering to a patient twice daily one capsule or the contents of a packet or pack containing a mini-tablet or a plurality of mini-tablets, each mini -tablet contains a pharmaceutical composition containing a solid dispersion of Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, where the capsule, packet or pack contains at least 75 mg (for example, at least 100 mg, at least at least 125 mg, at least 140 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, or at least 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1 In another example, a method of administering a pharmaceutical composition comprises orally administering to a patient twice daily a mini-tablet or a plurality of capsules (eg, two capsules, three capsules, four or five capsules) or the contents of a packet or packet, wherein each capsule, packet or packet contains a mini-tablet. - a tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition containing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, and wherein said capsule, pack or packet contains at least 5 mg (for example, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 37.5 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 62.5 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least about 150 mg, at least 175 mg, at least 200 mg, at least 225 mg , or at least about 250 mg) of essentially amorphous Compound 1 or amorphous Compound 1.

[00762] It is noted that the methods of administration of the present invention may optionally include oral administration of a beverage (milk (including breast milk), infant formula or formula, or the like), soft food (including applesauce, plain yogurt additives, ice cream, baby food product (including carrots and carrot puree) or the like), and/or additional pharmaceutical compositions, including additional APIs. In some embodiments, the liquid may also include water. In cases where the route of administration involves the oral administration of a beverage (water, milk (including breast milk), infant formula or formula, or the like), soft food or foodstuff (including a standard high-calorie CF meal or snack high fat content), and/or additional pharmaceutical compositions, including additional APIs, oral administration of the beverage, food, and/or additional APIs may occur concurrently with oral administration of the mini-tablets or multiple mini-tablets, prior to oral administration of the mini-tablets, or a plurality of mini-tablets and/or after administration of the mini-tablets or a plurality of mini-tablets. In one embodiment, the unit dosage form is sprayed into soft foods, including, but not limited to, applesauce, plain yogurt, ice cream, baby food (including carrots and carrot puree), and administered. In another embodiment, the unit dosage form is injected into soft foods, including, but not limited to, applesauce, plain yogurt, ice cream, baby food (including carrots and carrot puree), mixed and administered. In one embodiment, the unit dosage form is injected into a liquid, including, but not limited to, formula, formula, milk or breast milk, mixed and administered. In another embodiment, the unit dosage form is injected into a liquid, including, but not limited to, formula, formula, milk, or breast milk, and administered. The methods of administration of the present invention may also optionally include, for mini-tablets or reduced-size granules, administration of the contents of packets, pouches, capsules, bottles or sachets directly into the oral cavity, followed by the introduction of breast milk or formula. The methods of administration of the present invention may also optionally include, for mini-tablets or reduced-size granules, administration of the contents of packets, pouches, capsules, bottles or sachets directly into the oral cavity followed by administration of a liquid or drink. It is also noted that all modes of administration in accordance with the present invention may optionally involve oral administration simultaneously with, before or after the administration of a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. In some embodiments, all modes of administration in accordance with the present invention may optionally include oral administration with a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. In one example, a method of administering a pharmaceutical composition includes orally administering to a patient, at least once daily, at least one capsule or one pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, and a second API. In another example, a method of administering a pharmaceutical composition includes orally administering to a patient, at least once daily, at least one capsule or the contents of a pack or packet containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a solid dispersion of a substantially amorphous Compound 1 or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule, packet or packet contains at least 5 mg (e.g., at least 10 mg, at least 15 mg , at least 20 mg, at least 25 mg, at least 30 mg, at least 37.5 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg , at least 55 mg, at least 60 mg, at least 62.5 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 100 mg, at least 125 mg , at least about 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, or at least about 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1, and orally administering to the patient at least at least once daily of a second pharmaceutical composition containing a second API. In other examples, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition described in the present invention, wherein said mini-tablet or a plurality of mini-tablets are mixed with a food or beverage for consumption by a patient who has difficulty swallowing an adult tablet, such as a pediatric patient, including, but not limited to, patients under six years of age, patients 2 to 5 years of age, patients younger than 2 years, patients from zero (i.e. from birth) to 2 years of age, patients who are from 1 to 2 years, who are from 9 months to 2 years, who are from 6 months to 2 years, who are from 3 months to 2 years old and those between 2 months and 2 years old. In some embodiments, birth means birth after a normal gestational age. In other examples, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition described in the present invention, wherein said mini-tablet or a plurality of mini-tablets are mixed with a food or beverage for consumption by a patient who has difficulty swallowing an adult tablet, such as a pediatric patient, including, but not limited to, a body weight greater than or equal to approximately 14 kilograms, less than 14 kilograms , approximately 7.5 kilograms to 14 kilograms, approximately 5 kilograms to 7.5 kilograms, and approximately 2.5 kilograms to 5 kilograms.

[00763] It is also noted that the methods of administration of the present invention may optionally involve oral administration of a pharmaceutical composition described herein in the absence of a food or beverage. In the present method, oral administration is performed immediately after or shortly after (eg, within 30 minutes) the patient has consumed food or drinks. In another embodiment, oral administration occurs after at least 1 hour (e.g., at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 8 hours, at least 12 hours or at least 24 hours) after eating or drinking. For example, in one example, a method of administering a pharmaceutical composition includes orally administering to a patient, at least once daily, at least one capsule or the contents of a pack or packet containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, and a second API. In another example, a method of administering a pharmaceutical composition includes orally administering to a patient, at least once daily, at least one capsule of the contents of a pack or bag containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a solid dispersion of substantially amorphous Compound 1 or amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, optionally a humectant, a glidant and a lubricant, wherein the capsule, packet or packet contains at least 5 mg (for example, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 37.5 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 62.5 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least about 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, or at least about 250 mg) of substantially amorphous Compound 1 or amorphous Compound 1, and orally administering to the patient at least one once daily of a second pharmaceutical composition containing a second API. In other examples, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition described in the present invention, wherein said mini-tablet or a plurality of mini-tablets are administered to a patient who has difficulty swallowing an adult tablet, such as a pediatric patient, including, but not limited to, patients under six years of age, those between 2 and 5 years of age, those under 2 years of age, those from zero (i.e., from birth) to 2 years, from 1 to 2 years, from 9 months to 2 years, from 6 months to 2 years, from 3 months to 2 years and from 2 months up to 2 years. In some embodiments, birth means birth after a normal gestational age. In other examples, a method of administering a pharmaceutical composition includes orally administering to a patient every 12 hours at least one capsule or pack containing a mini-tablet or a plurality of mini-tablets, each mini-tablet containing a pharmaceutical composition described in the present invention, wherein said mini-tablet or a plurality of mini-tablets are mixed with a food or beverage for consumption by a patient who has difficulty swallowing an adult tablet, such as a pediatric patient, including, but not limited to, a body weight greater than or equal to approximately 14 kilograms, less than 14 kilograms , from about 7.5 kilograms to 14 kilograms, from about 5 kilograms to 7.5 kilograms, and from about 2.5 kilograms to 5 kilograms. It will also be understood that the compound and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, that is, the compound and pharmaceutically acceptable compositions can be administered simultaneously, before or sequentially with one or more other desired drugs or medical procedures. The specific combination of treatments (drugs or procedures) to be used in a combination regimen will take into account the compatibility of the desired drugs and/or procedures and the desired therapeutic effect to be achieved. It will also be understood that the drugs used may achieve the desired effect for the same disorders (eg, a compound of the present invention may be taken concomitantly with another drug used to treat the same disorder), or they may achieve different effects (eg, control any of the side effects). In the context of the present invention, additional therapeutic agents that are typically administered for the treatment or prevention of a particular disease or condition are known as “suitable for the disease or condition being treated.”

[00764] In one embodiment, the additional agent is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1 of the present invention, or a nutrient.

[00765] In some embodiments in which cystic fibrosis is treated, prevented, and/or monitored, a compound or composition of the present invention can be combined with, for example, 552-02, 5-methyltetrahydrofolate and vitamin B12, Ad5-CB-CFTR , adeno-associated virus-CFTR vector, albuterol, alendronate, alpha tocopherol plus ascorbic acid, amiloride HCl, aquADEK™, ataluren (PTC124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin (clarithromycin), BIIL 283 BS (amelubent ), buprofen, calcium carbonate, ceftazidime, cholecalciferol, choline supplement, CPX, cystic fibrosis transmembrane conductance regulator, DHA enriched supplement, digitoxin, docosahexaenoic acid (DHA), doxycycline, ECGC, recombinant human IGF-1, sodium reduced glutathione, ergocalciferol (vitamin D2), fluorometholone, gadobutrol (GADOVIST®, BAY86-4875), gentamicin, ghrelin, glargine, glutamine, growth hormone, GS-9411, H5.001CBCFTR, recombinant human growth hormone, hydroxychloroquine, hyperbaric oxygen, hypertonic saline, proanthocyanidin extract grape seed IH636, insulin, interferon gamma-1b, IoGen (molecular iodine), losartan potassium, isotonic saline, itrconazole, gallium nitrate IV (GANITE.RTM.) for infusion, ketorolac acetate, lansoprazole, L-arginine, linezolid, lubiprostone , meropenem, miglustat, MP-376 (levofloxacin inhalation solution), normal saline for intravenous administration, Nutropin AQ, omega-3 triglycerides, pGM169/GL67A, pGT-1 gene lipid complex, pioglitazone, PTC124, QAU145, salmeterol, SB656933 , SB656933, simvastatin, sitaglipin, sodium 4-phenylbutyrate, goldenseal standardized extract, tgAAVCF, TNF blocker, TOBI, tobramycin, tocotrienol, unconjugated isoflavones 100, vitamins: choline bitartrate (2-hydroxyethyl) trimethylammonium salt 1:1, acetate zinc, or combinations thereof.

[00766] In one embodiment, the present invention provides a kit containing a tablet of the present invention and a single therapeutic agent or pharmaceutical composition thereof. In one embodiment, the additional therapeutic agent is a CFTR regulator. In another embodiment, the therapeutic agent is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid or (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide In another embodiment, the therapeutic agent is (3-(6-(1-(2,2-difluorobenzo[d][1, 3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid In another embodiment, the therapeutic agent is (R)-1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. In another embodiment, the tablet and the therapeutic agent are in separate containers. In another embodiment, the separate containers are vials. In another embodiment, the separate containers are vials. In another embodiment, the individual containers are blister packs.

[00767] In one embodiment, the additional agent is an antibiotic. Exemplary antibiotics used in the present invention include tobramycin, including tobramycin inhalation powder (TIP), azithromycin, aztreonam, including aerosol form of aztreonam, amikacin, including liposome formulations thereof, ciprofloxacin, including its formulations suitable for administration by inhalation, levofloxacin, including its aerosol formulations, and combinations of two antibiotics, for example fosfomycin and tobramycin.

[00768] In another embodiment, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful in the present invention include Pulmozyme®.

[00769] In another embodiment, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol and terbutaline sulfate.

[00770] In another embodiment, the additional agent is effective for restoring surface fluid of the pulmonary airways. Such agents promote the movement of salt in and out of cells, thereby helping to hydrate mucus where it accumulates in the pulmonary airways and, therefore, helping to clear them. Typical agents above include hypertonic saline, denofozol tetrasodium ([[(3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl][[[ (2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]hydrogen phosphate), or bronchitol (inhalation drug mannitol).

[00771] In another embodiment, the additional agent is an anti-inflammatory agent, i.e. a drug that can reduce inflammation in the lungs. Typical agents used herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simvastatin.

[00772] In another embodiment, the additional agent is a CFTR modulator other than Compound 1, that is, an agent that has CFTR activity modulator properties. Exemplary agents listed above include ataluren ("PTC124®"; 3-[5-(2-fluorophenyl)-1,2,4-oxadicazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (recombinant neutrophil elastase inhibitor human), cobiprostone (7-{(2R, 4aR, 5R, 7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxooctahydrocyclopeta[b]pyran-5- yl}heptanoic acid) or (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)benzoic acid In another embodiment, the additional agent is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropacarboxamido)-3-methylpyridin-2-yl)benzoic acid.

[00773] In another embodiment, the additional agent is a nutrient. Examples of such agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase® or Creon®, Liprotamase® (formerly Trizytek®), Aquadeks®, or inhaled glutathione. In one embodiment, the additional nutrient is pancrelipase.

V. EXAMPLES

[00774] For a more complete understanding of the invention presented in this description, the following examples are provided. It should be understood that these examples are presented for purposes of illustration only and should not be construed as limiting the present invention in any way.

[00775] A. Capsule production

[00776] Example 1: Preparation of Intermediate 1 Containing Substantially Amorphous or Amorphous Compound 1

[00777] The synthesis of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is described in United States Patent Application Publication US 2006/0074075 ( currently US Pat. No. 7,495,103), US 2011/0064811, US 2010/0267768 and US 2011/0230519, the contents of which are hereby incorporated by reference in their entirety. A solvent system of MEK and DI [deionized] water obtained at a ratio of 90% wt. MEK/10% wt. DI water was heated to a temperature of 20-30°C in a reactor equipped with a magnetic stirrer and a thermal circuit. To this solvent system were added the polymer hypromellose acetate succinate (HPMCAS) (high purity), SLS and N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline- 3-carboxamide in accordance with the ratio of 19.5 wt.% hypromelose acetate succinate/0.5 wt.% SLS/80 wt.% N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]- 1,4-dihydro-4-oxoquinoline-3-carboxamide. The resulting mixture contained 10.5 wt.% solids. The actual quantities of ingredients and solvents used to prepare this mixture are listed in Table 1a below:

[00778] Table 1a
Solid spray dispersion ingredients for intermediate 1 Units The consignment N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide kg 70.0 HPMCAS kg 17.1 SLS kg 0.438 Total solids kg 87.5 MEK kg 671 Water kg 74.6 Total solvents kg 746 Total mass of sprayed solution kg 833

[00779] The temperature of the mixture is set in the range of 20-45°C and stirred until the mixture is substantially homogeneous and all components are substantially dissolved.

[00780] A spray dryer, Niro PSD4 Commercial Spray Dryer, equipped with a high pressure nozzle (Spray Systems Maximum Passage series SK-MFP, having a nozzle/core size of 54/21) equipped with a cap to level the spray jet, is used in a conventional spray drying mode, following the parameters of the spray drying method presented in Table 1b below.

[00781] Table 1b
Spray drying process parameters used to prepare Intermediate 1. Parameter Meaning Supply pressure 20 bar Flow rate 92-100 kg/h Inlet temperature 93-99°C Outlet temperature 53-57°C Vacuum dryer temperature 80°C for 2 hours,
then 110°C (±5°C) Vacuum drying time 20-24 hours

[00782] The cyclone separated the wet product from the atomizing gas and solvent vapors with high efficiency. The wet product contained 8.5-9.7% MEK and 0.56-0.83% water and had an average particle size of 17-19 microns and a bulk density of 0.27-0.33 g/cm ³ . The wet product was transferred to a 4000 L stainless steel double cone vacuum dryer for further drying to reduce residual solvents to less than approximately 5000 ppm and produce dry Intermediate 1. Dry Intermediate 1 contained <0.03% MEK and 0.3% water.

[00783] Notwithstanding the above description of preparing Intermediate 1, in part, by mixing the ingredients of a sprayable solids dispersion using heat to form a homogeneous mixture, the ingredients of the sprayable solids dispersion can also be mixed without the use of heat to produce a mixture of sprayable solids dispersion ingredients substances.

[00784] Example 2: Preparation of a powder mixture containing about 75 mg of substantially amorphous or amorphous Compound 1 encapsulated in exemplary capsule 1

[00785] Prepare a batch of powdered encapsulation mixture containing approximately 75 mg of Compound 1 per capsule using the amounts of ingredients presented in Table 2.

[00786] Table 2
Ingredients for exemplary capsule 1 containing powder mixture. Compound Relative dose Dose The consignment wt.%/mass. (mg) (G) Intermediate 1 46.9% 95.2 952 Mannitol 49.1% 99.7 997 Sucralose 2.0% 4.1 41 Colloidal silicon dioxide 1.0% 2.0 20 Magnesium stearate 1.0% 2.0 thirty Total 100% 203 2030

[00787] Intermediate 1, mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), sucralose (Splenda®, commercially available from Tate and Lyle of Decatur, IL), colloidal silica (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) and magnesium stearate (Fisher Scientific or as Hyqual®, commercially available from Mallinckrodt Chemicals) are sieved through 20 and 60 mesh screens to removing lumps.

[00788] Intermediate 1, colloidal silica and sucralose are mixed together for 25 minutes and sifted through a 20 mesh sieve to remove any lumps. The magnesium stearate is sifted through a 60 mesh sieve to remove lumps. The mixture of intermediate 1 is added to 20% of the total magnesium stearate and combined in an 8 quart V-blender and mixed for 25 minutes at 20-24 rpm, thereby obtaining the first blended mixture. The mannitol is sifted through a 20 mesh sieve to remove lumps. Mannitol is then added to the first mixed mixture and mixed for an additional 25 minutes at 20-24 rpm to obtain a second mixed mixture. The second blended mixture is further pressed through a 024R sieve using Comil, and then the remaining 80% of the total magnesium stearate is added to the screened second blended mixture to obtain a powder mixture. One unit dose equivalent of a powder mixture (203 mg total) containing approximately 75 mg of substantially amorphous or amorphous Compound 1 is then encapsulated using an IN-CAP® automatic tabletop capsule filling machine using hard gelatin or HPMC capsules.

[00789] Example 3: Preparation of a powder mixture containing about 75 mg of substantially amorphous or amorphous Compound 1 encapsulated in exemplary capsule 2

[00790] A batch of powdered encapsulation mixture containing approximately 75 mg of Compound 1 per capsule was prepared using the amounts of ingredients presented in Table 3.

[00791] Table 3
Ingredients for Example Capsule 2,
containing a powder mixture. Compound Relative dose Dose The consignment wt.%/mass. (mg) (G) Intermediate 1 46.9% 93.8 469.07 Mannitol 49.1% 98.2 491.17 Sucralose 2.0% 4.0 20.01 Colloidal silicon dioxide 1.0% 2.0 10.02 Magnesium stearate 1.0% 2.0 10.03 Total 100% 200 1000.3

[00792] Intermediate 1 and sucralose (commercially available from Tate and Lyle of Decatur, IL) were screened together through a 20 mesh (850 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) together sifted through a 20 mesh (850 micrometer) sieve. Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve to remove lumps.

[00793] Intermediate 1 and sucralose (sifted together) and mannitol and colloidal silica (sifted together) were mixed together for 6.5 minutes at 20-27 rpm in a 4-quart V-mixer. Magnesium stearate (pre-sieved) was added to this mixture in a 4-quart V-mixer and mixed for 4 minutes at 20-27 rpm. One unit dose equivalent of the powder mixture (200 mg total, containing approximately 75 mg of substantially amorphous or amorphous Compound 1) was then encapsulated using an IN-CAP® automatic tabletop capsule filling machine. using hard gelatin or HPMC capsules.

[00794] Example 4: Preparation of a powder mixture containing about 75 mg of substantially amorphous or amorphous Compound 1 encapsulated in exemplary capsule 3

[00795] A batch of powdered encapsulation mixture containing approximately 75 mg of Compound 1 per capsule was prepared using the amounts of ingredients presented in Table 4.

[00796] Table 4
Ingredients for Example Capsule 3,
containing a powder mixture. Compound Relative dose Dose The consignment wt.%/mass. (mg) (G) Intermediate 1 46.875% 93.75 234.4 Mannitol 49.375% 98.75 246.8 Sucralose 2.0% 4.0 10 Colloidal silicon dioxide 0.875% 1.75 4.4 Magnesium stearate 0.875% 1.75 4.4 Total 100% 200 500

[00797] Intermediate 1 and sucralose (commercially available from Tate and Lyle of Decatur, IL) were screened together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) together sifted through a 30 mesh (600 micrometer) sieve. Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve to remove lumps.

[00798] Intermediate 1 and sucralose (sifted together), mannitol, and colloidal silica (sifted together) were mixed together for 7 minutes at 20-27 rpm in a 2 quart V-mixer. This mixture was passed through a 024R (610 micrometer) sieve at 5000 rpm using Quadro Comil U5. Magnesium stearate (pre-sifted) is added to this mixture in a 2-quart V-mixer and mixed for 5.5 minutes at 20-27 rpm. One unit dose equivalent of the powder mixture (200 mg total, containing approximately 75 mg of substantially amorphous or amorphous Compound 1) was then encapsulated using an IN-CAP® automatic tabletop capsule filling machine using HPMC capsules.

[00799] Example 5: Preparation of a powder mixture containing approximately 15 mg of substantially amorphous or amorphous Compound 1 encapsulated in exemplary capsule 4

[00800] A batch of powdered encapsulation mixture containing approximately 15 mg of Compound 1 per capsule was prepared using the amounts of ingredients presented in Table 5.

[00801] Table 5
Ingredients for Exemplary Capsule 4 Containing Powder Blend Compound Relative dose wt.%/wt. Dose (mg) Batch (g) Intermediate 1 15.63 18.8 94.05 Mannitol 80.37 96.4 483.16 Sucralose 2 2.4 12.17 Colloidal silicon dioxide 1 1.2 6.35 Magnesium stearate 1 1.2 6.14 Total 100 120 601.87

[00802] Intermediate 1 and Sucralose (commercially available from Tate and Lyle of Decatur, IL) were screened together through a 20 mesh (850 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) together sifted through a 20 mesh (850 micrometer) sieve. Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve to remove lumps.

[00803] Intermediate 1 and sucralose (sifted together) and mannitol and colloidal silica (sifted together) were mixed together for 6 minutes at 20-27 rpm in a 4-quart V-mixer. Magnesium stearate (pre-sieved) was added to this mixture in a 4-quart V-mixer and mixed for 4 minutes at 20-27 rpm. One unit dose equivalent of the powder mixture (120 mg total, containing approximately 15 mg of substantially amorphous or amorphous Compound 1) was then encapsulated using an IN-CAP® automatic tabletop capsule filling machine using hard gelatin or HPMC capsules.

[00804] Example 6: Preparation of a powder mixture containing approximately 50 mg of substantially amorphous or amorphous Compound 1 encapsulated in exemplary capsule 5.

[00805] A batch of powdered encapsulation mixture containing approximately 50 mg of Compound 1 per capsule was prepared using the amounts of ingredients presented in Table 6.

[00806] Table 6
Ingredients for Exemplary Capsule 5 Containing Powder Blend Compound Relative dose wt.%/wt. Dose (mg) Batch (g) Intermediate 1 36.76 62.7 367.6 Mannitol 59.28 100.8 592.8 Sucralose 1.96 3.3 19.6 Colloidal silicon dioxide 1 1.7 10 Magnesium stearate 1 1.7 10 Total 100 170 1000

[00807] Intermediate 1 and sucralose (commercially available from Tate and Lyle of Decatur, IL) were screened together through a 20 mesh (850 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) together sifted through a 30 mesh (600 micrometer) sieve. Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve to remove lumps.

[00808] Intermediate 1 and sucralose (sifted together) and mannitol and colloidal silica (sifted together) were mixed together for 6 minutes at 20-27 rpm in a 4-quart V-mixer. This mixture was passed through a 018R sieve at 5000 rpm using Quadro Comil U5. Magnesium stearate (pre-sieved) was added to this mixture in a 4 Q V-mixer and mixed for 4 minutes at 20-27 rpm. One unit dose equivalent of the powder mixture (170 mg total, containing approximately 50 mg of substantially amorphous or amorphous Compound 1) was then encapsulated using an IN-CAP automatic tabletop capsule filling machine using hard gelatin or HPMC capsules.

[00809] B. Preparation of mini-tablets and capsules containing mini-tablets

[00810] Example 7: Exemplary mini-tablet 1 in exemplary capsule 6 (capsule formulated to contain approximately 75 mg of Compound 1)

[00811] A batch of 2 mm diameter, 2 mm long cylindrical mini-tablets (each mini-tablet weighing approximately 7.0 mg each) containing approximately 75 mg of Compound 1 per approximately 29 mini-tablets was prepared using the amounts of ingredients provided in Table 7 below.

[00812] Table 7
Ingredients for Example Mini Tablets
for capsule 6 Compound Relative dose Dose The consignment wt.%/mass. (mg) (G) Intermediate 1 46.9% 95.2 952 Mannitol 45.1% 91.6 916 Sucralose 2.0% 4.1 41 Croscarmellose sodium 3.0% 6.1 61 SLS 0.5% 1.0 10 Colloidal silicon dioxide 1.0% 2.0 20 Magnesium stearate 1.5% 3.0 thirty Total 100% 203 2030

[00813] Intermediate 1, mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), sucralose (Splenda® commercially available from Lyle and Tate of Decatur, IL), croscarmellose sodium (FMC Ac- Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA), sodium lauryl sulfate (SLS), available from Fischer Scientific, and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) and magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) are sieved through 30 and 60 mesh screens to remove lumps.

[00814] Intermediate 1, fumed silica, sucralose and SLS are stirred together for 25 minutes and screened through a 20 mesh sieve to remove any lumps. The magnesium stearate is sifted through a 60 mesh sieve to remove lumps. The mixture of intermediate 1 is added to 20% of the total magnesium stearate and combined in an 8 quart V-blender and mixed for 25 minutes at 20-24 rpm, thereby obtaining the first blended mixture. Mannitol and croscarmellose sodium are added together and sifted through a 20 mesh sieve to remove lumps. The mixture of mannitol and croscarmellose sodium is then added to the first blended mixture and mixed for an additional 25 minutes at 20-24 rpm to obtain a second blended mixture. The second blend is further pressed using Comil through a 30 mesh screen and then the remaining 80% of the total magnesium stearate is added to the screened second blend to form a compressible blend. Once the compression mixture is completed, the compression mixture is transferred to a Kikusui B-Tooling 19-station rotary tablet press (semi-equipped) for compression (Kikusui USA, Lakewood, NJ). Compression of the mixture into mini-tablets yielded cylindrical mini-tablets 2 mm in diameter, 2 mm in length, each mini-tablet containing approximately 2.63 mg of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]- 1,4-dihydro-4-oxoquinoline-3-carboxamide and has an initial tensile strength between about 0.5 MPa and about 4 MPa. Approximately 29 mini-tablets (203 mg total) are then encapsulated using the IN-CAP® automatic tabletop capsule filling machine using hard gelatin or HPMC capsules.

[00815] Example 8: Exemplary mini-tablet 1 in exemplary capsule 7 (capsule formulated to contain approximately 75 mg of Compound 1)

[00816] A batch of small convex cylindrical mini-tablets with a diameter of 2 mm, a length of 2 mm (each mini-tablet weighing approximately 7.0 mg) containing approximately 75 mg of Compound 1 per approximately 29 mini-tablets was prepared using the amounts of ingredients provided in Table 8 below.

[00817] Table 8
Ingredients for Example Mini Tablets
for capsule 7 Compound Relative dose Dose The consignment wt.%/mass. (mg) (G) Intermediate 1 46.9% 95.2 469 Mannitol 45.1% 91.6 451 Sucralose 2.0% 4.1 20 Croscarmellose sodium 3.0% 6.1 thirty SLS 0.5% 1.0 5 Colloidal silicon dioxide 1.0% 2.0 10 Magnesium stearate 1.5% 3.0 15 Total 100% 203 1000

[00818] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL), sodium lauryl sulfate (SLS, of Fisher Scientific) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) were screened together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and croscarmellose sodium (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were sieved together through a 30 mesh sieve ( 600 micrometers). Magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) was sieved through a 60 mesh (250 micrometer) sieve.

[00819] Co-sifted Intermediate 1, colloidal silica, sucralose and SLS, and 20 wt% sieved magnesium stearate were mixed together for 15 minutes at 20-27 rpm in a 4-quart V-mixer. Co-sifted mannitol and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 20-27 rpm. The second blended mixture was passed through a 610 micrometer sieve using Comil. The remaining 80% of the total magnesium stearate was added to this mixture in a 4 quart V-mixer and mixed for 5 minutes at 20-27 rpm to obtain a compressible mixture. After completing the production of the compressed mixture, the compressed mixture is transferred to the Kikusui B-tooling rotary tablet press. The powder mixture was compressed into mini-tablets using all 19 positions of a 19 Kikusui tablet press (Kikusui USA, Lakewood, NJ). The mini-tablets were compressed into a small convex cylindrical shape with a diameter of 2 mm, a thickness of approximately 2 mm, weighing approximately 7 mg, each mini-tablet containing approximately 2.6 mg of N-[2,4-bis(1,1-dimethylethyl)-5- hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 3.1 MPa. Approximately 29 mini-tablets (203 mg total) are then encapsulated using the IN-CAP® automatic tabletop capsule filling machine using HPMC capsules.

[00820] Example 9: Exemplary mini-tablet 1 in exemplary capsule 8 (capsule formulated to contain approximately 75 mg of Compound 1)

[00821] A batch of small convex cylindrical mini-tablets with a diameter of 2 mm, a length of 2 mm (each mini-tablet weighing approximately 7.0 mg) containing approximately 75 mg of Compound 1 per approximately 29 mini-tablets was prepared using the amounts of ingredients provided in Table 9 below.

[00822] Table 9
Ingredients for Example Mini Tablets
for capsule 8 Compound Relative dose Dose The consignment wt.%/mass. (mg) (G) Intermediate 1 46.9% 95.2 469 Mannitol 45.1% 91.6 451 Sucralose 2.0% 4.1 20 Croscarmellose sodium 3.0% 6.1 thirty SLS 0.5% 1.0 5 Colloidal silicon dioxide 1.0% 2.0 10 Magnesium stearate 1.5% 3.0 15 Total 100% 203 1000

[00823] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL), sodium lauryl sulfate (SLS, of Fisher Scientific) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) were screened together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and croscarmellose sodium (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were sieved together through a 30 mesh sieve ( 600 micrometers). Magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) was sieved through a 60 mesh (250 micrometer) sieve.

[00824] Co-sifted Intermediate 1, colloidal silica, sucralose and SLS, and 20 wt% sieved Mg stearate were mixed together for 15 minutes at 20-27 rpm in a 4-quart V-mixer. Co-sifted mannitol and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 20-27 rpm. This mixture was pureed through a 024R (610 micrometer) screen at 2700 rpm using Quadro Comil 197. The remaining 80% of the total magnesium stearate was added to this mixture (mashed using a cone mill) in a 4-quart V-mixer and stirred for 5 minutes at 20-27 rpm to obtain a compressible mixture. After the production of the compressed mixture was completed, the compressed mixture was transferred to a Kikusui B-tooling rotary tablet press. The powder mixture was compressed into mini-tablets using all 19 positions of a Kikusui tablet press (Kikusui USA, Lakewood, NJ). The mini-tablets were compressed into small convex cylindrical shapes with a diameter of 2 mm, a thickness of approximately 2 mm, weighing approximately 7 mg, each mini-tablet containing approximately 2.6 mg of N-[2,4-bis(1,1-dimethylethyl)-5 -hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 2.5 MPa. Approximately 29 mini-tablets (203 mg total) were then encapsulated using the IN-CAP® automatic tabletop capsule filling machine using HPMC capsules.

[00825] Example 10: Exemplary mini-tablet 2 containing approximately 10 mg of substantially amorphous or amorphous Compound 1

[00826] A batch of standard 4 mm diameter convex cylindrical tablets, approximately 2.5-3 mm thick, containing approximately 10 mg of Compound 1 per tablet was prepared using the amounts of ingredients presented in Table 10.

[00827] Table 10
Ingredients for Example Mini Tablet 2 Compound Relative dose wt.%/wt. Dose (mg) Batch (g) Intermediate 1 46.9 12.5 468.8 Mannitol 43.1 11.5 431.3 Sucralose 2 0.53 20.1 Croscarmellose sodium 5 1.33 5 SLS 0.5 0.13 50 Colloidal silicon dioxide 1 0.27 10 Magnesium stearate 1.5 0.4 14.8 Total 100 26.66 1000

[00828] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL), sodium lauryl sulfate (SLS, of Fisher Scientific) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) were screened together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and croscarmellose sodium (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were sieved together through a 30 mesh sieve ( 600 micrometers). Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve.

[00829] Co-sifted Intermediate 1, colloidal silica, sucralose and SLS, and 20 wt% sieved magnesium stearate were mixed together for 15 minutes at 20-27 rpm in a 4-quart V-mixer. Co-sifted mannitol and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 20-27 rpm. The second blended mixture was passed through a 610 micrometer sieve using Comil. The remaining 80% of the total magnesium stearate was added to this mixture in a 4-quart V-mixer and mixed for 5 minutes at 20-27 rpm to obtain a compressible mixture. The compressed mixture was transferred to a Piccola 8-station tablet press. Round convex tablets with a diameter of 4 mm were compressed using a standard round cup tool with a diameter of 4 mm. The weight of each tablet was approximately 26.7 mg and the thickness was ~2.5-3 mm. Each tablet contained approximately 10 mg of Compound 1.

[00830] Example 11: Exemplary mini-tablet 3 containing approximately 10 mg of substantially amorphous or amorphous Compound 1

[00831] A batch of standard 4 mm diameter convex cylindrical tablets, approximately 2.5-3.5 mm thick, containing approximately 10 mg of Compound 1 per tablet was prepared using the amounts of ingredients presented in Table 11.

[00832] Table 11
Ingredients for Example Mini Tablet 3 Compound Relative dose wt.%/wt. Dose (mg) Batch (g) Intermediate 1 35 12.5 350.1 Mannitol 55 19.6 550 Sucralose 2 0.71 20 Croscarmellose sodium 5 1.79 5 SLS 0.5 0.18 50 Colloidal silicon dioxide 1 0.36 10 Magnesium stearate 1.5 0.54 14.7 Total 100 35.7 1000

[00833] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL), sodium lauryl sulfate (SLS, of Fisher Scientific) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) were screened together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and croscarmellose sodium (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were sieved together through a 30 mesh sieve ( 600 micrometers). Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve.

[00834] Co-sifted Intermediate 1, colloidal silica, sucralose and SLS, and 20 wt% sieved magnesium stearate were mixed together for 15 minutes at 20-27 rpm in a 4-quart V-mixer. Co-sifted mannitol and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 20-27 rpm. The second blended mixture was passed through a 610 micrometer sieve using Comil. The remaining 80% of the total magnesium stearate was added to this mixture in a 4-quart V-mixer and mixed for 5 minutes at 20-27 rpm to obtain a compressible mixture. The compressed mixture was transferred to a Piccola 8-station tablet press. Round convex tablets with a diameter of 4 mm were compressed using a standard round cup tool with a diameter of 4 mm. The weight of each tablet was approximately 35.7 mg and the thickness was 2.5-3.5 mm. Each tablet contained approximately 10 mg of Compound 1.

[00835] Example 12: Exemplary mini-tablet 4 in exemplary capsule 9 (capsule contains approximately 75 mg of Compound 1)

[00836] A batch of 2 mm diameter, approximately 2 mm thick cylindrical mini-tablets (each mini-tablet weighing approximately 7 mg) containing approximately 75 mg of Compound 1 per approximately 38 mini-tablets was prepared using the amounts of ingredients presented in Table 12 .

[00837] Table 12
Ingredients for Example Mini Tablet 4 Compound Relative dose wt.%/wt. Dose (mg) Batch (g) Intermediate 1 35 93.8 210 Mannitol 55 147.4 330 Sucralose 2 5.36 12 Croscarmellose sodium 5 13.4 thirty SLS 0.5 1.34 3 Colloidal silicon dioxide 1 2.68 6 Magnesium stearate 1.5 4.02 8.8 Total 100 268 599.8

[00838] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL), sodium lauryl sulfate (SLS, of Fisher Scientific) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA) were screened together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and croscarmellose sodium (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were sieved together through a 30 mesh sieve ( 600 micrometers). Magnesium stearate (commercially available from Fisher Scientific, Pittsburgh, PA) was sieved through a 60 mesh (250 micrometer) sieve.

[00839] Co-sifted Intermediate 1, colloidal silica, sucralose and SLS, and 20 wt% sieved magnesium stearate were mixed together for 15 minutes at 20-27 rpm in a 2 quart V-mixer. Co-sifted mannitol and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 20-27 rpm. The second blended mixture was passed through a 610 micrometer sieve using Comil. The remaining 80% of the total magnesium stearate was added to this mixture in a 2 quart V-mixer and mixed for 5 minutes at 20-27 rpm to obtain a compressible mixture. The compressed mixture was transferred to a Piccola 8-position tablet press. Round convex tablets with a diameter of 2 mm were compressed using a round shallow cup tool with a diameter of 2 mm. The weight of each tablet was approximately 7 mg and the thickness was ~2 mm. Each tablet contains approximately 1.97 mg of Compound 1.

[00840] Example 13: Exemplary dry granulation mini-tablet 5 contained in exemplary capsule 10 (capsule containing approximately 75 mg of Compound 1)

[00841] A batch of cylindrical mini-tablets with a diameter of 2 mm, a thickness of approximately 2 mm, (each mini-tablet weighing approximately 7 mg) containing approximately 75 mg of Compound 1 per approximately 29 mini-tablets was prepared using the amounts of ingredients presented in the Table 13.

[00842] Table 13
Ingredients for Example Mini Tablet 5 Compound Relative dose wt.%/wt. Dose (mg) Batch (g) Intermediate 1 46.9 93.8 74.6 Mannitol
(Pearlitol 25C) 42.1 84.2 66.9 Sucralose 2 4 3.18 Croscarmellose sodium 6 12 9.5 SLS 0.5 1 0.8 Colloidal silicon dioxide 1 2 1.6 Magnesium stearate 1.5 3 2.4 Total 100 200 159

[00843] Intermediate 1 and Cabosil were screened through a 20 mesh screen and then mixed by hand in a small container and then screened together through a 40 mesh screen. This mixture was mixed in a Turbula mixer for 10 minutes at 32 rpm. This mixture was passed through Comil 193 at 2000 rpm using a 032R sieve. Mannitol (Pearlitol 25C) and SLS and Sucralose and AcDiSol were sieved through a 20 mesh sieve. This mixture and a mixture of intermediate 1 and Cabosil were mixed for 10 minutes at 32 rpm in a Turbula mixer. This mixture was passed through Comil 193 at 2000 rpm using a 032R sieve. This product was then mixed for 15 minutes in a Turbula mixer at 32 rpm. Magnesium stearate was sieved through a 40 mesh screen and half mixed by hand with 3 volumes of the mixture. This mixture was mixed for 4 minutes in a Turbula mixer with the remaining mixture at 32 rpm. The powder mixture was then pressed into ~0.5 inch flat rounds having a tensile strength of ~0.25 MPa using an F-Press. These blanks were carefully crushed by hand using a mortar and pestle and passed through a 30 mesh sieve. The remaining half of the sifted magnesium stearate was mixed by hand with three volumes of the mixture. This mixture was mixed for 4 minutes with the remaining mixture in a Turbula mixer at 32 rpm to obtain a compressible mixture. The compressed mixture was then compressed into 2 mm diameter convex mini-tablets on a Key Press using a 2 mm diameter fine round cup tool. Each mini-tablet weighed ~7 mg and contained ~2.63 mg of Compound 1.

[00844 ] Example 14: Exemplary mini-tablet 6 in exemplary capsule 11 (capsule contains approximately 50 mg and approximately 75 mg of Compound 1)

[00845] A batch of cylindrical mini-tablets with a diameter of ~2 mm, a thickness of ~2 mm (each mini-tablet weighing approximately 6.9 mg) was prepared such that it contained approximately 50 mg of Compound 1 per 26 mini-tablets and approximately 75 mg of Compound 1 per 39 mini-tablets, using the amounts of ingredients listed in Table 14 below.

[00846] Table 14
Ingredients for mini tablets for 11 capsules with activity
50 mg and 75 mg Composition of the tablet Relative dose Dose (mg) Dose (mg) The consignment wt.%/mass. 50 mg activity 75 mg activity (G) Intermediate 1 35 62.5 93.8 1753.4 Mannitol 13.5 24.1 36.2 675.2 Lactose 41 73.2 109.8 2050.2 Sucralose 2.0 3.6 5.4 100.06 Croscarmellose sodium 6.0 10.7 16.1 300.1 Colloidal silicon dioxide 1.0 1.8 2.7 50.0 Magnesium stearate 1.5 2.7 4.0 74.19 Total 100 178.6 268 5003.15

[00847] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA ) were sieved together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), lactose (Fast Flo 316 spray-dried lactose monohydrate, commercially available from Foremost Bara-boo, WI) and croscarmellose sodium (Ac-Di-Sol ®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were co-screened through a 30 mesh (600 micrometer) sieve. Magnesium stearate (commercially available from Fisher Scientific) was sieved through a 60 mesh (250 micrometer) sieve.

[00848] Co-sifted Intermediate 1, colloidal silica, sucralose and 20 wt% sieved Mg stearate were mixed together for 15 minutes at 35 rpm in a 20-liter Bohle stainless steel hopper mixer. Co-sieved mannitol and lactose and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 35 rpm. This mixture was cone milled through a 024R (610 micrometer) screen at 5000 rpm using Quadro Comil 197. The remaining 80% of the total magnesium stearate was added to the cone milled mixture in a 20 liter stainless steel hopper mixer Bohle and mixed for 5 minutes at 35 rpm to form a pressing mixture. This compaction mixture was transferred to a Korsch XM12 B-tooling rotary tablet press equipped with 9 tool sets with multiple attachments (8 attachments per punch). This mixture was compressed into cylindrical mini-tablets with a diameter of ~2 mm, a thickness of approximately 1.94 mm, weighing approximately 6.9 mg, each mini-tablet containing approximately 1.92 mg of N-[2,4-bis(1 ,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 1 MPa. 26 mini-tablets (~178.6 mg total, with 50 mg potency) were then encapsulated using an IN-CAP® automatic tabletop capsule filling machine using Vcaps Plus HPMC capsules. Capsules with a potency of 75 mg were prepared by filling Vcaps Plus HPMC capsules with 39 mini-tablets.

[00849 ] Example 15: Exemplary mini-tablet 7 in exemplary capsule 12 (capsule contains approximately 40 mg and approximately 100 mg of Compound 1)

[00850] A batch of cylindrical mini-tablets with a diameter of ~2 mm, a thickness of ~2 mm (each mini-tablet weighing approximately 6.9 mg) was prepared such that it contained approximately 40 mg of Compound 1 per 21 mini-tablets and approximately 100 mg of Compound 1 per 52 mini-tablets, using the amounts of ingredients presented in Table 15 below.

[00851] Table 15
Ingredients for mini tablets for 12 capsules with activity
40 mg and 100 mg. Composition of the tablet Relative dose Dose (mg) Dose (mg) The consignment wt.%/mass. 40 mg activity 100 mg activity (G) Intermediate 1 35 50 125 1046.1 Mannitol 13.5 19.3 48.2 402.4 Lactose 41 58.6 146.4 1229.0 Sucralose 2.0 2.9 7.1 57.0 Croscarmellose sodium 6.0 8.6 21.4 178.7 Colloidal silicon dioxide 1.0 1.4 3.6 28.1 Magnesium stearate 1.5 2.1 5.4 45.03 Total 100 142.9 357.1 2986.33

[00852] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA ) were sieved together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), lactose (Fast Flo 316 spray-dried lactose monohydrate, commercially available from Foremost Bara-boo, WI) and croscarmellose sodium (Ac-Di-Sol ®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were co-screened through a 30 mesh (600 micrometer) sieve. Magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) was sieved through a 60 mesh (250 micrometer) sieve.

[00853] Co-sifted Intermediate 1, colloidal silica, sucralose, and 20 wt% sieved Mg stearate were mixed together for 41 minutes at 12 rpm in an 8-quart stainless steel V-mixer. Co-sifted mannitol and lactose and croscarmellose sodium were added to this mixture and stirred for 15 minutes at 12 rpm. This mixture was cone milled through a 024R (610 micrometer) screen at 5000 rpm using Quadro Comil 197. The remaining 80% of the total magnesium stearate was added to the cone milled mixture and mixed for 10 minutes at 12 rpm. /min in an 8-quart stainless steel V-mixer to form a pressing mixture. This compaction mixture was transferred to a Korsch XM12 B-tooling rotary tablet press equipped with 9 tool sets with multiple attachments (8 attachments per punch). This mixture was compressed into cylindrical mini-tablets with a diameter of ~2 mm, a thickness of approximately 1.97 mm, a weight of approximately 6.9 mg, each mini-tablet containing approximately 1.92 mg of N-[2,4-bis(1, 1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 1 MPa. 21 mini-tablets (~142.9 mg total, with 40 mg potency) were then encapsulated using the IN-CAP® automatic tabletop capsule filling machine using Vcaps Plus HPMC capsules. Capsules with a potency of 100 mg were prepared by filling Vcaps Plus HPMC capsules with 52 mini-tablets.

[00854] Example 16: Exemplary 10 mg Potency Tablet 8

[00855] A batch of standard cylindrical convex tablets ~4 mm in diameter, ~3 mm in thickness (each tablet weighing approximately 35.7 mg) containing approximately 10 mg of Compound 1 per tablet was prepared using the amounts of ingredients presented in Table 16 below.

[00856] Table 16
Ingredients for Example Tablet 8 with 10 mg Potency Composition of the tablet Relative dose Dose (mg) The consignment wt.%/mass. 10 mg activity (G) Intermediate 1 35 12.50 1046.1 Mannitol 13.5 4.82 402.4 Lactose 41 14.64 1229.0 Sucralose 2.0 0.71 57.0 Croscarmellose sodium 6.0 2.14 178.7 Colloidal silicon dioxide 1.0 0.36 28.1 Magnesium stearate 1.5 0.54 45.03 Total 100 35.7 2986.33

[00857] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA ) were sieved together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), lactose (Fast Flo 316 spray-dried lactose monohydrate, commercially available from Foremost Bara-boo, WI) and croscarmellose sodium (Ac-Di-Sol ®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were co-screened through a 30 mesh (600 micrometer) sieve. Magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) was sieved through a 60 mesh (250 micrometer) sieve.

[00858] Co-sifted Intermediate 1, colloidal silica, sucralose and 20 wt% sieved Mg stearate were mixed together for 41 minutes at 12 rpm in an 8-quart stainless steel V-mixer. Co-sifted mannitol and lactose and croscarmellose sodium were added to this mixture and stirred for 15 minutes at 12 rpm. This mixture was cone milled through a 024R (610 micrometer) screen at 5000 rpm using Quadro Comil 197. The remaining 80% of the total magnesium stearate was added to the cone milled mixture and mixed for 10 minutes at 12 rpm. /min in an 8-quart stainless steel V-mixer to form a pressing mixture. The pressing mixture was transferred to a Piccola D-tooling 8-station rotary tablet press equipped with 4 tool sets. The powder mixture was compressed into standard convex tablets ~4 mm in diameter, approximately 3 mm in thickness, weighing approximately 35.7 mg, each tablet containing approximately 10 mg of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 1 MPa.

[00859] Example 17: Exemplary 12.5 mg Potency Tablet 9

[00860] A batch of standard convex cylindrical tablets of ~4 mm diameter, ~3.7 mm thickness (each tablet weighing approximately 44.7 mg) containing approximately 12.5 mg of Compound 1 per tablet was prepared using the amounts of ingredients presented in Table 17 given below.

[00861] Table 17
Ingredients for the example 12.5 mg tablet Composition of the tablet Relative dose Dose (mg) The consignment wt.%/mass. 12.5 mg activity (G) Intermediate 1 35 15.65 1046.1 Mannitol 13.5 6.03 402.4 Lactose 41 18.33 1229.0 Sucralose 2.0 0.89 57.0 Croscarmellose sodium 6.0 2.68 178.7 Colloidal silicon dioxide 1.0 0.45 28.1 Magnesium stearate 1.5 0.67 45.03 Total 100 44.7 2986.33

[00862] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA ) were sieved together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), lactose (Fast Flo 316 spray-dried lactose monohydrate, commercially available from Foremost Bara-boo, WI) and croscarmellose sodium (Ac-Di-Sol ®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were co-screened through a 30 mesh (600 micrometer) sieve. Magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) was sieved through a 60 mesh (250 micrometer) sieve.

[00863] Co-sifted Intermediate 1, colloidal silica, sucralose, and 20 wt% sieved Mg stearate were mixed together for 41 minutes at 12 rpm in an 8-quart stainless steel V-mixer. Co-sifted mannitol and lactose and croscarmellose sodium were added to this mixture and stirred for 15 minutes at 12 rpm. This mixture was cone milled through a 024R (610 micrometer) screen at 5000 rpm using Quadro Comil 197. The remaining 80% of the total magnesium stearate was added to the cone milled mixture and mixed for 10 minutes at 12 rpm. /min in an 8-quart stainless steel V-mixer to form a pressing mixture. The pressing mixture was transferred to a Piccola D-tooling 8-station rotary tablet press equipped with 4 tool sets. The powder mixture was compressed into standard convex tablets ~4 mm in diameter, approximately 3.7 mm thick, weighing approximately 44.7 mg, each tablet containing approximately 12.5 mg N-[2,4-bis(1,1-dimethylethyl)- 5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 1 MPa.

[00864] Example 18: Exemplary mini-tablet 10

[00865] A batch of cylindrical mini-tablets ~2 mm in diameter, ~2 mm in thickness (each mini-tablet weighing approximately 7 mg) was prepared containing approximately 50 mg of Compound 1 per 26 mini-tablets and approximately 75 mg of Compound 1 per 39 mini-tablets -tablets using the quantities of ingredients presented in Table 18 below.

[00866] Table 18
Ingredients for 50 mg and 75 mg mini-tablets Composition of the tablet Relative dose Dose (mg) Dose (mg) The consignment wt.%/mass 50 mg activity 75 mg activity (G) Intermediate 1 35 62.5 93.8 525.07 Mannitol 13.5 24.1 36.2 202.54 Lactose 41 73.2 109.8 614.99 Sucralose 2.0 3.6 5.4 30.10 Croscarmellose sodium 6.0 10.7 16.1 90.06 Colloidal silicon dioxide 1.0 1.8 2.7 15.00 Magnesium stearate 1.5 2.7 4.0 22.54 Total 100 178.6 268 1500.3

[00867] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA ) were sieved together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA), lactose (Fast Flo 316 spray-dried lactose monohydrate, commercially available from Foremost Bara-boo, WI) and croscarmellose sodium (Ac-Di-Sol ®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA) were co-screened through a 30 mesh (600 micrometer) sieve. Magnesium stearate (commercially available from Fisher Scientific) was sieved through a 60 mesh (250 micrometer) sieve.

[00868] Co-sieved Intermediate 1, fumed silica and sucralose were mixed together for 15 minutes at 35 rpm in a 5 liter Bohle stainless steel hopper mixer. Co-sieved mannitol and lactose and croscarmellose sodium were added to this mixture and stirred for 7 minutes at 35 rpm. This mixture was cone milled through a 024R (610 micrometer) sieve at 5000 rpm using Quadro Comil 197. 50% of the total magnesium stearate was added to the cone milled mixture and mixed for 5 minutes at 35 rpm. min in a 5 liter Bohle stainless steel hopper mixer to produce a dry granulation mixture.

[00869] Dry granulation of the above mixture was carried out on an Alexanderwerk WP-120 roller press with a constant rotation speed of 3.0 rpm, a gap size of 2.5 mm and a rolling pressure of 30 and 40 bar. The tapes were ground using an Alexanderwerk Rotary Fine Granulator (100 rpm) or Comil (3000 rpm) using a sieve size of ~500 microns.

[00870] Four batches of crushed granules were lubricated with the remaining magnesium stearate. Mg stearate was added at 0.75 wt% and mixed in a glass container for 5 minutes at 32 rpm using a Turbula mixer.

[00871] The lubricated granules were transferred to a Piccola D-tooling 8-station rotary tablet press equipped with 1 set of multi-tooling tools (10 bits per punch) and compressed into cylindrical mini-tablets with a diameter of ~2 mm, a thickness of approximately 1.95 mm, weighing approximately 7 mg, each mini-tablet approximately contains 1.92 mg N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3- carboxamide and has an average tensile strength of approximately 1-1.5 MPa.

[00872] Example 19: Exemplary mini-tablets 11

[00873] A batch of small convex cylindrical mini-tablets of 2 mm diameter, 2 mm length (each mini-tablet weighing approximately 7.0 mg) was prepared using the quantities of ingredients presented in Table 19 below.

[00874] Table 19
Ingredients for Example Mini Tablets Composition of the tablet Relative dose The consignment wt.%/mass. (kg) Intermediate 1 35.0% 8,750 Mannitol 13.5% 3.375 Lactose 41 10.25 Sucralose 2.0% 0.50 Croscarmellose sodium 6.0% 0.25 Colloidal silicon dioxide 1.0% 1.50 Magnesium stearate 1.5% 0.375 Total 100% 25,000

[00875] Intermediate 1, sucralose (commercially available from Tate and Lyle of Decatur, IL) and fumed silicon dioxide (Cabot Cab-O-Sil® M-5P Fumed Silicon Dioxide, commercially available from Cabot Corporation of Alpharetta, GA ) were sieved together through a 30 mesh (600 micrometer) sieve. Mannitol (Pearlitol® 100 SD, commercially available from Roquette America Inc. of Keokuk IA) and croscarmellose sodium (FMC Ac-Di-Sol®, commercially available from FMC BioPolymer Corporation of Philadelphia, PA), and lactose (Fast Flo Lactose 316, available from Foremost of Baraboo, WI) were screened together through a 30 mesh (600 micrometer) sieve. Magnesium stearate (Hyqual®, commercially available from Mallinckrodt Chemicals) was sieved through a 60 mesh (250 micrometer) sieve.

[00876] Co-sifted Intermediate 1, fumed silica and sucralose were mixed together for 40 minutes at 12 rpm in a 3 cc hopper mixer. ft. Co-sifted mannitol, lactose and croscarmellose sodium were added to this mixture and stirred for 15 minutes at 12 rpm. The second blended mixture was ground together through a 610 micrometer sieve. Screened magnesium stearate was added to the cone milled mixture in a 3 cc hopper mixer. ft. and mixed for 10 minutes at 12 rpm to obtain a pressing mixture. After the molding mixture was completely formed, the molding mixture was transferred to a Kilian TX32 B-tooling rotary tablet press. The powder mixture was compressed into mini-tablets using a Kilian tablet press (IMA KILIAN GMBH & CO. KG, Koln, Germany). The mini-tablets were compressed to 2 mm diameter, small, convex cylindrical shape, approximately 2 mm thick, weighing approximately 7 mg, each mini-tablet approximately containing 1.92 mg N-[2,4-bis(1,1-dimethylethyl)- 5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and has an average tensile strength of approximately 1 MPa.

[00877] Example 20: Exemplary mini-tablets 12

[00878] A batch of small convex cylindrical mini-tablets with a diameter of 2 mm, a length of 2 mm (each mini-tablet weighing approximately 7.0 mg) was prepared in accordance with Example 19 above. Dosages of 25 mg, 50 mg, 75 mg and 100 mg was prepared by varying the number of batch mini-tablets used in Example 19 above (see Table 20) per capsule, pack or pouch.

[00879] Table 20
Ingredients for Example Mini Tablets Tablet composition Relative dose Quantity per dose 25 mg Quantity per 50 mg dose Quantity per dose 75 mg Quantity per 100 mg dose wt.%/mass. (mg) (mg) (mg) (mg) Intermediate 1 35.0% 31.25 62.5 93.8 125 Mannitol 13.5% 12.05 24.1 36.2 48.2 Lactose 41 36.6 73.2 109.9 146.4 Sucralose 2.0% 1.8 3.6 5.4 7.2 Croscarmellose sodium 6.0% 5.35 10.7 16.0 21.4 Colloidal silicon dioxide 1.0% 0.9 1.8 2.7 3.6 Magnesium stearate 1.5% 1.35 2.7 4.0 5.4 Number of mini tablets Not applicable 13 26 39 52 Total 100% 89.3 178.6 268 357.2

[00880] One skilled in the art will appreciate that other dosages can also be obtained by varying the number of mini-tablets from Example 19 above used per capsule, pack or pouch.

[008801] As will be apparent to one skilled in the art, the above listing of the percentages and/or weights of each of the ingredients may also include variations typically expected in the fields of drug technology. For example, each amount of excipient, Compound 1, the weight of the powder mixture, and the weight of each mini-tablet may vary by an amount of 0.01%, or about 0.1%, or about 0.5%, or about 1.0%, or about 1.5%, or about 2%, or up to about 5%, or at least up to the value of the standard deviation of each measurement allowed by the measuring instruments used in this application for the corresponding measurements. For example, a 7 mg mini-tablet may have a weight from about 0.01 to about 5% higher or lower than the intended 7 mg. Likewise, the amount of Compound 1 in each of the doses obtained can vary from about 0.01 to about 5% above or below the intended amounts disclosed in the compositions and methods described in the present invention. In another example, the weight of each mini-tablet may vary by 0.01%, or about 0.1%, or about 0.5%, or about 1.0%, or about 1.5%, or about 2%, or about 5%, or about 7.5%, or about as much as 15%, or at least twice the standard deviation of each measurement allowed by the measuring instruments used in this application. For example, a 7 mg mini-tablet may weigh from about 0.01 to about 15% higher or lower than the intended 7 mg.

[00882] C. Administration of Pharmaceutical Compositions

[00883] Example 21: Example Introduction "A"

[00884] Pediatric patients are orally administered a pharmaceutical composition in accordance with Table 21:

[00885] Table 21
An example is the administration of "A" pharmaceutical compositions of the present invention to pediatric patients. Administration frequency (per day) Description Conditions One introduction 1x75 mg dose of Compound 1 according to any of Examples 7-9 or 13 mini tablets are administered (approximately 29) in 5 ml of infant formula or 5 ml of applesauce. One introduction 1x75 mg dose of Compound 1 according to Example 12 mini tablets are administered (approximately 38) in 5 ml of infant formula or 5 ml of applesauce. One introduction 1x75 mg dose of Compound 1 according to Example 3 The powdered mixture is added (approximately 200 mg) to 5 ml of infant formula or 5 ml of applesauce. One introduction 2x75 mg dose of Compound 1 according to Example 3 The powdered mixture is added (approximately 400 mg) to 5-10 ml of baby formula or 5-10 ml of applesauce. One introduction 2x75 mg dose of Compound 1 according to any of Examples 7-9 or 13 mini tablets are administered (approximately 58) in 10 ml of infant formula or 10 ml of applesauce. One introduction 2x75 mg dose of Compound 1 according to Example 12 mini tablets are administered (approximately 76) in 10 ml of infant formula or 10 ml of applesauce. One introduction 1x10 mg of Compound 1 in 1 mini-tablet according to Example 10 or 11 The mini-tablet is added to 5 ml of baby formula or 5 ml of applesauce. One introduction 2x10 mg Compound 1 in 2 mini-tablets according to Example 10 or 11 The mini-tablet is added to 5 ml of baby formula or 5 ml of applesauce. One introduction 1x50 mg Compound 1 according to Example 14 or 18 mini-tablets are administered (approximately 26) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 2x50 mg of Compound 1 according to Example 14 or 18 mini-tablets are administered (approximately 52) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 1x75 mg Compound 1 according to Example 14 or 18 mini tablets are administered (approximately 39) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 2x75 mg of Compound 1 according to Example 14 or 18 mini-tablets are administered (approximately 78) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 1x40 mg Compound 1 according to Example 15 mini-tablets are administered (approximately 21) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 2x40 mg of Compound 1 according to Example 15 mini-tablets are administered (approximately 42) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 1x100 mg Compound 1 according to Example 15 mini-tablets are administered (approximately 52) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 2x100 mg of Compound 1 according to Example 15 mini-tablets are administered (approximately 104) in 5-10 ml of infant formula or 5-10 ml of applesauce. One introduction 1, 2, 3 or 4 x 10 mg of Compound 1 according to Example 16 The tablet(s) are administered into 5-10 ml of baby formula or 5-10 ml of applesauce. One introduction 1, 2, 3, 4 or 5 x 12.5 mg of Compound 1 according to Example 17 The tablet(s) are administered into 5-10 ml of baby formula or 5-10 ml of applesauce.

[00886] Pharmaceutical compositions are administered to patients in the morning after meals, and the pharmaceutical composition is given at approximately the same time (within 1 hour) on each administration occasion. Prior to administration, the contents of the appropriate container (e.g., capsule, sachet, blister pack, pouch, pack, vial or the like) containing Compound 1 is added to infant formula or formula or applesauce, mixed and allowed to dissolve for approximately 3 minutes before introduction. These compositions are administered orally with a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. For food-able children, examples of a standard CF high-calorie, high-fat meal or snack may include eggs, butter, nut butter, cheese pizza, and the like. For young children who are unable to feed themselves, examples include formula and breast milk. For children who are able to handle soft foods, examples of a standard CF high-calorie, high-fat meal or snack may include ice cream and yogurt.

[00887] Example 22: Example Introduction "B"

[00888] Pediatric patients are orally administered a pharmaceutical composition in accordance with Table 22:

[00889] Table 22
Exemplary administration of "B" pharmaceutical compositions of the present invention. Administration frequency (per day) Description Conditions 12 hour intervals 1x75 mg dose of Compound 1 according to any of Examples 7-9 or 13 mini tablets are administered (approximately 29) in 5 ml of infant formula or 5 ml of applesauce. 12 hour intervals 1x75 mg dose of Compound 1 according to Example 12 mini tablets are administered (approximately 38) in 5 ml of infant formula or 5 ml of applesauce. 12 hour intervals 1x75 mg dose of Compound 1 according to Example 3 The powdered mixture is added (approximately 200 mg) to 5 ml of infant formula or 5 ml of applesauce. 12 hour intervals 2x75 mg dose of Compound 1 according to Example 3 The powdered mixture is added (approximately 400 mg) to 5-10 ml of baby formula or 5-10 ml of applesauce. 12 hour intervals 2x75 mg dose of Compound 1 according to any of Examples 7-9 or 13 mini tablets are administered (approximately 58) in 10 ml of infant formula or 10 ml of applesauce. 12 hour intervals 2x75 mg dose of Compound 1 according to Example 12 mini tablets are administered (approximately 76) in 10 ml of infant formula or 10 ml of applesauce. 12 hour intervals 1x10 mg of Compound 1 in 1 mini-tablet according to Examples 10 or 11 The mini-tablet is added to 5 ml of baby formula or 5 ml of applesauce. 12 hour intervals 2 x 10 mg of Compound 1 in 2 mini-tablets according to Examples 10 or 11 The mini-tablet is added to 5 ml of baby formula or 5 ml of applesauce. 12 hour intervals 1x50 mg Compound 1 according to Example 14 or 18 mini-tablets are administered (approximately 26) in 10 ml of infant formula or 10 ml of applesauce. 12 hour intervals 2x50 mg of Compound 1 according to Example 14 or 18 mini-tablets are administered (approximately 52) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 1x75 mg Compound 1 according to Example 14 or 18 mini tablets are administered (approximately 39) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 2x75 mg of Compound 1 according to Example 14 or 18 mini-tablets are administered (approximately 78) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 1x40 mg Compound 1 according to Example 15 mini-tablets are administered (approximately 21) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 2x40 mg of Compound 1 according to Example 15 mini-tablets are administered (approximately 42) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 1x100 mg Compound 1 according to Example 15 mini-tablets are administered (approximately 52) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 2x100 mg of Compound 1 according to Example 15 mini-tablets are administered (approximately 104) in 5-10 ml of infant formula or 5-10 ml of applesauce. 12 hour intervals 1, 2, 3, or 4 x 10 mg of Compound 1 according to Example 16 The tablet(s) are administered into 5-10 ml of baby formula or 5-10 ml of applesauce. 12 hour intervals 1, 2, 3, 4, or 5 x 12.5 mg of Compound 1 according to Example 17 The tablet(s) are administered into 5-10 ml of baby formula or 5-10 ml of applesauce.

[00890] Pharmaceutical compositions are administered to pediatric patients approximately every 12 hours, with each administration being administered to the patient after a meal. In other embodiments, pharmaceutical compositions containing 75 Compound 1 are administered to adult patients every 12 hours. Prior to administration, the contents of an appropriate container (e.g., capsule, sachet, blister pack, pouch, pack, vial or the like) containing Compound 1 is added to infant formula or formula or applesauce, mixed and allowed to disintegrate for approximately 3 minutes until introduction. These compositions are administered orally with a fat-containing meal, such as a standard CF high-calorie, high-fat meal or snack. For food-able children, examples of a standard CF high-calorie, high-fat meal or snack may include eggs, butter, nut butter, cheese pizza, and the like. For young children who are unable to feed themselves, examples include formula and breast milk. For children who are able to handle soft foods, examples of a standard CF high-calorie, high-fat meal or snack may include ice cream and yogurt.

VI. IMPLEMENTATION OPTIONS/PARTS OF THE INVENTION

[00891] Embodiment 1. A pharmaceutical composition comprising a solid dispersion of amorphous or substantially amorphous Compound 1, one or more excipients, a sweetener, a disintegrant, a glidant and a lubricant, and optionally a humectant.

[00892] Embodiment 2. The pharmaceutical composition according to Embodiment 1, wherein the pharmaceutical composition contains from about 30 to about 50 percent solid dispersion by weight of the composition.

[00893] Embodiment 3. The pharmaceutical composition according to Embodiment 2, wherein the pharmaceutical composition contains approximately 35 percent solid dispersion by weight of the composition.

[00894] Embodiment 4. The pharmaceutical composition according to Embodiment 1, wherein one or more excipients contains:

mannitol, lactose, sucrose, dextrose, maltodextrin, sorbitol, xylitol, powdered cellulose, polyhydric alcohols, microcrystalline cellulose, silicated microcrystalline cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, talc, starch, pregelatinized starch, dibasic calcium phosphate , calcium sulfate, calcium carbonate or combinations thereof.

[00895] Embodiment 5. The pharmaceutical composition according to Embodiment 4, wherein one or more excipients is selected from the group consisting of mannitol, lactose, sucrose, dextrose and maltodextrin.

[00896] Embodiment 6. The pharmaceutical composition according to Embodiment 5, wherein one or more excipients are collectively present in an amount of from about 30 to about 60 percent by weight of the composition.

[00897] Embodiment 7. The pharmaceutical composition according to any of embodiments 1-6, wherein one or more excipients contain mannitol.

[00898] Embodiment 8. The pharmaceutical composition according to Embodiment 7, wherein mannitol is present in an amount of from about 0 wt.% to about 60 wt.%.

[00899] Embodiment 9. The pharmaceutical composition according to Embodiment 7, wherein one or more excipients further comprise lactose.

[00900] Embodiment 10. The pharmaceutical composition according to Embodiment 9, wherein lactose is present in an amount of from about 0 wt% to about 60 wt%.

[00901] Embodiment 11. The pharmaceutical composition according to Embodiment 10, wherein mannitol is present in an amount of from about 0 wt.% to about 60 wt.%.

[00902] Embodiment 12. The pharmaceutical composition according to any of embodiments 1-6, wherein one or more excipients contain lactose.

[00903] Embodiment 13. The pharmaceutical composition according to Embodiment 12, wherein lactose is present in an amount of from about 0 wt% to about 60 wt%.

[00904] Embodiment 14. The pharmaceutical composition according to Embodiment 9, wherein the excipient contains mannitol and mannitol and lactose in a ratio of approximately 3:1 mannitol to lactose.

[00905] Embodiment 15. The pharmaceutical composition according to Embodiment 9, wherein the excipient contains mannitol and mannitol and lactose in a ratio of approximately 1:1 mannitol to lactose.

[00906] Embodiment 16. The pharmaceutical composition according to Embodiment 9, wherein the excipient contains mannitol and mannitol and lactose in a ratio of approximately 1:3 mannitol to lactose.

[00907] Embodiment 17. The pharmaceutical composition according to Embodiment 16, wherein mannitol is present in an amount of approximately 13.5 percent by weight of the composition.

[00908] Embodiment 18. The pharmaceutical composition according to embodiments 16 or 17, wherein lactose is present in an amount of approximately 41 percent by weight of the composition.

[00909] Embodiment 19. The pharmaceutical composition according to Embodiment 1, wherein the sweetener contains:

glucose, sucrose, maltose, mannose, dextrose, fructose, lactose, trehalose, maltitol, lactitol, xylitol, sorbitol, mannitol, tagatose, glycerin, erythritol, isomalt, maltose, sucralose, aspartame, neotame, alitame, neohesperidin dihydrochalcone, cyclamate, thaumatin , acesulfame potassium, saccharin, sodium saccharin or combinations thereof.

[00910] Embodiment 20. The pharmaceutical composition of Embodiment 19, wherein the sweetener comprises sucralose, which is present in an amount of from about 0.1 to about 5 percent by weight of the composition.

[00911] Embodiment 21. The pharmaceutical composition according to Embodiment 1, wherein the disintegrant contains: croscarmellose sodium, sodium alginate, calcium alginate, alginic acid, starch, pregelatinized starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpyrrolidone copolymers, crospovidone, calcium carboxymethylcellulose, cellulose and its derivatives, sodium carboxymethylcellulose, soybean polysaccharide, clay, gum and ion exchange resin, effervescent system based on food acids and alkali carbonate component, sodium bicarbonate or combinations thereof.

[00912] Embodiment 22. The pharmaceutical composition according to Embodiment 21, wherein the disintegrant contains croscarmellose sodium, which is present in an amount of from about 4 to about 8 percent by weight of the composition.

[00913] Embodiment 23. The pharmaceutical composition according to Embodiment 1, wherein the humectant contains: sodium lauryl sulfate, cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, sodium docusate, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, fatty esters polyoxyethylene sorbitan acids, acacia gum, cholesterol, tragacanth, polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, PEGylated hydrogenated castor oils, sorbitan fatty acid esters, vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters , lecithin, phospholipids and their derivatives, poloxamers, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, mono- and diglycerides, propylene glycol fatty acid esters, glycerol fatty acid esters, ethylene glycol palmitostearate, polyoxylglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkylaryl polyether alcohols and polyglyceryl oleate or combinations thereof.

[00914] Embodiment 24. The pharmaceutical composition according to Embodiment 23, wherein the humectant contains sodium lauryl sulfate, which is present in an amount of about 2 percent or less by weight of the composition.

[00915] Embodiment 25. The pharmaceutical composition according to Embodiment 1, wherein the glidant contains: talc, colloidal silica, precipitated silica, magnesium oxide, magnesium silicate, leucine and starch.

[00916] Embodiment 26. The pharmaceutical composition of Embodiment 25, wherein the glidant comprises colloidal silica that is present in an amount of from about 0.1 to about 5 percent by weight of the composition.

[00917] Embodiment 27. The pharmaceutical composition according to Embodiment 1, wherein the lubricant contains: talc, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, stearic acid, glyceryl monostearate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated oils, polyethylene glycol, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, leucine, sodium benzoate or combinations thereof.

[00918] Embodiment 28. The pharmaceutical composition according to embodiment 27, wherein the lubricant contains magnesium stearate, which is present in an amount of from about 0.1 to about 7 percent by weight of the composition.

[00919] Embodiment 29. The pharmaceutical composition of Embodiment 1, wherein the solid dispersion contains approximately 80 percent amorphous Compound 1 by weight of the solid dispersion, and approximately 19.5 percent HPMCAS by weight of the solid dispersion, and approximately 0.5 percent SLS by mass of dispersion.

[00920] Embodiment 30. A pharmaceutical composition comprising:

a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of from about 30 to about 50 percent by weight of the pharmaceutical composition;

sucralose in an amount of from about 1.5 wt.% to about 2.5 wt.% percent by weight of the pharmaceutical composition;

croscarmellose sodium in an amount of from about 4 to about 8 percent by weight of the pharmaceutical composition;

colloidal silicon dioxide in an amount of from about 0.5 wt.% to about 1.5 wt.% percent by weight of the pharmaceutical composition;

magnesium stearate in an amount of from about 0.5 wt.% to about 1.5 wt.% percent by weight of the pharmaceutical composition; And

one or more excipients, in total, in an amount of from about 30 to about 60 percent by weight of the pharmaceutical composition.

[00921] Embodiment 31. The pharmaceutical composition according to Embodiment 30, wherein one or more excipients contain mannitol.

[00922] Embodiment 32. The pharmaceutical composition according to embodiments 30 or 31, wherein one or more excipients contain lactose.

[00923] Embodiment 33. The pharmaceutical composition according to Embodiment 32, wherein the excipient contains mannitol and lactose in a ratio of approximately 3:1 mannitol to lactose.

[00924] Embodiment 34. The pharmaceutical composition according to Embodiment 32, wherein the excipient contains mannitol and lactose in a ratio of approximately 1:1 mannitol to lactose.

[00925] Embodiment 35. The pharmaceutical composition according to Embodiment 32, wherein the excipient contains mannitol and lactose in a ratio of approximately 1:3 mannitol to lactose.

[00926] Embodiment 36. The pharmaceutical composition according to Embodiment 30, wherein the one or more excipients contains mannitol in an amount of approximately 13.5 percent by weight of the composition.

[00927] Embodiment 37. The pharmaceutical composition according to Embodiment 36, wherein one or more excipients contain lactose.

[00928] Embodiment 38. The pharmaceutical composition according to Embodiment 37, wherein lactose is present in an amount of approximately 41 percent by weight of the composition.

[00929] Embodiment 39. The pharmaceutical composition according to any of embodiments 30-38, wherein croscarmellose sodium is present in an amount of approximately 6 percent by weight of the pharmaceutical composition.

[00930] Embodiment 40. The pharmaceutical composition according to any of embodiments 30-39, wherein the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition.

[00931] Embodiment 41. A pharmaceutical composition comprising:

about 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by mass dispersion;

approximately 13.5 wt.% mannitol by weight of the composition;

approximately 41 wt.% lactose by weight of the composition;

approximately 2 wt.% sucralose by weight of the composition;

approximately 6 wt.% croscarmellose sodium by weight of the composition;

about 1 wt.% colloidal silicon dioxide by weight of the composition; And

approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00932] Embodiment 42. The pharmaceutical composition according to any of embodiments 30-41, wherein the pharmaceutical composition is a unit dosage form containing one or a plurality of granules, pellets, particles, or mini-tablets, and where the unit dosage form contains from about 1 mg to about 250 mg of substantially amorphous or amorphous Compound 1.

[00933] Embodiment 42.5. The pharmaceutical composition according to embodiment 42, wherein the unit dosage form contains approximately 5 mg of substantially amorphous or amorphous Compound 1.

[00934] Embodiment 43. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 10 mg of substantially amorphous or amorphous Compound 1.

[00935] Embodiment 44. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 12.5 mg of substantially amorphous or amorphous Compound 1.

[00936] Embodiment 45. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 15 mg of substantially amorphous or amorphous Compound 1.

[00937] Embodiment 46. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 20 mg of substantially amorphous or amorphous Compound 1.

[00938] Embodiment 47. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 25 mg of substantially amorphous or amorphous Compound 1.

[00939] Embodiment 48. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 30 mg of substantially amorphous or amorphous Compound 1.

[00940] Embodiment 48.5. The pharmaceutical composition according to embodiment 42, wherein the unit dosage form contains approximately 35 mg of substantially amorphous or amorphous Compound 1.

[00941] Embodiment 49. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 40 mg of substantially amorphous or amorphous Compound 1.

[00942] Embodiment 49.5. The pharmaceutical composition according to embodiment 42, wherein the unit dosage form contains approximately 45 mg of substantially amorphous or amorphous Compound 1.

[00943] Embodiment 50. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains from about 50 mg of substantially amorphous or amorphous Compound 1.

[00944] Embodiment 51. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 62.5 mg of substantially amorphous or amorphous Compound 1.

[00945] Embodiment 52. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains from about 75 mg of substantially amorphous or amorphous Compound 1.

[00946] Embodiment 53. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 100 mg of substantially amorphous or amorphous Compound 1.

[00947] Embodiment 54. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 125 mg of substantially amorphous or amorphous Compound 1.

[00948] Embodiment 55. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 150 mg of substantially amorphous or amorphous Compound 1.

[00949] Embodiment 56. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 175 mg of substantially amorphous or amorphous Compound 1.

[00950] Embodiment 57. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 200 mg of substantially amorphous or amorphous Compound 1.

[00951] Embodiment 58. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 225 mg of substantially amorphous or amorphous Compound 1.

[00952] Embodiment 59. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains approximately 250 mg of substantially amorphous or amorphous Compound 1.

[00953] Embodiment 60. The pharmaceutical composition according to Embodiment 42, wherein the unit dosage form contains from about 25 to about 40 mini-tablets.

[00954] Embodiment 61. The pharmaceutical composition of Embodiment 42, wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition and the unit dosage form contains from about 26 mini-tablets.

[00955] Embodiment 62. The pharmaceutical composition according to Embodiment 61, wherein the unit dosage form contains approximately 50 mg of substantially amorphous or amorphous Compound 1.

[00956] Embodiment 63. The pharmaceutical composition of Embodiment 42, wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition and the unit dosage form contains from about 21 mini-tablets.

[00957] Embodiment 64. The pharmaceutical composition according to Embodiment 63, wherein the unit dosage form contains from about 40 mg of substantially amorphous or amorphous Compound 1.

[00958] Embodiment 65. The pharmaceutical composition of Embodiment 42, wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition, and the unit dosage form contains from about 39 mini-tablets.

[00959] Embodiment 66. The pharmaceutical composition according to Embodiment 65, wherein the unit dosage form contains from about 75 mg of substantially amorphous or amorphous Compound 1.

[00960] Embodiment 67. The pharmaceutical composition of Embodiment 42, wherein the solid dispersion is present in an amount of about 35 percent by weight of the pharmaceutical composition and the unit dosage form contains from about 52 mini-tablets.

[00961] Embodiment 68. The pharmaceutical composition according to Embodiment 67, wherein the unit dosage form contains from about 100 mg of substantially amorphous or amorphous Compound 1.

[00962] Embodiment 69. The pharmaceutical composition according to any of embodiments 60-68, wherein said mini-tablet has a cylindrical, oval, cone-shaped, spherical, elliptical, polygonal shape, or combinations thereof, wherein said mini-tablet has the largest size or a diameter length of approximately 2 mm.

[00963] Embodiment 70. The pharmaceutical composition according to Embodiment 42, wherein the pharmaceutical composition is a unit dosage form including a granule, pellet, particle, or mini-tablet, and wherein the unit dosage form contains from about 10 mg of substantially amorphous or amorphous Compound 1.

[00964] Embodiment 71. The pharmaceutical composition according to Embodiment 42, wherein the pharmaceutical composition is a unit dosage form including a granule, pellet, particle, or mini-tablet, and wherein the unit dosage form contains from about 12.5 mg of essentially amorphous or amorphous Compound 1.

[00965] Embodiment 72. The pharmaceutical composition according to Embodiment 70 or Embodiment 71, wherein the solid dispersion is present in an amount of approximately 35 percent by weight of the pharmaceutical composition and the unit dosage form is a mini-tablet having a cylindrical, oval, cone-shaped, spherical, elliptical, polygonal, or combinations thereof, wherein said mini-tablet has a largest dimension or diameter length of approximately 4 mm.

[00966] Embodiment 73. A method of treating or reducing the severity of a CFTR-mediated disease in a pediatric patient, comprising administering to the pediatric patient a pharmaceutical composition in accordance with any of embodiments 1-72 and 78-80.

[00967] Embodiment 74. The method of Embodiment 73, wherein the CFTR-mediated disease is selected from cystic fibrosis, smoking-induced asthma COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility due to 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 disorders such as protein C deficiency, hereditary angioedema type 1, lipid processing disorders such as familial hypercholesterolemia, cheilomicronemia type 1, abetalipoproteinemia, lysosomal storage diseases such as inclusion cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhoff/Tay-Sachs disease, Crigler-Najjar disease type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus diabetes, Laronov type dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycogenosis, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, AST deficiency, diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, certain neurological disorders characterized by the deposition of polyglutamine-containing proteins [in the nuclei of neurons], such as Huntington's disease, spinal cerebellar ataxia type I, spinal bulbar muscular atrophy, dentatorubro-pallidoluis atrophy and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (due to impaired prion protein processing), Fabry disease, Gerstmann-Straussler-Scheinker syndrome, COPD , dry eye disease, Sjögren's disease, osteoporosis, osteopenia, Gorham's disease, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Barter syndrome type III, Dent's disease, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome and primary ciliary dyskinesia (PCD), a term for inherited disorders of the structure and/or function of the ciliary epithelium, including PCD with complete splanchnic inversion (also known as Kartagener's syndrome), PCD without complete splanchnic inversion, and ciliary aplasia.

[00968] Embodiment 75. The method of Embodiment 74, wherein the CFTR-mediated disease is cystic fibrosis, COPD, emphysema, dry eye disease, or osteoporosis.

[00969] Embodiment 76. The method according to embodiment 75, wherein the CFTR-mediated disease is cystic fibrosis.

[00970] Embodiment 77. The method of Embodiment 76, wherein the patient has one or more of the following human CFTR mutations: ΔF508, R117H, and G551D.

[00971] Embodiment 78. A pharmaceutical composition comprising:

a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of from about 30 to about 50 percent by weight of the pharmaceutical composition;

sucralose in an amount of from about 1.5 wt.% to about 2.5 wt.% percent by weight of the pharmaceutical composition;

croscarmellose sodium in an amount of from about 4 to about 8 percent by weight of the pharmaceutical composition;

colloidal silicon dioxide in an amount of from about 0.5 wt.% to about 1.5 wt.% percent by weight of the pharmaceutical composition;

magnesium stearate in an amount of from about 0.5 wt.% to about 5 wt.% percent by weight of the pharmaceutical composition; And

one or more excipients, in total, in an amount of from about 30 to about 60 percent by weight of the pharmaceutical composition.

[00972] Embodiment 79. A pharmaceutical composition comprising:

a solid dispersion of amorphous or substantially amorphous Compound 1 in an amount of from about 30 to about 50 percent by weight of the pharmaceutical composition;

sucralose in an amount of from about 1.5 wt.% to about 2.5 wt.% percent by weight of the pharmaceutical composition;

croscarmellose sodium in an amount of from about 4 to about 8 percent by weight of the pharmaceutical composition;

colloidal silicon dioxide in an amount of from about 0.5 wt.% to about 1.5 wt.% percent by weight of the pharmaceutical composition;

magnesium stearate in an amount of from about 0.5 wt.% to about 5 wt.% percent by weight of the pharmaceutical composition; And

lactose in an amount of from about 30 to about 60 percent by weight of the pharmaceutical composition.

[00973] Embodiment 80. A pharmaceutical composition comprising:

about 35 wt% solid dispersion by weight of the composition, wherein said dispersion contains about 80 wt% substantially amorphous or amorphous Compound 1 by weight of the dispersion, about 19.5 wt% HPMCAS by weight of the dispersion, and about 0.5 wt% SLS by mass dispersion;

approximately 54.5 wt.% lactose by weight of the composition;

approximately 2 wt.% sucralose by weight of the composition;

approximately 6 wt.% croscarmellose sodium by weight of the composition;

approximately 1 wt.% colloidal silicon dioxide by weight of the composition; And

approximately 1.5 wt.% magnesium stearate by weight of the composition.

[00974] Embodiment 81. The method according to embodiment 76, where the patient has a CFTR gating mutation.

[00975] Embodiment 82. The method of Embodiment 81, wherein the gating mutation is selected from G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N.

[00976] Embodiment 83. The method of Embodiment 81, wherein the CFTR gating mutation is in at least one allele.

[00977] Embodiment 84. The method of Embodiment 81, wherein the CFTR gating mutation is present on both alleles.

[00978] Embodiment 85. The method according to embodiments 73-77 and 81-84, where the patient's age is from 2 to 5 years.

[00979] Embodiment 86. The method according to embodiments 73-77 and 81-84, where the patient's age is from 0 to 2 years.

[00980] Embodiment 87. The method according to embodiments 73-77 and 81-84, wherein the body weight of the patient is 14 kilograms or more than 14 kilograms.

[00981] Embodiment 88. The method according to embodiments 73-77 and 81-84, wherein the patient's body weight is less than 14 kilograms.

[00982] Embodiment 89. The method of Embodiment 76, wherein the patient has a residual function phenotype.

[00983] Embodiment 90. The method according to embodiment 76, where the patient has residual CFTR function.

[00984] Embodiment 91. The method according to embodiment 76, where the patient has the R117H CFTR mutation.

Claims (38)

1. A pharmaceutical composition for the treatment of cystic fibrosis in pediatric patients in a unit dosage form, including one or a plurality of granules or mini-tablets, where the composition contains: (a) a solid dispersion in an amount of from 30 to 40% by weight of the composition, wherein the dispersion contains: (i) 80% by weight of substantially amorphous or amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) by mass of dispersion, (ii) 19.5 wt.% hydroxypropyl methylcellulose acetate succinate (HPMCAS) by weight of the dispersion, and (iii) 0.5 wt.% sodium lauryl sulfate (SLS) by weight of the dispersion; (b) a two-component filler containing mannitol and lactose in a ratio of 1:3 mannitol to lactose; (c) a sweetener which is sucralose; (d) a disintegrant; (e) glidant; And (f) lubricant; wherein the unit dosage form contains from 1 to 250 mg of substantially amorphous or amorphous Compound 1 and wherein the substantially amorphous Compound 1 has less than 15% crystallinity. 2. The pharmaceutical composition according to claim 1, wherein the two-component excipient is present in an amount of from 30 to 60 percent by weight of the composition. 3. The pharmaceutical composition according to claim 1, where the sweetener is sucralose in an amount of 1.5 to 2.5 wt.% by weight of the composition. 4. The pharmaceutical composition according to claim 1, where the disintegrant is croscarmellose sodium in an amount of 4 to 8 wt.% by weight of the composition. 5. The pharmaceutical composition according to claim 1, where the glidant is colloidal silicon dioxide in an amount of 0.5 to 3 wt.% by weight of the composition. 6. The pharmaceutical composition according to claim 1, where the lubricant is magnesium stearate in an amount of from 0.3 to 5 wt.% by weight of the composition. 7. The pharmaceutical composition according to claim 1, where the pharmaceutical composition does not contain SLS outside the solid suspension. 8. The pharmaceutical composition according to claim 1, wherein the unit dosage form contains from 1 to 100 mg of substantially amorphous or amorphous Compound 1. 9. The pharmaceutical composition according to claim 8, wherein the unit dosage form contains 50 mg of substantially amorphous or amorphous Compound 1. 10. The pharmaceutical composition according to claim 8, wherein the unit dosage form contains 75 mg of substantially amorphous or amorphous Compound 1. 11. Pharmaceutical composition according to claim 8, where the unit dosage form contains from 25 to 40 granules. 12. The pharmaceutical composition according to claim 1, wherein the solid dispersion is present in an amount of 35 percent by weight of the pharmaceutical composition and the unit dosage form contains 26 granules. 13. The pharmaceutical composition according to claim 12, wherein the unit dosage form contains 50 mg of substantially amorphous or amorphous Compound 1. 14. The pharmaceutical composition according to claim 1, wherein the solid dispersion is present in an amount of 35 percent by weight of the pharmaceutical composition and the unit dosage form contains 39 granules. 15. The pharmaceutical composition according to claim 12, wherein the unit dosage form contains 75 mg of substantially amorphous or amorphous Compound 1. 16. The pharmaceutical composition according to claim 1, wherein said granule has a cylindrical, oval, cone-shaped, spherical, elliptical, polygonal shape or combinations thereof, where the granule has a largest size or diameter length of 2 mm. 17. The pharmaceutical composition according to claim 1, wherein the substantially amorphous Compound 1 contains less than 5% crystalline Compound 1. 18. A method of treating or reducing the severity of cystic fibrosis in a pediatric patient, comprising administering to the pediatric patient a pharmaceutical composition according to any one of claims. 1-17. 19. The method of claim 18, wherein the patient has a CFTR gating mutation. 20. The method of claim 19, wherein the CFTR gating mutation is selected from G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. 21. The method of claim 19, wherein the CFTR gating mutation is in at least one allele. 22. The method according to claim 19, wherein the CFTR gate mutation is present in both alleles. 23. The method of claim 18, wherein the patient has one or both of the following mutations in the human cystic fibrosis transmembrane conductance regulator ( CFTR) gene: ΔF508 and R117H. 24. The method according to claim 18, where the patient’s age is from 2 to 5 years. 25. The method according to claim 18, where the patient’s age is from 0 to 2 years. 26. The method according to claim 18, where the patient's body weight is 14 kilograms or more than 14 kilograms. 27. The method according to claim 18, where the patient’s body weight is less than 14 kilograms.

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