Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator-mediated diseases

Abstract

The present invention comprises compositions comprising a plurality of therapeutic agents, wherein the presence of one therapeutic agent enhances the properties of at least one other therapeutic agent. In one embodiment, the therapeutic agents are cystic fibrosis transmembrane conductance regulators (CFTR), such as a CFTR corrector or a CFTR enhancer, for the treatment of CFTR-mediated diseases such as cystic fibrosis. Methods and kits thereof are also described.

Description

Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator-mediated diseases FIELD OF INVENTION The present invention comprises pharmaceutical combination compositions as defined in the appended claims, and methods for treating Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-mediated diseases related thereto. BACKGROUND OF THE INVENTION 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 progress in the treatment of CF, there is no cure. In patients with cystic fibrosis (CF), endogenously expressed CFTR mutations in respiratory epithelia lead to reduced apical anion secretion, resulting in an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs and the accompanying microbial infections, which ultimately lead to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, are fatal. Furthermore, most men with cystic fibrosis are infertile, and fertility is reduced among women with the disease.In contrast to the severe effects of two copies of the CF-associated gene, individuals with a single copy of the CF-associated gene show greater resistance to cholera and the dehydration resulting from diarrhea, perhaps explaining the relatively high frequency of the CF gene in the population. Sequence analysis of the CFTR gene on CF chromosomes has revealed a variety of disease-causing mutations (Cutting, GR et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, BS. et al. (1989) Science 245:1073-1080; Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, more than 1000 disease-causing mutations have been identified in the CF gene (http: / / www.genet.sickkids.on.ca / cftr / app). The most common mutation is a phenylalanine deletion at position 508 of the CFTR amino acid sequence, commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with severe disease. The deletion of residue 508 in AF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER and traffic to the plasma membrane. Consequently, the number of channels present in the membrane is much lower than that observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel activation. Together, the reduced number of channels in the membrane and the defective activation lead to reduced anion transport across epithelia, resulting in impaired ion and fluid transport. (Quinton, PM (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that reduced numbers of AF508-CFTR in the membrane are functional, although less so 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 AF508-CFTR, other disease-causing mutations in CFTR that result in defective channel trafficking, synthesis and / or activation can be upregulated or downregulated to alter anion secretion and modify disease progression and / or severity. Therefore, there is a need for new treatments for CFTR-mediated diseases. SUMMARY OF THE INVENTION The present invention is defined in the appended claims and relates to a pharmaceutical composition comprising: a first spray-dried dispersion and a second spray-dried dispersion, wherein the first spray-dried dispersion contains approximately 70 wt% to approximately 90 wt% of an amorphous form of (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 (Compound 1) and approximately 10 wt% to approximately 30 wt% of a polymer, and wherein the second spray-dried dispersion contains an amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1, 4-dihydro-4-oxoquinolin-3-carboxamide (Compound 2), and wherein the pharmaceutical composition is a tablet. In one embodiment, the polymer comprises hydroxypropylmethylcellulose. In one embodiment, the second spray-dried dispersion further comprises a polymer. In one embodiment, the second spray-dried dispersion comprises from approximately 70 wt% to approximately 90 wt% of Compound 2 and from approximately 10 wt% to approximately 30 wt% of the polymer. In one embodiment, the pharmaceutical composition comprises from approximately 5% by weight to approximately 20% by weight of the first spray-dried dispersion. In another embodiment, the pharmaceutical composition comprises from approximately 15% by weight to approximately 60% by weight of the second spray-dried dispersion. In one embodiment, the pharmaceutical composition is a tablet. In one embodiment, the tablet comprises approximately 25 mg to 125 mg of Compound 1. In one embodiment, the tablet comprises approximately 100 mg of Compound 1. In one embodiment, the tablet comprises approximately 50 mg of Compound 1. In one embodiment, the tablet comprises approximately 100 mg to 200 mg of Compound 2. In one embodiment, the tablet comprises approximately 150 mg of Compound 2. In one embodiment, the tablet comprises one or more excipients selected from a filler, a disintegrant, a lubricant, or any combination thereof. In one embodiment, the tablet comprises approximately 30% to approximately 50% by weight of a filler. In one embodiment, the filler comprises microcrystalline cellulose. In one embodiment, the tablet comprises approximately 1% to approximately 10% by weight of a disintegrant. In one embodiment, the disintegrant comprises croscarmellose sodium. In one embodiment, the tablet comprises approximately 1% by weight of a lubricant. In one embodiment, the lubricant comprises magnesium stearate. In one embodiment, the tablet comprises from approximately 30 mg to approximately 85 mg of the first spray-dried dispersion. In another embodiment, the tablet comprises from approximately 150 mg to approximately 250 mg of the second spray-dried dispersion. In one embodiment, the tablet comprises from approximately 100 mg to approximately 300 mg of a filler. In one embodiment, the tablet comprises from approximately 12 mg to approximately 36 mg of a disintegrant. In one embodiment, the tablet comprises from approximately 1 mg to approximately 5 mg of a lubricant. In one embodiment, the pharmaceutical composition further comprises an additional therapeutic agent. In one embodiment, the additional therapeutic agent is a CFTR corrector other than Compound 1. In one embodiment, the additional therapeutic agent is a CFTR enhancer other than Compound 2. In one embodiment, the additional therapeutic agent is selected from In one aspect, the present invention presents a pharmaceutical composition as claimed for use in a method for treating cystic fibrosis in a patient. In one embodiment, the pharmaceutical composition is administered orally to the patient. In one embodiment, the patient is also administered an additional therapeutic agent. In one embodiment, the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition. In one embodiment, the patient is homozygous for the CFTR AF508 mutation. In another embodiment, the patient is heterozygous for the CFTR AF508 mutation. BRIEF DESCRIPTION OF THE FIGURES The following figures are provided by way of example and are not intended to limit the scope of the claimed invention. Figure 1 is an XRPD pattern for the substantially polymer-free pure spray-dried dispersion formulated with a 1:1 ratio, by weight, of Compound 1 and Compound 2. Figure 2 is a heat flow plot as a function of temperature generated by differential scanning calorimetry (DSC) analysis of the substantially polymer-free pure spray-dried dispersion formulated with a 1:1 ratio, by weight, of Compound 1 and Compound 2, showing a glass transition temperature (Tg) of 124°C. Figure 3 A) represents 1H solid-state NMR spectra for the substantially polymer-free pure spray-dried dispersion formulated with a 1:1 wt ratio of Compound 1 and Compound 2, generated by cross-polarization of fluorine atoms with protons in Compound 1, and B) graph depicting cross-polarization between fluorine atoms and protons in Compound 1 and spin diffusion between protons in Compound 1 and Compound 2. Figure 4 represents an overlay of 13C NMR solid-state spectra (top) for the substantially polymer-free pure spray-dried dispersion, and Compound 1 and cryoground / cryocrushed Compound 2 formulated in a 1:1 wt ratio, and 19F NMR spectra (bottom) for the substantially polymer-free pure spray-dried dispersion formulated in a 1:1 wt ratio of Compound 1 and Compound 2. Figure 5 is an SEM image of the substantially polymer-free pure spray-dried dispersion of the present invention formulated with a 1:1 ratio, by weight, of Compound 1 and Compound 2 at 5000x. Figure 6 is an XRPD pattern for the substantially polymer-free pure spray-dried dispersion formulated with a 1:3 ratio, by weight, of Compound 1 and Compound 2. Figure 7 is a heat flow graph as a function of temperature generated by differential scanning calorimetry (DSC) analysis of the substantially polymer-free pure spray-dried dispersion formulated with a 1:3 ratio, by weight, of Compound 1 and Compound 2, showing a Tg of 155°C. Figure 8 is a SEM image of the substantially polymer-free pure spray-dried dispersion formulated with a 1:3 ratio, by weight, of Compound 1 and Compound 2 at 5000x. Figure 9 represents the results of the kinetic dissolution experiments of Compound 1 in fed-state simulated intestinal fluid (FedSIF) solutions in the presence of Compound 2 in a substantially polymer-free pure coSDD, measured by concentration versus time. Figure 10 represents the results of the kinetic dissolution experiments of Compound 2 in FedSIF solutions in the presence of Compound 1 in a substantially polymer-free, pure coSDD alone, measured by concentration versus time. Figure 11 represents the dissolution data of Compound 2 in simulated fasting fluids alone and in the presence of Compound 1 in a substantially polymer-free pure coSDD. Figure 12 compares the crystallization kinetics for Compound 1 at 80°C and 75% relative humidity when in a Compound 2-free tablet (circles), a spray-dried dispersion (squares), and a tablet comprising Compound 2 (triangles). Figure 13 compares the crystallization kinetics for Compound 1 at 70°C and 75% relative humidity when in a Compound 2-free tablet (circles), a spray-dried dispersion (squares), and a tablet comprising Compound 2 (triangles). Figure 14 represents a solid-state 1H NMR spectrum of a tablet comprising a mixture of a spray-dried dispersion of Compound 1 and a spray-dried dispersion of Compound 2 at 70°C and 75% relative humidity. The upper spectrum is the reference 1H NMR spectrum that identifies the tablet components, and the lower spectrum is generated by cross-polarization of the fluorine atom with protons in Compound 1 and spin diffusion between protons in Compound 1 and Compound 2, resulting in peak growth for Compound 2. DETAILED DESCRIPTION The present invention provides pharmaceutical formulations and compositions that are useful for treating cystic fibrosis. I. DEFINITIONS As used herein, "CFTR" stands for cystic fibrosis transmembrane conductance regulator. As used herein, "mutations" can refer to mutations in the CFTR gene or the CFTR protein. A "CFTR mutation" refers to a mutation in the CFTR gene, and a "CFTR mutation" refers to a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides of a gene, generally results in a mutation in the CFTR protein translated from that gene. As used herein, an "AF508 mutation" or "F508-del mutation" is a specific mutation within the CFTR protein. The mutation is a deletion of the three nucleotides comprising the codon for the amino acid phenylalanine at position 508, resulting in a CFTR protein that lacks this phenylalanine residue. The term "CFTR activation mutation" as used herein means a CFTR mutation that results in the production of a CFTR protein for which the predominant defect is a low probability of channel opening 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)). Activation mutations include, but are not limited to, G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. As used herein, a patient who is "homozygous" for a particular mutation, for example, AF508, has the same mutation on each allele. As used herein, a patient who is "heterozygous" for a particular mutation, e.g., AF508, has this mutation on one allele, and a different mutation on the other allele. As used herein, the term "CFTR corrector" refers to a compound that increases the amount of functional CFTr protein on the cell surface, resulting in improved ion transport. As used herein, the term "CFTR enhancer" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, resulting in enhanced ion transport. As used herein, the term "induce," as in inducing CFTR activity, refers to an increase in CFTR activity, whether by the corrector, enhancer, or other mechanism. As used herein, the terms "active pharmaceutical ingredient", "API" and "therapeutic agent" are used interchangeably to refer to a biologically active compound. The terms "patient," "subject," and "individual" are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. As used herein, the term "solvent system" refers to a system comprising an organic solvent capable of dissolving Compound 1 and Compound 2. As used herein, the term "biological medium" refers to real or simulated gastrointestinal fluid. Simulated gastrointestinal fluid would be in vitro gastrointestinal fluid such as, for example, simulated fed intestinal fluid (FedSIF). Real gastrointestinal fluid would be in vivo gastrointestinal fluid such as that found within a patient. The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the quantity that produces the desired effect for which it is administered (e.g., improvement of CF or a symptom of CF, or reduction of the severity of CF or a symptom of CF). The exact quantity will depend on the purpose of the treatment and will be verified by an expert in the technique using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). As used herein, the terms "treatment," "treat," and the like refer generally to the improvement of CF or its symptoms or the reduction in the severity of CF or its symptoms in a subject. "Treatment," as used herein, includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and / or hepatic function, reduced instances of chest infections, and / or reduced instances of cough or shortness of breath. Improvements in or reductions in the severity of any of these conditions can be readily assessed according to standard methods and techniques known in the field. As used herein, the term "in combination with", when referring to two or more compounds or agents, means that the order of administration includes the compounds or agents being administered before, concurrently with, or subsequently to the patient. The terms "around" and "approximately," when used in relation to doses, quantities, or weight percentages of ingredients in a composition or dosage form, mean a dose, quantity, or weight percentage that is recognized by a person skilled in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, quantity, or weight percentage. Specifically, the term "around" or "approximately" means an acceptable error for a particular value determined by a person skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "around" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain realizations, the term "around" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or interval. As used herein, "Compound 1" and "Cmpd 1" are used interchangeably to refer to compound (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. This compound has the structure: As used herein, "Compound 2" and "Cmpd 2" are used interchangeably to refer to the compound N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamide. This compound has the structure: As used herein, the terms "substantially free" and "pure" are used interchangeably to refer to a mixture or material that has a concentration of less than approximately 1% by weight (e.g., less than approximately 0.5% by weight, less than approximately 0.1% by weight, less than approximately 1000 ppm, or less than approximately 500 ppm) of another dopant, compound, impurity, or material (e.g., polymer). A dopant, compound, impurity, or material (e.g., polymer) is not present in a mixture or material when that mixture or material is substantially free of the compound, impurity, or material (e.g., polymer).For example, a mixture or dispersion that is substantially free of a polymer has a concentration of less than approximately 1% by weight (e.g., less than approximately 0.5% by weight, less than approximately 0.1% by weight, less than approximately 1000 ppm, or less than approximately 500 ppm) of polymer. As used herein, "glass transition temperature" or "Tg" refers to the temperature below which the physical properties of amorphous materials vary similarly to those of a solid phase (glassy state), and above which amorphous materials behave like liquids (rubber state). As used herein, the term "amorphous" refers to a solid material that lacks long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are randomly arranged, so there is no well-defined arrangement, such as molecular packing, and no long-range order. Amorphous solids are generally isotropic, meaning they exhibit similar properties in all directions and do not have defined melting points. For example, an amorphous material is a solid that does not have a characteristic sharp crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., it is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.See US 2004 / 0006237 for an XRPD comparison of an amorphous material and a crystalline material. As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than approximately 15% crystallinity (e.g., less than approximately 10% crystallinity or less than approximately 5% crystallinity). It is also noted that the term "substantially amorphous" includes the descriptor "amorphous," which refers to materials that have no crystallinity (0%). As used herein, the term "dispersion" refers to a dispersed system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., colloidal particles on the nanometer scale, multiple microns in size). In general, dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, both the dispersed and continuous phases are solid. In pharmaceutical applications, a solid dispersion may include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion includes the polymer that constitutes the dispersed phase, and the drug constitutes the continuous phase.Or, a solid dispersion includes the drug that constitutes the dispersed phase, and the polymer that constitutes the continuous phase. As used herein, an "excipient" is an inactive ingredient in a pharmaceutical composition. Examples of excipients include fillers or diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, or the like. As used herein, a "disintegrant" is an excipient that hydrates a pharmaceutical composition and aids in the dispersion of tablets. Examples of disintegrants include croscarmellose sodium and / or sodium starch glycolate. As used herein, a "diluent" or "filler" is an excipient that adds volume to a pharmaceutical composition. Examples of fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or similar), or any combination thereof. As used herein, a "lubricant" is an excipient added to pharmaceutical compositions that are pressed into tablets. The lubricant aids in the compaction of granules into tablets and in the ejection of a tablet from a pharmaceutical composition through a molding press. An example of a lubricant is magnesium stearate. As used herein, a "wetting agent" or "surfactant" is an excipient that imparts improved solubility and / or wettability to pharmaceutical compositions. Examples of wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene sorbitan monooleate 20 (e.g., Tween™), or any combination thereof. As used herein, a "binder" is an excipient that imparts improved cohesion or tensile strength (e.g., hardness) to a pharmaceutical composition. Examples of binders include dibasic calcium phosphate, sucrose, maize (corn) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethylcellulose). As used herein, a "glide" is an excipient that imparts improved flow properties to pharmaceutical compositions. Examples of glides include colloidal silica and / or talc. II. SUBSTANTIALLY POLYMER-FREE SPRAY-DRIED DISPERSIONS A. Methods for Preparing a Spray-Dried Dispersion Spray drying is a process that converts a liquid feed into a dry, particulate form. Optionally, a secondary drying process such as fluidized bed drying or vacuum drying can be used to reduce residual solvents to pharmaceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to produce evaporation and dry the liquid droplets. The preparation to be spray dried can be any solution, thick suspension, slurry, colloidal dispersion, or paste that can be sprayed using the selected spray-drying apparatus. In one procedure, the preparation is sprayed into a stream of hot, filtered gas that evaporates the solvent and carries the dried product to a collector (e.g., a cyclone).The spent gas is then expelled with the solvent, or alternatively, the expelled air is sent to a condenser to capture and potentially recycle the solvent. Commercially available types of equipment can be used to perform spray drying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray dryers manufactured by Niro) (see US 2004 / 0105820; US 2003 / 0144257). Techniques and methods for spray drying can be found in Perr and his Chemical Engineering Handbook, 6th Ed., R.H. Perr and D.W. Green & J.O. Maloney, eds.), McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). All three references are incorporated herein in their entirety as references. Solvent removal may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from approximately room temperature to approximately 100°C), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (e.g., from approximately room temperature to approximately 200°C). In one process, the solid dispersion is dried in a fluidized bed. In a process, the solvent includes a volatile solvent, for example, a solvent that has a boiling point below approximately 100°C. In a process, the solvent includes a mixture of solvents, for example, a mixture of volatile solvents or a mixture of volatile and non-volatile solvents. When solvent mixtures are used, the mixture may include one or more non-volatile solvents, for example, when the non-volatile solvent is present in the mixture at less than approximately 15%, such as less than approximately 12%, less than approximately 10%, less than approximately 8%, less than approximately 5%, less than approximately 3%, or less than approximately 2%. In some processes, the solvents are those solvents in which Compound 1 and Compound 2 have solubilities of at least approximately 10 mg / ml (for example, at least approximately 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, or more). In other processes, the solvents include those solvents in which Compound 1 has a solubility of at least approximately 20 mg / ml. Exemplary solvents that could be tested include acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, DCM, and toluene. Exemplary co-solvents include acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, and dioxane / water. In a two-solvent system, the solvents can be present in concentrations ranging from approximately 0.1% to approximately 99.9%. In a process where water is a co-solvent with acetone, the concentration ranges from approximately 0.1% to approximately 15%, or from approximately 9% to approximately 11%, or approximately 10%.In one process, water is a co-solvent with MEK, where the water is present from approximately 0.1% to approximately 15%, for example, from approximately 9% to approximately 11%, or approximately 10%. In some embodiments, the solvent system includes three solvents. In cases where the amorphous Compound 1 is a component of a solid amorphous dispersion, the preferred solvents dissolve both Compound 1 and the polymer. Suitable solvents include those described above, for example, MEK, DCM, water, methanol, IPA, and mixtures thereof. The particle size and drying temperature range can be modified to prepare an optimal solid dispersion. As those skilled in the art will appreciate, a small particle size will lead to improved solvent removal. The applicants have discovered, however, that smaller particles can lead to spongy particles which, under some circumstances, do not provide optimal solid dispersions for downstream processing such as tablet formation. At higher temperatures, crystallization or chemical degradation of Compound 1 or Compound 2 may occur. At lower temperatures, insufficient solvent removal may occur. The methods presented herein provide an optimal particle size and drying temperature. A surfactant or surfactant mixture would generally decrease the interfacial tension between the solid dispersion and an aqueous medium. An appropriate surfactant or surfactant mixture can also improve the aqueous solubility and bioavailability of Compound 1 or Compound 2 from a solid dispersion. Surfactants for use in connection with the present invention include, but are not limited to, sorbitan fatty acid esters (e.g., Spans®), polyoxyethylsorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS), sodium dioctyl sulfosuccinate (Docusate), sodium salt of deoxycholic acid (DOSS), sorbitan monostearate, sorbitan tristearate, hexadecyltrimethylammonium bromide (HTAB), sodium N-lauroylsarcosine, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, Gelucire 44 / 14, ethylenediaminetetraacetic acid (EDTA),vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), lecithin, MW 677-692, monosodium glutanic acid monohydrate, Labrasol, caprylic / capric glycerides PEG 8, Transcutol, diethylene glycol monoethyl ether, Solutol HS-15, polyethylene glycol / hydroxystearate, acid taurocholic, Pluronic F68, Pluronic F108 and Pluronic F127 (or any other polyoxyethylene-polyoxypropylene copolymer (Pluronics®) or saturated polyglycolized glyceride (Gelucirs®)). Specific examples of such surfactants that may be used in connection with this invention include, but are not limited to, Span 65, Span 25, Tween 20, Caprylic / Oil 90, Pluronic F108, sodium lauryl sulfate (SLS), Vitamin E TPGS, pluronics, and copolymers. SLS is generally preferred. The amount of surfactant (e.g., SLS) relative to the total weight of the solid dispersion can be between 0.1 and 15%. Preferably, it is approximately 0.5% to approximately 10%, more preferably approximately 0.5% to approximately 5%, for example, approximately 0.5% to 4%, approximately 0.5% to 3%, approximately 0.5% to 2%, approximately 0.5% to 1%, or approximately 0.5%. In certain processes, the amount of surfactant relative to the total weight of the solid dispersion is at least approximately 0.1%, and preferably at least approximately 0.5%. In these embodiments, the surfactant would be present in an amount of no more than approximately 15%, and preferably no more than approximately 12%, approximately 11%, approximately 10%, approximately 9%, approximately 8%, approximately 7%, approximately 6%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, or approximately 1%. An embodiment in which the surfactant is present in an amount of approximately 0.5% by weight is preferred. Candidate surfactants (or other components) can be tested for suitability for use in the invention in a manner similar to that described for testing polymers. B. Beneficial Properties of Substantially Polymer-Free Spray-Dried Dispersions. Compound 1 and Compound 2, in the presence of each other, unexpectedly demonstrate improved properties over individual formulations. Figure 9 depicts the fluid stability of Compound 1 in simulated fed intestinal fluid (FedSIF). The set of bars labeled Pure 1:1 coSDD represents the pure coSDD of the substantially polymer-free Compound 1 and Compound 2 presented in the present invention. Along the y-axis is the concentration of Compound 1 in mg / ml, and each bar along the x-axis represents time: 0, 5 h, 1 h, 3 h, 5 h, 29 h, and 72 h. The stability of Compound 1 in the pure spray-dried dispersions (SDD) of Compound 1 and Compound 2 of the present invention for 72 h was compared to the set of bar graphs labeled Compound 1 s Dd (50% HPMCAS), which is Compound 1 alone in a 50 wt% SDD with the HPMCAS polymer. Achieving such stability in the absence of a polymer is surprising, as a polymer is considered necessary in the art to obtain stable spray-dried dispersions. The fact that greater and more consistent stability is achieved is truly unexpected. Such spray-dried dispersions would be advantageous for high-dose drug formulations because more drug could be formulated without the additional bulk of a polymer. The same unexpected phenomena exist for Compound 2, as can be seen in the analogous set of experiments in Figure 10. Figure 10 represents the fluid stability of Compound 2 in the compositions of the present invention in FedSIF. The set of bars labeled Pure 1:1 coSDD is the pure oSDD of Compound 1 and Compound 2 substantially free of polymer presented in the present invention. As with Compound 1 in Figure 9, the increased stability of Compound 2 can be seen in the pure coSDD of Compound 1 and Compound 2 of the present invention for 72 h compared to the set of bar charts labeled Compound 2 SDD (20% HPMCAS), which is Compound 2 alone in 20 wt% SDD with the HPMCAS polymer. In addition to greater physical stability in solution, Compound 2 in the compositions of the present invention has unexpectedly increased dissolution rates. Figure 11 depicts the results of dissolution rate experiments for a tablet comprising the pure co-spray dried dispersion of Compound 1 and Compound 2 (circles) and a tablet comprising a spray-dried dispersion of Compound 2 alone and polymer (triangles). The pure co-spray dried dispersion of Compound 1 and Compound 2 demonstrates a significant increase in dissolution rates for Compound 2 over those of Compound 2 in the absence of Compound 1. The increased dissolution rate translates into statistically significant increases in in vivo exposure for Compound 2.Table 1 shows the dog pK results for Compound 2 in a tablet of pure coSDD of Compound 1 and Compound 2 of the present invention relative to a tablet of Compound 2 alone. Table 1. When Compound 2 is in the presence of Compound 1, the maximum concentration and the area under the curve increase by 73% and 47%, respectively, with respect to Compound 2 alone. Not wishing to limit themselves to theory, the inventors maintain that Compound 1, in the presence of Compound 2, interacts unexpectedly to such an extent that even when in the medium, they do not behave as completely individual species. Figure 1 represents an XRPD pattern of a pure 1:1 co-spray dried dispersion of Compound 1 and Compound 2 as an amorphous entity. Figure 2 represents a differential scanning calorimetry (DSC) trace of a pure 1:1 co-spray dried dispersion of Compound 1 and Compound 2 showing a transition at a Tg of 124°C. Interestingly, Figure 3 represents the solid-state NMR spectra of a pure 1:1 co-spray dried dispersion of Compound 1 and Compound 2 showing spin diffusion interactions between protons in the different compounds, respectively. Figure 6 represents an XRPD pattern of a pure 1:3 co-spray dried dispersion of Compound 1 and Compound 2 as an amorphous entity.Figure 7 represents a differential scanning calorimetry (DSC) trace of a pure 1:3 coSDD of Compound 1 and Compound 2 showing a transition to a Tg of 155°C. III. SPRAY-DRIED DISPERSIONS COMPRISING LOVE THERAPEUTIC AGENTS A. Spray-Dried Dispersions Unlike the embodiments described above, which were substantially polymer-free, the spray-dried dispersions of the present embodiment may comprise a polymer. Starting from Compound 1 or Compound 2, the amorphous form of Compound 1 or Compound 2 may be prepared by spray-drying methods described above, except that a polymer may be present. Solid dispersions comprising amorphous Compound 1 and Compound 2, and a polymer (or solid carrier) are also included herein. For example, Compound 1 and Compound 2 are present as amorphous compounds as a component of a solid amorphous dispersion. The solid amorphous dispersion generally includes Compound 1 and Compound 2 and a polymer. Illustrative polymers include cellulosic polymers such as HPMc, HPMCAS, or pyrrolidone-containing polymers such as PVP / VA. In some embodiments, the solid amorphous dispersion includes one or more additional excipients, such as a surfactant. In one embodiment, a polymer is capable of dissolving in aqueous media. The solubility of polymers can be pH-independent or pH-dependent. The latter includes one or more enteric polymers. The term "enteric polymer" refers to a polymer that is preferentially soluble in the less acidic environment of the intestine compared to the more acidic environment of the stomach; for example, a polymer that is insoluble in acidic aqueous media but soluble when the pH is above 5–6. A suitable polymer must be chemically and biologically inert. To improve the physical stability of solid dispersions, the glass transition temperature (Tg) of the polymer should be as high as possible. For example, the polymers have a glass transition temperature at least equal to or higher than the glass transition temperature of the drug (i.e., Compound 1).Other polymers have a glass transition temperature that is within approximately 10 to approximately 15°C of the drug (i.e., Compound 1). Examples of suitable glass transition temperatures for polymers include at least approximately 90°C, at least approximately 95°C, at least approximately 100°C, at least approximately 105°C, at least approximately 110°C, at least approximately 115°C, at least approximately 120°C, at least approximately 125°C, at least approximately 130°C, at least approximately 135°C, at least approximately 140°C, at least approximately 145°C, at least approximately 150°C, at least approximately 155°C, at least approximately 160°C, at least approximately 165°C, at least approximately 170°C, or at least approximately 175°C (measured under dry conditions).Without wishing to limit ourselves to theory, it is believed that the underlying mechanism is that a polymer with a higher Tg generally has lower molecular mobility at room temperature, which may be a crucial factor in stabilizing the physical stability of the solid dispersion. Additionally, the hygroscopicity of the polymers should be as low as, for example, less than approximately 10%. For the purpose of comparison in this application, the hygroscopicity of a polymer or composition is characterized at approximately 60% relative humidity. In some preferred embodiments, the polymer has less than approximately 10% water absorption, for example, less than approximately 9%, less than approximately 8%, less than approximately 7%, less than approximately 6%, less than approximately 5%, less than approximately 4%, less than approximately 3%, or less than approximately 2% water absorption. Hygroscopicity can also affect the physical stability of solid dispersions.Generally, moisture adsorbed onto polymers can greatly reduce the Tg of the polymers as well as the resulting solid dispersions, which will further reduce the physical stability of the solid dispersions as described above. In one embodiment, the polymer is one or more water-soluble polymers or partially water-soluble polymer(s). Water-soluble or partially water-soluble polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., p-cyclodextrin) and copolymers and derivatives thereof, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate). In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC), such as HPMC E50, HPMC E15, or HPMC E3. As discussed herein, the polymer may be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methylcellulose phthalates (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC), or a salt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP); or polymethacrylates (e.g., Eudragit® S). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the polymer is HG grade hydroxypropyl methylcellulose acetate succinate (HPMCAS-HG). In yet another embodiment, the polymer is a polyvinylpyrrolidone copolymer, for example, vinylpyrrolidone / vinyl acetate (PVP / VA) copolymer. According to the invention, where Compound 1 forms a solid dispersion with a polymer, for example with an HPMC, HPMCAS, or PVP / VA polymer, the amount of polymer relative to the total weight of the solid dispersion varies from approximately 10% to 30% by weight. Unless otherwise specified, the percentages of drug, polymer, and other excipients as described in a dispersion are given as weight percentages. The amount of polymer is typically at least approximately 20%, and preferably at least approximately 30%, for example, at least approximately 35%, at least approximately 40%, at least approximately 45%, or approximately 50% (e.g., 49.5%).The amount is typically approximately 99% or less, and preferably approximately 80% or less, for example, approximately 75% or less, approximately 70% or less, approximately 65% ​​or less, approximately 60% or less, or approximately 55% or less. In one embodiment, the polymer is present in an amount of up to approximately 50% of the total weight of the dispersion (and even more specifically, between approximately 40% and 50%, such as approximately 49%, approximately 49.5%, or approximately 50%). HPMCAS is available in several varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, and AS-HG. Each of these grades varies with the percentage of acetate and uccinate substitution. In some embodiments, Compound 1 or Compound 2 and the polymer are present in approximately equal amounts; for example, each of the polymers and the drug constitutes approximately half the weight percent of the dispersion. For example, the polymer is present at approximately 49.5% and Compound 1 or Compound 2 is present at approximately 50%. In another embodiment, Compound 1 or Compound 2 is present in an amount greater than half the weight percent of the dispersions. For example, the polymer is present at approximately 20% and Compound 1 or Compound 2 is present at approximately 80%. In some embodiments, Compound 1 or Compound 2 and the combined polymer represent from 1% to 20% w / w of the total solid content of the non-solid dispersion before spray drying. In some embodiments, Compound 1 or Compound 2 and the combined polymer represent from 5% to 15% w / w of the total solid content of the non-solid dispersion before spray drying. In some embodiments, Compound 1 or Compound 2 and the combined polymer represent approximately 11% w / w of the total solid content of the non-solid dispersion before spray drying. In some embodiments, the dispersion also includes other minor ingredients, such as a surfactant (e.g., SLS). In some embodiments, the surfactant is present in less than approximately 10% of the dispersion, for example, less than approximately 9%, less than approximately 8%, less than approximately 7%, less than approximately 6%, less than approximately 5%, less than approximately 4%, less than approximately 3%, less than approximately 2%, approximately 1%, or approximately 0.5%. The polymer should be present in an amount effective in stabilizing the solid dispersion. Stabilization includes inhibiting or preventing the crystallization of Compound 1 or Compound 2. Such stabilization would inhibit the conversion of Compound 1 or Compound 2 from the amorphous to the crystalline form. For example, the polymer would prevent at least a portion (e.g., approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, or more) of Compound 1 or Compound 2 from converting from an amorphous to a crystalline form.Stabilization can be measured, for example, by measuring the glass transition temperature of the solid dispersion, measuring the relaxation rate of the amorphous material, or by measuring the solubility or bioavailability of Compound 1 or Compound 2. The polymers suitable for use in combination with Compound 1 or Compound 2, for example to form a solid dispersion such as an amorphous solid dispersion, must have one or more of the following properties: The glass transition temperature of the polymer should be at least approximately 10–15°C lower than the glass transition temperature of Compound 1 or Compound 2. In some cases, the glass transition temperature of the polymer is higher than the glass transition temperature of Compound 1 or Compound 2, and generally at least 50°C higher than the desired storage temperature of the pharmaceutical product. For example, at least approximately 100°C, at least approximately 105°C, at least approximately 105°C, at least approximately 110°C, at least approximately 120°C, at least approximately 130°C, at least approximately 140°C, at least approximately 150°C, at least approximately 160°C, at least approximately 160°C, or higher. The polymer should have similar or better solubility in solvents suitable for spray drying processes relative to Compound 1 or Compound 2. In some embodiments, the polymer will dissolve in one or more of the same solvents or solvent systems as Compound 1 or Compound 2. The polymer, when combined with Compound 1 or Compound 2, for example in a solid dispersion or a liquid suspension, should increase the solubility of Compound 1 in aqueous media and physiologically relative to, or relative to, the solubility of Compound 1 or Compound 2 in the absence of the polymer or relative to the solubility of Compound 1 or Compound 2 when combined with a reference polymer. For example, the polymer could increase the solubility of amorphous Compound 1 or Compound 2 by reducing the amount of amorphous Compound 1 or Compound 2 that is converted to crystalline Compound 1 or Compound 2, either from an amorphous solid dispersion or from a liquid suspension. The polymer should decrease the relaxation rate of the amorphous substance. The polymer should increase the physical and / or chemical stability of Compound 1 or Compound 2. The polymer should improve the manufacturability of either Compound 1 or Compound 2. The polymer should improve one or more of the handling, administration, or storage properties of Compound 1 or Compound 2. The polymer should not interact unfavorably with other pharmaceutical components, for example, excipients. The suitability of a candidate polymer (or other component) can be tested using the spray-drying (or other) methods described herein to form an amorphous composition. The candidate composition can be compared in terms of stability, resistance to crystallization, or other properties, and is compared to a reference preparation, for example, a preparation of pure amorphous Compound 1 or Compound 2. For example, a candidate composition could be tested to determine whether it inhibits the time to onset of solvent-mediated crystallization, or the percentage conversion at a given time under controlled conditions, by at least 50%, 75%, or 100%, as well as the reference preparation; or a candidate composition could be tested to determine whether it has improved bioavailability or solubility relative to crystalline Compound 1 or Compound 2. The spray-dried dispersion of the present embodiment may include a surfactant as described above. B. Spray-dried dispersion mixtures The pharmaceutical composition according to the invention comprises a mixture of a first spray-dried dispersion and a second spray-dried dispersion, wherein the first spray-dried dispersion comprises (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, and the second spray-dried dispersion comprises N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamide. In some embodiments, the pharmaceutical composition comprises a ratio of (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 to N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamide ranging from approximately 1:10 to approximately 10:1 by weight. For example, the ratio of (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 to N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamide is approximately 1:1 by weight.In other examples, the ratio of (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 amory to N-[2, 4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl]-1, 4-dihydro-4-oxoquinolin-3-carboxamide amory is approximately 1:3 by weight. In some examples, the ratio of (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 amory to N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamide amory is approximately 1:6 by weight.In some examples, the ratio of (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 amory to N-[2, 4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl]-1, 4-dihydro-4-oxoquinolin-3-carboxamide amory is approximately 2:3 by weight. In some embodiments, the pharmaceutical composition comprises a ratio of the first spray-dried dispersion to the second spray-dried dispersion of approximately 1:10 to approximately 10:1 by weight. For example, the ratio of the first spray-dried dispersion to the second spray-dried dispersion is approximately 1:1 by weight. In other examples, the ratio of the first spray-dried dispersion to the second spray-dried dispersion is approximately 1:3 by weight. In some examples, the ratio of the first spray-dried dispersion to the second spray-dried dispersion is approximately 1:6 by weight. In some examples, the ratio of the first spray-dried dispersion to the second spray-dried dispersion is approximately 2:3 by weight. In some embodiments, the first spray-dried dispersion further comprises a cellulose polymer. For example, the first spray-dried dispersion further comprises hydroxypropyl methylcellulose (HPMC). For example, the first spray-dried dispersion comprises a ratio of HPMC to (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 ranging from approximately 1:10 to approximately 1:1. In some cases, the ratio of HPMC to (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 is approximately 1:3 to approximately 1:5. In other embodiments, the second spray-dried dispersion further comprises a cellulose polymer. For example, the second spray-dried dispersion further comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the spray-dried dispersion comprises a plurality of particles having an average particle diameter of approximately 5 to approximately 100 micrometers. In some embodiments, the first spray-dried dispersion comprises a particle having an average particle diameter of approximately 5 to approximately 30 micrometers. In some embodiments, the first spray-dried dispersion comprises a particle having an average particle diameter of approximately 15 micrometers. In some embodiments, the spray-dried dispersion comprises a plurality of particles having an average particle diameter of approximately 5 to approximately 100 micrometers. In some embodiments, the second spray-dried dispersion comprises a particle having an average particle diameter of approximately 5 to approximately 30 micrometers. In some embodiments, the second spray-dried dispersion comprises a particle having an average particle diameter of approximately 15 micrometers. In some embodiments, the first spray-dried dispersion comprises from approximately 70% by weight to approximately 95% by weight (e.g., from approximately 75% by weight to approximately 85% by weight) of Compound 1. In some embodiments, the second spray-dried dispersion comprises from approximately 70% by weight to approximately 95% by weight (e.g., from approximately 75% by weight to approximately 85% by weight) of Compound 2. In one embodiment, the pharmaceutical composition comprises a mixture of a first spray-dried dispersion and a second spray-dried dispersion generated by combining a first spray-dried dispersion and a second spray-dried dispersion, wherein the first spray-dried dispersion comprises 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 (Compound 1), and the second spray-dried dispersion comprises N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamide (Compound 2). In some embodiments, the pharmaceutical composition comprises a ratio of amorphous Compound 1 to amorphous Compound 2 that varies from approximately 1:10 to approximately 10:1 by weight. For example, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 1:1 by weight. In other examples, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 1:3 by weight. In some examples, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 1:6 by weight. In some examples, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 2:3 by weight. In some embodiments, the first spray-dried dispersion further comprises a cellulose polymer. For example, the first spray-dried dispersion further comprises hydroxypropyl methylcellulose (HPMC). In other embodiments, the second spray-dried dispersion further comprises a cellulose polymer. For example, the second spray-dried dispersion further comprises hypromellose acetate succinate (HPMCAS). A method for generating a pharmaceutical composition comprising (i) providing a first mixture comprising Compound 1, a cellulose polymer, and a solvent; (ii) forcing the first mixture through a nozzle under spray-drying conditions to generate the first spray-dried dispersion comprising the amorphous Compound 1; (iii) providing a second mixture comprising Compound 2, a cellulose polymer, and a solvent; (iv) forcing the second mixture through a nozzle under spray-drying conditions to generate the second spray-dried dispersion comprising the amorphous Compound 2; and (v) combining the first spray-dried dispersion and the second spray-dried dispersion. In some implementations, the cellulose polymer of the first mixture is HPMC. In some implementations, the initial mixture comprises a ratio of HPMC to Compound 1 that varies from approximately 1:10 to approximately 1:1 by weight. For example, the ratio of HPMC to Compound 1 is approximately 1:3 to approximately 1:5 (e.g., approximately 1:4) by weight. In some implementations, the first mixture further comprises a solvent, and the solvent comprises a polar organic solvent. Examples of polar organic solvents include methyl ethyl ketone, THF, methanol, DCM, or IPA, or any combination thereof, such as a DCM / methanol mixture. In other examples, the solvent further comprises water. For example, the solvent could be methyl ethyl ketone / water, THF / water, methanol / water, or methyl ethyl ketone / water / IPA. For example, the ratio of the polar organic solvent to water is approximately 70:30 to approximately 95:5 by volume. In other cases, the ratio of the polar organic solvent to water is approximately 90:10 by volume. In other implementations, the cellulose polymer of the second mixture is HPMCAS. In some implementations, the second mixture comprises a ratio of HPMCAS to Compound 2 that varies from approximately 1:14 to approximately 1:2 by weight. For example, the ratio of HPMCAS to Compound 2 is approximately 1:4 to approximately 1:6 (e.g., approximately 1:5) by weight. In some implementations, the second mixture also comprises a solvent, and the solvent comprises a polar organic solvent. Examples of polar organic solvents include methyl ethyl ketone, THF, methanol, DCM, or IPA, or any combination thereof, such as a DCM / methanol mixture. In other examples, the solvent also comprises water. For example, the solvent could be methyl ethyl ketone / water, THF / water, methanol / water, or methyl ethyl ketone / water / IPA. For example, the ratio of the polar organic solvent to water is approximately 70:30 to approximately 95:5 by volume. In other cases, the ratio of the polar organic solvent to water is approximately 90:10 by volume. Some implementations also involve filtering the first mixture before it is forced through the nozzle. Such filtration can be achieved using any suitable filter medium with an appropriate pore size (e.g., 20 µm or less). Similarly, the second mixture can also be filtered before being forced through the nozzle. Some implementations also involve drying the first spray-dried dispersion, the second spray-dried dispersion, or both. For example, the spray-dried dispersion—that is, the first spray-dried dispersion, the second spray-dried dispersion, or both—is dried under reduced pressure. In other examples, the spray-dried dispersion is dried at a temperature of approximately 30°C to approximately 60°C. Figures 12 and 13 show that the same remarkable stability of Compound 1 in the presence of Compound 2 is present even in a mixture of two separate spray-dried dispersions. Figures 12 and 13 depict the crystallization kinetics of Compound 1 at 75% relative humidity and 80°C and 70°C, respectively. The triangles represent a tablet formulation of a mixture of the two separate spray-dried dispersions of Compound 1 and Compound 2. The circles represent the same tablet formulation but without Compound 2. The squares represent the separate spray-dried dispersion of Compound 1. Comparing the tablet mixture formulation with the Compound 2-free tablet formulation, it can be seen that Compound 1 is significantly more stable toward crystallization in the presence of Compound 2.Compound 1 is also more stable in the tablet formulation with Compound 2 than in the spray-dried dispersion of separate Compound 1. An explanation for this phenomenon is shown in Figure 14. As seen in the spray-dried dispersion of Compound 1 and Compound 2 substantially free of polymer (Figure 3A), a mixture of two spray-dried dispersions comprising Compound 1 and Compound 2 results in the two compounds interacting at the molecular level. Figure 14 represents the solid-state 1H NMR spectrum of a tablet comprising a mixture of a spray-dried dispersion of Compound 1 and a spray-dried dispersion of Compound 2 at 70°C and 75% relative humidity. The upper spectrum is the reference 1H NMR spectrum that identifies the tablet components, and the lower spectrum is generated by cross-polarization of the fluorine atom with protons in Compound 1 and spin diffusion between protons in Compound 1 and Compound 2, resulting in peak growth for Compound 2.Surprisingly, the molecular interaction between Compound 1 and Compound 2 exists in the mixture at temperatures above Tg, as well as in the co-spray dried dispersion that is substantially polymer-free. C. Spray-Dried CO2 Dispersions Comprising Multiple APIs A spray-dried dispersion comprising amorphous Compound 1 and amorphous Compound 2 prepared by jointly drying a mixture of Compound 1, Compound 2, a solvent, and a polymer. In some embodiments, the spray-dried dispersion comprises a ratio of amorphous Compound 1 to amorphous Compound 2 ranging from approximately 1:10 to approximately 10:1 by weight. For example, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 1:1 by weight. In other examples, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 1:3 by weight. In some examples, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 1:6 by weight. In some examples, the ratio of amorphous Compound 1 to amorphous Compound 2 is approximately 2:3 by weight. In some embodiments, the spray-dried dispersion further comprises a cellulose polymer. For example, the spray-dried dispersion comprises HPMC, HPMCAS, or any combination thereof. In some embodiments, the spray-dried dispersion comprises approximately 35% by weight to approximately 60% by weight of amorphous Compound 1. In some embodiments, the spray-dried dispersion comprises approximately 20% by weight to approximately 45% by weight of amorphous Compound 2. In some embodiments, the spray-dried dispersion has a glass transition temperature (Tg) of approximately 80°C to approximately 180°C. In some embodiments, the spray-dried dispersion comprises a plurality of particles having an average particle diameter of approximately 5 to approximately 100 micrometers. In some embodiments, the spray-dried dispersion comprises a plurality of particles having an average particle diameter of approximately 5 to approximately 30 micrometers. In some embodiments, the spray-dried dispersion comprises a plurality of particles having an average particle diameter of approximately 15 micrometers. In some embodiments, the spray-dried dispersion is substantially amorery. Examples of polar organic solvents include methyl ethyl ketone, THF, DCM, methanol, or IPA, or any combination thereof. In other examples, the solvent also includes water. For example, the solvent could be methyl ethyl ketone / water, THF / water, or methyl ethyl ketone / water / IPA. For example, the ratio of the polar organic solvent to water is approximately 70:30 to approximately 95:5 by volume. In other cases, the ratio of the polar organic solvent to water is approximately 90:10 by volume. Some embodiments further involve filtering the mixture before it is forced through the nozzle. Such filtration can be achieved using any suitable filter medium having an appropriate pore size (e.g., 20 µm or less). Some implementations also involve drying the spray-dried dispersion. For example, the spray-dried dispersion is dried under reduced pressure. In other examples, the spray-dried dispersion is dried at a temperature of approximately 30°C to approximately 60°C. D. Beneficial Properties of Spray-Dried Dispersions of API Amorías The phenomena of a therapeutic agent having enhanced properties in the presence of another therapeutic agent are not limited to the substantially polymer-free, pure spray-dried dispersions described above. These phenomena are demonstrated in the present embodiment of a mixture of two individual spray-dried dispersions. For example, Compound 1 has increased physical stability in a mixture of a spray-dried dispersion of Compound 1 and a spray-dried dispersion of Compound 2, as shown in Tables 2 and 3. Table 2 lists the % crystallization of an 80 wt% spray-dried dispersion of Compound 1 over time at 80°C and 75% relative humidity in the absence of Compound 2.Table 3 lists the % crystallization of Compound 1 in the presence of Compound 2 in a tablet of the present invention comprising a mixture of SDD of Compound 1 and SDD of Compound 2 at 80°C at 75% relative humidity. Table 2. Table 3. At approximately 25 hours, 46% of Compound 1 crystallized in the absence of Compound 2, whereas only 10% of Compound 1 crystallized when Compound 2 was present. This phenomenon of increased stability when one therapeutic agent is in the presence of another is also demonstrated when two therapeutic agents are co-spray dried from the same solvent. Referring to Figure 9, the three sets of bar graphs on the far right demonstrate that the unexpected stability of Compound 1 in the presence of Compound 2 is not limited to the pure co-spray dried dispersion of Compound 1 and Compound 2, nor to a mixture of the two individual spray-dried dispersions. The first of these bar sets, labeled Compound 1 SDD (50% HPMCAS), is a spray-dried dispersion of Compound 1 and HPMCAS, without Compound 2. The remaining two bar sets represent the concentration of Compound 1 within a co-spray dried dispersion of Compound 1, Compound 2, and a polymer.Comparing the concentrations of Compound 1 in sticks labeled 1:1 coSDD (20% HPMCAS), which is a 1:1 ratio of Compound 1 to spray-dried dispersion of Compound 2 with HPMCAS, to those labeled Compound 1 SDD (50% HPMCAS), which is a spray-dried dispersion of Compound 1 with HPMCAS alone, it can be seen that the concentration stability is greater for Compound 1 over the 72 h when Compound 2 is present. Greater stability can also be seen in the set of sticks labeled 2:1 coSDD (20% HPMCAS), which is a 2:1 ratio of Compound 1 to spray-dried dispersion of Compound 2 with HPMCAS, where the concentration of Compound 1 is more constant than in the spray-dried dispersion formulation of Compound 1 (50% HPMCAS). As with the spray-dried dispersion of Compound 1 and Compound 2, the unexpected stability in FedSIF solutions is not limited to Compound 1. In Figure 10, the first set of bars on the far right labeled Compound 2 SDD (20% HPMCAS) is a spray-dried dispersion of Compound 2 and HPMCAS, without Compound 1. The two remaining sets of bars represent the concentration of Compound 2 within a spray-dried dispersion of Compound 1, Compound 2, and polymer.Comparing the concentrations of Compound 2 in the sticks labeled 1:1 coSDD (20% HPMCAS), which is a 1:1 ratio of Compound 1 to spray-dried dispersion of Compound 2 with HPMCAS, with those labeled Compound 2 SDD (20% HPMCAS), which is a spray-dried dispersion of Compound 2 with HPMCAS alone, it can be seen that the concentration stability is greater for Compound 2 over the 72 h when Compound 1 is present. Greater stability can also be seen in the set of sticks labeled 2:1 coSDD (20% HPMCAS), which is a 2:1 ratio of Compound 1 to spray-dried dispersion of Compound 2 with HPMCAS, where the concentration of Compound 2 is more consistent than in the Compound 2 SDD (20% HPMCAS) formulation. Without wishing to limit themselves to theory, when dealing with solvent systems, such as in vitro solvent systems like FedSIF, or in vivo solvent systems such as those within a patient after ingesting Compound 1 before, after, or concurrently with Compound 2, the inventors propose that Compound 1 and Compound 2 act to prevent nucleation with each other. Such a phenomenon, sometimes called poisoning nucleation, is structurally unpredictable. IV. PHARMACEUTICAL COMPOSITIONS In one embodiment, the present invention provides a pharmaceutical composition as claimed, and a pharmaceutically acceptable vehicle, adjuvant or carrier. A. Pharmaceutically Acceptable Vehicles, Adjuvants and Carriers As described above, the pharmaceutical compositions of the present invention may further comprise a pharmaceutically acceptable vehicle, adjuvant, or carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface-active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, suitable for the particular desired dosage form. (Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC.)Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, describe various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Except to the extent that any conventional carrier medium is incompatible with the compounds of the invention, such as producing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. In one embodiment, the pharmaceutical compositions of the present invention comprise a filler, a disintegrant, and a lubricant. The fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition; that is, they do not substantially reduce the solubility, hardness, chemical stability, physical stability, or biological activity of the pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses (e.g., sodium carboxymethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g., corn starch, potato starch), sugars (e.g., sorbitol, lactose, sucrose, or the like), or any combination thereof. In one embodiment, the filler is microcrystalline cellulose. Therefore, in one embodiment, the pharmaceutical composition comprises at least one filler in an amount of at least 5% by weight (e.g., at least approximately 20% by weight, at least approximately 30% by weight, or at least approximately 40% by weight) of the composition. For example, the pharmaceutical composition comprises from approximately 10% to approximately 60% by weight (e.g., from approximately 20% to approximately 55% by weight, from approximately 25% to approximately 50% by weight, or from approximately 27% to approximately 45% by weight) of filler, by weight of the composition. In another example, the pharmaceutical composition comprises at least approximately 20% by weight (e.g., at least 30% or at least 40% by weight) of microcrystalline cellulose, for example, MCC Avicel PH102, by weight of the composition.In yet another example, the pharmaceutical composition comprises from approximately 10% by weight to approximately 60% by weight (e.g., from approximately 20% by weight to approximately 55% by weight or from approximately 25% by weight to approximately 45% by weight) of microcellulose, by weight of the composition. The disintegrants suitable for the invention improve the dispersion of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition; that is, they do not substantially reduce the chemical stability, physical stability, hardness, or biological activity of the pharmaceutical composition. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof. In one embodiment, the disintegrant is croscarmellose sodium. Therefore, in one embodiment, the pharmaceutical composition comprises a disintegrant in an amount of approximately 10% by weight or less (e.g., approximately 7% by weight or less, approximately 6% by weight or less, or approximately 5% by weight or less) by weight of the composition. For example, the pharmaceutical composition comprises from approximately 1% by weight to approximately 10% by weight (e.g., from approximately 1.5% by weight to approximately 7.5% by weight or from approximately 2.5% by weight to approximately 6% by weight) of the disintegrant, by weight of the composition. In another example, the pharmaceutical composition comprises approximately 10% by weight or less (e.g., 7% by weight or less, 6% by weight or less, or 5% by weight or less) of croscarmellose sodium, by weight of the composition.In another example, the pharmaceutical composition comprises approximately 1% to approximately 10% by weight (e.g., approximately 1.5% to approximately 7.5% or approximately 2.5% to approximately 6%) of croscarmellose sodium, by weight of the composition. In some examples, the pharmaceutical composition comprises approximately 0.1% to approximately 10% by weight (e.g., approximately 0.5% to approximately 7.5% or approximately 1.5% to approximately 6%) of disintegrant, by weight of the composition. In other examples, the pharmaceutical composition comprises from approximately 0.5% to approximately 10% by weight (e.g., from approximately 1.5% by weight to approximately 7.5% by weight or from approximately 2.5% by weight to approximately 6% by weight) of disintegrant, by weight of the composition. In some embodiments, the pharmaceutical composition may comprise a lubricant that prevents the adhesion of a granular-bead mixture to a surface (e.g., a mixing vessel surface, a compression die, and / or a punch). A lubricant may also reduce friction between particles within the granules and improve the compression and ejection of compressed pharmaceutical compositions from a die press. The lubricant is also compatible with the ingredients of the pharmaceutical composition; that is, it does not substantially reduce the solubility, hardness, or biological activity of the pharmaceutical composition. Examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, or any combination thereof. In this embodiment, the lubricant is magnesium stearate. Therefore, in one embodiment, the pharmaceutical composition comprises a lubricant in an amount of 5% by weight or less (e.g., 4.75% by weight, 4.0% by weight or less, or 3.00% by weight or less, or 2.0% by weight or less) by weight of the composition. For example, the pharmaceutical composition comprises from approximately 5% by weight to approximately 0.10% by weight (e.g., from approximately 4.5% by weight to approximately 0.5% by weight or from approximately 3% by weight to approximately 1% by weight) of lubricant, by weight of the composition. In another example, the pharmaceutical composition comprises 5% by weight or less (e.g., 4.0% by weight or less, 3.0% by weight or less, or 2.0% by weight or less, or 1.0% by weight or less) of magnesium stearate, by weight of the composition.In yet another example, the pharmaceutical composition comprises from approximately 5% by weight to approximately 0.10% by weight (e.g., from approximately 4.5% by weight to approximately 0.15% by weight or from approximately 3.0% by weight to approximately 0.50% by weight) of magnesium stearate, by weight of the composition. The pharmaceutical compositions of the invention may optionally comprise one or more colorants, flavorings, and / or fragrances to enhance the visual appearance, taste, and / or aroma of the composition. The suitable colorants, flavorings, or fragrances are compatible with the ingredients of the pharmaceutical composition; that is, they do not substantially reduce the solubility, chemical stability, physical stability, hardness, or biological activity of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a colorant, a flavoring, and / or a fragrance. In some embodiments, the tablets of the present invention may be coated with a colorant and optionally labelled with a logo, other image, and / or text using a suitable ink. In other embodiments, the pharmaceutical composition includes or may be prepared in tablets, and the tablets may be coated with a colorant, waxed, and optionally labelled with a logo, other image, and / or text using a suitable ink. The suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition; that is, they do not substantially reduce the solubility, chemical stability, physical stability, hardness, or biological activity of the pharmaceutical composition. The suitable colorants and inks may be of any color and are water-based or solvent-based.In one embodiment, tablets prepared from the pharmaceutical composition are coated with a dye and then labelled with a logo, other image, and / or text using suitable ink. For example, tablets comprising a pharmaceutical composition as described herein may be coated with approximately 3% by weight (e.g., less than approximately 6% by weight or less than approximately 4% by weight) of a film coating comprising a dye. The colored tablets may be labelled with a logo and text indicating the strength of the active ingredient in the tablet using suitable ink. In another example, tablets comprising a pharmaceutical composition as described herein may be coated with approximately 3% by weight (e.g., less than approximately 6% by weight or less than approximately 4% by weight) of a film coating comprising a dye. In another embodiment, tablets prepared from the pharmaceutical composition are coated with a dye, waxed, and then marked with a logo, other image, and / or text using suitable ink. For example, tablets comprising the pharmaceutical composition as described herein may be coated with approximately 3% by weight (e.g., less than approximately 6% by weight or less than approximately 4% by weight) of a film coating comprising a dye. The colored tablets may be waxed with carnauba wax powder weighed in an amount of approximately 0.01% w / w of the weight of the starting tablet core. The waxed tablets may be labelled with a logo and text indicating the strength of the active ingredient in the tablet using suitable ink.In another example, tablets comprising a pharmaceutical composition as described herein may be coated with approximately 3% by weight (e.g., less than approximately 6% by weight or less than approximately 4% by weight) of a film coating comprising a colorant. The colored tablets may be waxed with carnauba wax powder weighed in an amount of approximately 0.01% w / w of the weight of the starting tablet core. The waxed tablets may be labelled with a logo and text indicating the strength of the active ingredient in the tablet using a pharmaceutical-grade ink such as black ink (e.g., Opacode® S-1-17823, a solvent-based ink, commercially available from Colorcon, Inc. of West Point, PA). B. Additional Therapeutic Agent(s) In another embodiment, the pharmaceutical compositions of the present invention further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent is a CFTR modulator. In one embodiment, the additional therapeutic agent is a CFTR corrector. In one embodiment, the additional therapeutic agent is a CFTR enhancer. In another embodiment, the pharmaceutical composition comprises a spray-dried dispersion of the present invention and one or more of the following additional therapeutic agents. In another embodiment, the additional therapeutic agent is selected from: 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof; (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, or a pharmaceutically acceptable salt thereof; either 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid, or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition of the present invention comprises 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition of the present invention comprises (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, or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition of the present invention comprises 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-N)propanecarboxamido)isoquinoNn-1-N)benzoic acid, or a pharmaceutically acceptable salt thereof. In another embodiment, the additional therapeutic agent is selected from Table 4. Table 4: Additional agents for combination therapies. (continuation) In one embodiment, the additional therapeutic agent is selected from Table 5. T l : A n iin lrri min . (continuation) In another embodiment, the additional therapeutic agent is selected from N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinolin-3-carboxamide, or a pharmaceutically acceptable salt thereof; or N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinolin-3-carboxamide, or a pharmaceutically acceptable salt thereof. In another embodiment, the additional therapeutic agent is selected from Table 6. T l : A niinlrrim in i n. In one embodiment, the additional therapeutic agent is selected from a mucolytic agent, bronchodilator, antibiotic, anti-infective agent, CFTR modulator, or anti-inflammatory agent. In one embodiment, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosol form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for inhalation administration, levofloxacin, including aerosol formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin. In another embodiment, the additional therapeutic agent is a mucolith. Exemplary mucoliths useful herein include Pulmozyme®. In another embodiment, the additional therapeutic agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabulin sulfate. In another embodiment, the additional therapeutic agent is effective in restoring fluid to the surface of the pulmonary airways. Such agents enhance the movement of salt into and out of cells, allowing the mucus of the pulmonary airways to be more hydrated and thus cleared more easily. Examples of such agents include hypertonic saline solution, tetrasodium denufosol ([[(3S,5R)-5-(4-amino-2-oxopirimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxyhydroxyphosphoryl][[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxyhydroxyphosphoryl]oxyhydroxyphosphoryl]hydrogen phosphate), or bronchitol (an inhaled formulation of mannitol). In another embodiment, the additional therapeutic agent is an anti-inflammatory agent, that is, an agent that can reduce inflammation in the lungs. Examples of such useful agents include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin. In another embodiment, the additional therapeutic agent is a compound that induces CFTR activity other than a compound of formula I. Examples of such agents include ataluren ("PTC124®"; 3-[5-(2-fluorophenyl)-1,2,4]-oxadiazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (a recombinant human neutrophil elastase inhibitor), and cobiprostone (7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl}heptanoic acid). In another embodiment, the additional therapeutic agent is a nutritional agent. Exemplar nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase. In another embodiment, the additional therapeutic agent is a compound selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, phylloxine B, geniestein, apigenin, cAMP / cGMP enhancers or inducers such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol, albuterol, and almeterol, deoxyspergualine, HSP 90 inhibitors, HSP 70 inhibitors, proteasome inhibitors such as epoxomycin, lactacystin, or similar agents. In other embodiments, the additional therapeutic agent is a compound disclosed in WO 2004028480, WO 2004110352, WO 2005094374, WO 2005120497, or WO 2006101740. In another embodiment, the additional agent is a benzo[c]quinolizinium derivative exhibiting CFTR-inducing or augmenting activity or a benzopyran derivative exhibiting CFTR-inducing or augmenting activity. In another embodiment, the additional agent is a compound disclosed in US Patent No. 7,202,262, US Patent No. 6,992,096, US20060148864, US20060148863, US20060035943, US20050164973, WO2006110483, WO2006044456, WO2006044682, WO2006044505, WO2006044503, WO2006044502, or WO2004091502. In another embodiment, the additional agent is a compound disclosed in WO2004080972, WO2004111014, WO2005035514, WO2005049018, WO2006099256, WO2006127588, or WO2007044560. In another embodiment, the additional therapeutic agent is selected from the categories of ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HI antihistamines, PAF antagonists, MAP-kinase inhibitors, MPR4 inhibitors, iNOS inhibitors, or SYK inhibitors, or double or triple combinations thereof. In another embodiment, the additional therapeutic agent is an ENaC inhibitor selected from dipropylcarbamoylmethyl ester of 3-(3-{2-[(E)-3,5-diamino-6-chloropyrazine-2-carbonilimino]-1,3,8-triazaspiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid; cyclohexyloxycarbonylmethyl ester of [4-(3-{2-[(Z)-3.5-diamino-6-chloropyrazine-2-carbonilimino]-1,3,8-triazaspiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]acetic acid; [(2-hydroxyethyl)-methylcarbamoyl]-methyl ester; cyclohexyloxycarbonylmethyl ester of acid [4-(3-{2-[(E)-3,5-diamino-6-chloropyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid; 3-(3-{2-[(E)-3,5-diamino-6-chloropyrazine-2-carbonylimino]-1,3,8-triazaspiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid; dimethylcarbamoylmethyl acid ester [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triazaspiro[4.5]dec-8-yl}-3-oxo-propyl) -fhenoxi]-acético; dipropylcarbamoylmetil éster de ácido [4- (3-{2-[ (E) -3, 5-diamino-6-cloro-pyrazine-2-carbonilimino]-1, 3, 8-triazaspiro[4.5]dec-8-yl}-3-oxo-propyl) -fenoxi]-acético; terc-butoxicarbonilmetil éster de ácido [4- (3-{2-[ (E) -3, 5-diamino-6-cloro-pyrazine-2-carbonilimino]-1, 3, 8-triaza- -spiro[4.5]dec-8-yl}-3-oxopropyl) -fenoxi]-acético; benzyloxycarbonylmetil éster de ácido [4- (3-{2-[ (E) -3, 5-diamino-6-cloro-pyrazine-2-carbonilimino]-1, 3, 8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl) -fenoxi]-acético; diethylcarbamoylmetil éster de ácido [4- (3-{2-[ (E) -3, 5-diamino-6-cloro-pyrazine-2-carbonilimino]- 1, 3, 8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl) -fenoxi]-acético; 2-oxo-2-piperidin-1 -il-etil éster de ácido [4- (3-{2-[ (E) -3, 5-diamino-6-cloro-pyrazine-2-carbonilimino]-1, 3, 8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl) -fenoxi]-acetic acid; dipropylcarbamoylmethyl ester of [2-chloro-4-(3-{2-[ (E)-3, 5-diamino-6-chloropyrazine-2-carbonilimino]-1, 3-, 8-triazaspiro[4.5]dec-8-yl}-3-oxo-propyl) -fenoxi]-acetic acid; 2-oxo-2-(2-trifluorometilpirrolidin-1 -yl) -ethyl ester of 3-(3-{2-[ (E)-3, 5-diamino-6-chloropyrazine-2-carbonilimino]-1, 3, 8-triazaspiro[4.5]decano-8-carbonyl}-bencenosulfonilamino) -propionic acid; 2-(2-oxo-piperidin-1-yl)-ethyl ester of [2-chloro-4-(3-{2-[ (E)-3, 5-diamino-6-chloro-pyrazine-2-carbonilimino]-1, 3-, 8-triaza-spiro[4.5]dec-8-yl}-3-oxopropyl) -fenoxi]-acetic acid; 2-morfolin-4-yl-2-oxo-ethyl ester of [4-(3-{2-[ (E)-3, 5-diamino-6-chloro-pyrazine-2-carbonilimino]-1, 3, 8-triazaspiro[4.5]dec-8-yl}-3-oxo-propyl) -fenoxi]-acetic acid; dipropylcarbamoylmethyl éster de ácido 1-[ (3-{2-[ (E) -3, 5-diamino-6-chloro-pyrazine-2-carbonylimino]-1, 3, 8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino) -methyl]-cyclobutanecarboxylic acid; dipropylcarbamoylmethyl ester of 3-[3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonilimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-phenyl) -ureido]-propionic acid; and 2-oxo-2-(2-trifluoromethyl-pyrrolididin-1-yl) -ethyl ester of 1-[(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonilimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino) -methyl]-cyclobutanecarboxylic acid; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the additional therapeutic agent is dipropylcarbamoylmethyl ester of 3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonilimino]1,3,8-triaza-spiro[4,5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid. In another embodiment, the additional agent is a compound disclosed in U.S. Patent No. 8,247.436 and International PCT Application WO2011113894, incorporated herein by reference in their entirety. In another embodiment, the additional agent is a compound disclosed in U.S. Publication No. 20130316981. In another embodiment, the additional therapeutic agent is a beta-mimetic selected from Albuterole, Arformoterole, Bambuterole, Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprenaline, Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Milveterol, Orciprenaline, Pirbuterole, Procaterole, Reproterole, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbutaline, Tiaramide, Tolubuterole, Zinterole, Nolomirole, and 1-(2-chloro-4-hydroxyphenyl)-t-butylaminoethanol; (-)-2-[7(S)-[2(R)-hydroxy-2-(4-hydroxyphenyl)-ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamide hydrochloride monohydrate; 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulfonamide; 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-one;4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl-1]-2(3H)-benzothiazolone; 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino-o]ethanol; 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-m-ethyl-2-butylamino]ethanol; 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol; 1-[2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol; 1-[2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol; 1-[2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1, 2, 4-triazol-3-yl]-2-methyl-2-butylamino}ethanol; 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1, 4-benzoxazin-3-(4H)-one; 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol; 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;6-hydroxy-8-{1-hydroxy-2-[2-(ethylester of 4-phenoxyacetic acid)-1, 1-dimethylethylamino]-ethyl}-4H-benzo[1, 4]oxazin-3-one; 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic acid)-1, 1-dimethylethylamino]-ethyl}-4H-benzo[1, 4]oxazin-3-one; 8-{2-[1, 1-Dimethyl-2-(2, 4, 6-trimethylphenyl)-ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1, 4]oxazin-3-one; 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1, 1-dimethylethylamino]-ethyl}-4H-benzo[1, 4]oxazin-3-one; 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1, 1dimethylethylamino]-ethyl}-4H-benzo[1, 4]oxazin-3-one; 8-{2-[2-(4-Ethyl-phenyl)-1, 1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1, 4]oxazin-3-one; 8-{2-[2-(4-Ethoxyphenyl)-1, 1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1, 4]oxazin-3-one; 4- (4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3, 4-dihydro-2H-benzo[1, 4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid;8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol; N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide; 8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one; 8-Hydroxy-5-[1-hydroxy-2-(6-phenethylaminohexylamino)-ethyl]-1H-quinolin-2-one; 5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one; [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]hexyl-oxy}-butyl)-5-methyl-phenyl]-urea;4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethyl-phenol; 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyl-oxy}-butyl)-benzenesulfonamide;3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]heptyloxy}-propyl)-benzenesulfonamide; 4-(2-{6-[4-(3-cyclopentanesulfonylphenyl)butoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethylphenol; N-adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-propyl}-phenyl)-acetamide; (R, S)-4-(2-{[6-(2, 2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R, S)-4-(2-{[6-(2, 2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R, S) -4-(2-{[4, 4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R, S) -4-(2-{[6-(4, 4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R, S) -5-(2-{[6-(2, 2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one; (R, SH2-({6-[2, 2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;4-(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5-tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenol; (R,S)-[5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl-)-2-hydroxyphenyl]formamide; (R,S)-4-[2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol; (R, S) -N-[3-(1, 1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]urea; 3-[3-(1, 1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2, 4-dione; (R, S) -4-[2-({6-[2, 2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol; 5-((1R)-2-{[6-(2, 2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one;4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[6-(3,3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl-)-2-(hydroxymethyl)phenol; (R,S)-(2-{[6-(2,2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; 3-[2-(3-chlorophenyl)ethoxy]-N-(2-diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)ethylamino]ethyl}propionamide; N-(2-diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)ethylamino]ethyl}-3-(2-naphthalen-1-ylethoxy)propionamide; 7-[2-(2-{3-[2-(2-chlorophenyl)ethylamino]propylsulfanyl}ethylamino)-1-hydroxyethyl]-4-hydroxy-3H-benzothiazol-2-one; o 7-[(1R)-2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}ethylamino)-1-hydroxyethyl]-4-hydroxy-3H-benzothiazol-2-one;optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. Preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate; In one embodiment, the additional therapeutic agent is an anticholinergic selected from the following salts: Tiotropium salts, preferably the bromide salt; Oxytropium salts, preferably the bromide salt; Flutropium salts, preferably the bromide salt; Ipratropium salts, preferably the bromide salt; Aclidinium salts, preferably the bromide salt; Glycopyrronium salts, preferably the bromide salt; Trospium salts, preferably the chloride salt; or Tolterodin. Of the aforementioned salts, the pharmaceutically active part is the cation; the possible anions are chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, or p-toluenesulfonate. Additional examples of preferred anticholinergics are selected from tropenol ester-2,2-diphenylpropionic acid netobromide; scopine ester-2,2-diphenylpropionic acid methobromide;Scopine ester-methobromide of 2-fluoro-2,2-diphenylacetic acid; Troponel ester-methobromide of 2-fluoro-2,2-diphenylacetic acid; Troponel ester-methobromide of 3,3',4,4'-tetrafluorobenzyl acid; Scopine ester-methobromide of 3,3',4,4'-tetrafluorobenzyl acid; Troponel ester-methobromide of 4,4'-difluorobenzyl acid; Scopine ester-methobromide of 4,4'-difluorobenzyl acid; Troponel ester-methobromide of 3,3'-difluorobenzyl acid; Scopine ester-methobromide of 3,3'-difluorobenzyl acid; Tropenol 9-hydroxyfluorene-9-carbon ester-methobromide; Tropenol 9-fluorofluorene-9-carbon ester-methobromide; Scopine 9-hydroxyfluorene-9-carbon ester-methobromide; Scopine 9-fluorofluorene-9-carbon ester-methobromide; Tropenol 9-methylfluorene-9-carbon ester-methobromide; Scopine 9-methylfluorene-9-carbon ester-methobromide; Cyclopropyltropine benzyl acid ester-methobromide;cyclopropyl tropine ester-methobromide of 2,2-diphenylpropionic acid; cyclopropyl tropine ester-methobromide of 9-hydroxyxanthene-9-carbon acid; cyclopropyl tropine ester-methobromide of 9-methylfluorene-9-carbon acid; cyclopropyl tropine ester-methobromide of 9-methylxanthan-9-carbon acid; cyclopropyl tropine ester-methobromide of 9-hydroxyfluorene-9-carbon acid; methyl ester cyclopropyl tropine ester-methobromide of 4,4'-difluorobenzyl acid; tropenol ester-methobromide of 9-hydroxyxanthene-9-carbon acid; scopine ester-methobromide of 9-hydroxyxanthan-9-carbon acid; Tropenol ester-methobromide of 9-methylxanthan-9-carbon acid; Scopine ester-methobromide of 9-methylxanthan-9-carbon acid; Tropenol ester-methobromide of 9-ethylxanthan-9-carbon acid; Tropenol ester-methobromide of 9-difluoromethylxanthan-9-carbon acid; or Scopine ester-methobromide of 9-hydroxymethylxanthan-9-carbon acid. In one embodiment, the additional therapeutic agent is a corticosteroid selected from Beclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Dexamethasone, Etiprednol, Flunisolide, Fluticasone, Loteprednol, Mometasone, Prednisolone, Prednisone, Rofleponide, Triamcinolone, Tipredane, {20R-16alpha, 17alpha-[butylidenebis(oxy)]-6alpha, 9alpha-difluoro-11beta-hydroxy-17beta-(methylthio)androsta-4-en-3-one}; 9-fluoro-11beta, 17, 21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 21-cyclohexanecarboxylate 17-cyclopropanecarboxylate; 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one; flunisolide-21-[4'-(nitrooxymethyl)benzoate]; (S)-fluoromethyl ester of 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothion; (S)-(2-oxo-tetrahydro-furan-3S-yl) ester of 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothion;or 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester; optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. Examples of preferred salts and derivatives are alkali salts, i.e., sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates, or furoates. In one implementation, the additional therapeutic agent is a PDE4 inhibitor selected by Enprofilina, Teofilina, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste, Pumafentrina, Lirimilaste, Apremilaste, Arofilina, Atizorame, Oglemilastum, Tetomilaste; 5-[(N-(2, 5-dichloro-3-pyridinyl)-carboxamida]-8-methoxy-quinoline; 5-[N-(3, 5-dichloro-1-oxido-4-pyridinyl)-carboxamida]-8-methoxy-2-(trifluoro- methyl)-quinoline; N-(3, 5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hidroxiindol-3-yl]glioxyl ácido amida); 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine;4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine; N-[ (3R) -3, 4, 6, 7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrole[3, 2, 1-jk-][1, 4]benzodiazepin-3-yl]-4-pyridinecarboxamida; 4-[6, 7-diethoxy-2, 3-bis(hidroximethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone; 2-[4-[6, 7-dietoxi-2, 3-bis(hidroximethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone;(3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine; beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1, 3-dihydro-1, 3-dioxo-2H-isoindole-2-propanamide; 9-ethyl-2-methoxy-7-methyl-5-propyl-imidazo[1, 5-a]pyrido[3, 2-e]pyrazin-6(-5H)-one; 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl](3S, 5S)-2-piperidinone; 4-[1-[3, 4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha, alpha-bis(trifluoromethyl)-benzenemethanol; N-(3, 5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxy-benzamide; (-) p-[(4aR*, 10bS*) -9-ethoxy-1, 2, 3, 4, 4a, 10b-hexahydro-8-methoxy-2-methylbenzo[s][1, 6]naphthyridin-6-yl]-N, N-diisopropylbenzamide; (R) - (+) -1- (4-bromobenzyl) -4-[(3-cyclopentyloxy) -4-methoxyphenyl]-2-pyrrolidone;3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N'-[N-2-cyano-S-methyl-isothioureido]-benzyl) -2-pyrrolidone; cis[ 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carbonic acid];2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-1-ona; cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R) - (+) -ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; (S) - (-) -ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo[3, 4-c]-1, 2, 4- triazol[4, 3-a]pyridine; or 9-cyclopentyl-5, 6-dihydro-7-ethyl-3-(terc-butyl)-9H-pyrazolo[3, 4-c]-1, 2, 4-triazolo[4, 3-a]pyridine; optionally in competitive form, as enantiómeros, diastereómeros, or as sales, solvates or pharmaceutically acceptable hydrates. The preferred sales are selected from the group that consists of hydrochloride, bromide, hydrochloride, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hidrooxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenosulfonate.; In one embodiment, the additional therapeutic agent is a LTD4 antagonist selected from Montelukast, Pranlukast, Zafirlukast, Masikulast, L-733321 (see compound 2ab of D. Guay et al., Bioorg. Med. Chem. Lett. 8 (1998) 453-458); (E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one; 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid; 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic acid; 1-(((1(R)-3(3-(2-(2,3-dichlorothiene[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid; or [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid; optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates.The preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate. Additional examples of optionally preferred salts and derivatives are alkali salts, i.e., sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, or furoates. En una realización, el agente terapéutico adicional es un inhibidor de EGFR seleccionado de Cetuximab; Trastuzumab; Panitumumab; Gefitinib; Canertinib; Erlotinib; Mab ICR-62; 4-[ (3-clor-4-fluorofenil) amino]-6-{[4- (morfolina-4-yl)-1-oxo-2-buteno-1-yl]amino}-7-ciclopropilmetoxi-quinazolina; 4-[ (3-clor-4-fluorofenil) amino]-6-{[4- (N, N-diethylamino)-1-oxo-2-buteno-1-yl]amino}-7-ciclopropilmetoxi-quinazolina; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-cyclopropylmethoxyquinazoline; 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-buteno-1-yl-]amino}-7-cyclopentyloxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-buteno-1-yl]amino}-7-cyclopropylmethoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-buteno-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl) oxi]-quinazoline;4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1-oxo-2-buteno-1-yl]amino}-7-cyclopropylmethoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7-methoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-Nmethyl-amino]-1-oxo-2-buteno-1-yl}amino)-7-cyclopropylmethoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-cyclopentyloxyquinazoline; 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis-(2-methoxyethyl)-amino)-1-oxo-2-buteno-1-yl]amino}-7-cyclopropylmethoxyquinazoline; 4-[ (R) - (1-phenyl-ethyl) amino]-6- ({4-[N- (2-methoxy-ethyl) -N-ethyl-amino]-1-oxo-2-buteno-1-yl}amino) -7-cyclopropylmethoxyquinazoline;4-[ (R) - (1-phenyl-ethyl) amino]-6- ({4-[N- (2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buteno-1-yl}amino)-7-cyclopropylmethoxy-quinazoline;4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1-oxo-2-buteno-1-yl}amino)-7-cyclopropylmethoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buteno-1-yl}amino)-7-cyclopentyloxyquinazoline;4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buteno-1-yl]amino}-7-cyclopentyloxyquinazoline;4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline;4-[(3-ethynyl-phenyl)amino]-6, 7-bis-(2-methoxyethoxy)quinazoline; 4-[(3-Chlor-4-fluorophenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline; 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2, 3-d]pyrimidine; 3-cyano-4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buteno-1-yl]amino}-7-ethoxy-quinoline; 4-{[3-chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}-furan-2-yl)quinazoline; 4-[(R)-(1-phenylethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-buteno-1-yl]amino}-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-buteno-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline; 4-[ (3-chlor-4-fluorophenyl) amino]-6- ({4-[N, N-bis- (2-methoxy-ethyl) -amino]-1-oxo-2-buteno-1-yl}amino) -7-[ (tetrahidrofuran-2-yl) methoxy]-quinazoline;4-[(3-ethynyl-phenyl)amino]-6-{[4-(5, 5-dimethyl-2-oxo-morpholine-4-yl)-1-oxo-2-buteno-1-yl]amino}-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-[2-(2, 2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-[2-(2, 2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-7-[2-(2, 2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(trans-4-amino-cyclohexane-1-iloxy)-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexane-1-iloxi)-7-methoxy-quinazoline;4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-acetylaminoethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline;4-[(3-chlor-4-fluorophenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulfonylamine]-cyclohexane-1-yloxy}-7-methoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetyl-amino-ethoxy)quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(tetrahidropyran-4-iloxi)-7-(2-methane-sulfonylamino-ethoxi)-quinazoline; 4-[(3-chlor-4-fluorophenyl) amino]-6-{1-[(piperidine-1-yl) carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl) amino]-6- (1-aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxyquinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline;4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-ethanesulfonylaminocyclohexan-1-yloxy)-7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-ethoxyquinazoline;4-[ (3-chloro-4-fluorophenyl) amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline;4-[ (3-chloro-4-fluorophenyl) amino]-6-(1-(2-methoxy-acetyl)-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline; 4-[ (3-ethynyl-phenyl) amino]-6-(1-(tertbutyloxycarbonyl)-piperidin-4-yloxy)-7-methoxy-quinazoline; 4-[(3-ethynyl-fenil)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazolina; 4-[(3-chlor-4-fluorofenil)amino]-6-(cis-4-{N-[ (piperidina-1-yl)carbonyl]-N-metil-amino}-ciclohexano-1-yloxy)-7-methoxyquinazolina;4-[(3-chlor-4-fluorofenil)amino]-6-(cis-4-{N-[(4-metil-piperazine-1-yl)-carbonyl]-N-metil-amino} cidohexano-1-yloxy)-7-methoxy-quinazolina; 4-[(3-dor-4-fluorofenil)amino]-6-{cis-4-[(morpholina-4-yl)carbonylamino]-cyclohexano-1-yloxy}-7-methoxy-quinazolina; 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidina-4-yloxy}-7-methoxy-quinazolina; 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholina-4-yl)carbonyl]-piperidina-4-yloxy}-7-(2-methoxyethoxy)-quinazolina; 4-[ (3-ethynylphenyl) amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline; 4-[ (3-ethynyl-phenyl) amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxy-quinazoline; 4-[ (3-ethynyl-phenyl) amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline; 4-[ (3-dor-4-fluorophenyl) amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline; 4-[ (3-dor-4-fluorophenyl) amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline;4-[ (3-chloro-4-fluorophenyl) amino]-6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline; 4-[ (3-ethynyl-phenyl) amino]-6- (piperidin-4-yloxy) -7-methoxy-quinazoline; 4-[ (3-ethynyl-phenyl) amino]-6- [1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline; 4-[ (3-ethynyl-phenyl) amino]-6-{1- [(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[cis-2,6-dimethyl-morpholina-4-yl)-carbonyl]-piperidina-4-yloxy}-7-methoxy-quinazolina; 4-[(3-chlor-4-fluorofenil) amino]-6-{1-[ (2-metil-morpholina-4-yl) carboni-1]-piperidina-4-yloxy}-7-methoxy-quinazolina; 4-[(3-chloro-4-fluorofenil)amino]-6-{1-[ (S,S)-(2-oxa-5-aza-bicido[2.2.1]-hept-5-yl)carbonyl]-piperidina-4-yloxy}-7-methoxy-quinazolina;4-[ (3-dor-4-fluorophenyl) amino]-6-{1-[ (N-methyl-N-2-methoxyethyl-amino) -carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline; 4-[ (3-dor-4-fluorophenyl) amino]-6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-{1-[ (2-methoxyethyl) carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-{1-[ (3-methoxypropylamino) -carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6-[cis-4-(N-acetyl-N-methylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6- (trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline; 4-[ (3-chloro-4-fluorophenyl) amino]-6- [trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline; 4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-dimethylamino-cyclohexano-1-yloxy)-7-methoxyquinazoline;4-[(3-dor-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carboni-1]-N-methyl-amino}-cidohexane-1-yloxy)-7-methoxy-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholine-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline; 4-[(3-chlor-4-fluorophenyl)amino]-6-(1-methanesulfonyl-piperidine-4-yloxy)-7-methoxyquinazoline; or4-[(3-chlor-4-fluorophenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-methoxy-quinazoline; optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. Preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate; In another embodiment, the additional therapeutic agent is a dopamine antagonist selected from Bromocriptine, Cabergoline, Alpha-dihydroergocriptine, Lisuride, Pergolide, Pramipexole, Roxindole, Ropinirole, Talipexole, Terguride, and Viozane, optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. The preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, and hydroptoluenesulfonate. In another embodiment, the additional therapeutic agent is an anti-allergic agent selected from Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifen, Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine, Pheniramine, Doxylamine, Chlorphenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Ebastine, Olopatadine, Desloratadine, and Meclizine, optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. The preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate. In one embodiment, the additional therapeutic agent is a MAP kinase inhibitor selected from Bentamapimod, Doramapimod, 5-Carbamoylindol, 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridine carboxamide, alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazole acetonitrile, 9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazo-cine-10-carboxylic acid, or 4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazol-4-yl]-pyrimidine, Optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. Preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate. In one embodiment, the additional therapeutic agent is an MRP4 inhibitor selected from N-acetyldinitrophenylcysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone-3-glucuronide, dehydroepiandrosterone-3-sulfate, dilazep, dinitrophenyl-S-glutathione, estradiol-17-beta-glucuronide, estradiol-3,17-disulfate, estradiol-3-glucuronide, estradiol-3-sulfate, estrone-3-sulfate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, glycolithocholic acid sulfate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulfate, methotrexate, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]propanoic acid, alpha-naphthylbeta-D-glucuronide, nitrobenzylmercaptopurine riboside, probenecid, valspodar, sildenafil, sulfinpyrazone, aurochenodeoxycholate, taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholic acid sulfate, topotecan, trequinsin, zaprinast or dipyridamole, optionally in racemic form,as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. Preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydroptoluenesulfonate. En una realización, el agente terapéutico adicional es un inhibidor de iNOS seleccionado de S- (2-aminoetil) isotio-urea, aminoguanidina, 2-aminometilpiridina, 5, 6-dihidro-6-metil-4H-1, 3-tiacina-2-amina (AMT) , L-Canavanina, 2-iminopiperidina, S-isopropylisothiourea, S-metilisothiourea, S-etilisothiourea, S-metiltiocitrulina, S-etiltiocitrulina, L-NA (Nw-nitro-L-arginina) , L-nAm E (N^-nitro-L-argininometilester) , L-NMMA (Nw-monometil-L-arginina) , L-NIO (Nwiminoetil-L-ornitina) , L-NIL (N^-iminoethyl-lysine), (1H-tetrazol-5-yl)-amide de ácido (S)-6-acetimidoylamino-2-aminohexanoico; N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide; ácido (S)-4-(2-acetimidoylamino-ethylsulfanil)-2-aminobutúrico; 2-[2-(4-methoxy-pyridine-2-yl)-ethyl]-3H-imidazo[4, 5-b]pyridine; 2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorbenzonitrilo; 2-((1R,3S)-3-amino-4-hidroxi-1-thiazol-5-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile; 2- ( (1R,3S) -3-amino-4-hidroxi-1-thiazol-5-yl-butylsulfanyl) -4-chlor-benzonitrile; 2- ((1R,3S)-3-amino-4-hidroxi-1-thiazol-5-yl-butylsulfanyl)-5-chloro-benzonitrile; (2S, 4R) -2-amino-4- (2-chlor) -5-trifluoromethyl-phenylsulfanyl) -4-thiazol-5-yl-butane-1-ol; 2- ((1R,3S)-3-amino-4-hidroxi-1-thiazol-5-yl-butylsulfanyl)-5-chlor-nicotinonitrile; ;4- ((S)-3-amino-4-hidroxi-1-phenyl-butylsulfanyl)-6-methoxynicotinonitrile; or substituted 3-phenyl-3, 4-dihydro-1-isoquinolinamine substituted for, for example, 1S, 5S, 6R) -7-chlor-5-methyl-2-aza-biciclo[4.1.0]hept-2-eno-3-ilamin (4R, 5R) -5-ethyl-4-methyl-thiazolidine-2-ylidaneamine, (1s, 5S, 6R) -7-chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-eno-3-ylidaneamine, (4R, 5R) -5-ethyl-4-methyl-thiazolidine-2-ylidaneamine, (4R, 5R) -5-ethyl-4-methylselenazolidine-2-ylidaneamine, 4-aminotetrahidrobiopterin, (E) -3- (4-chlorphenyl) -N- (1-{2-oxo-2-[4- (6-trifluormethylpyrimidine-4-yloxy)-piperidine-1-yl]-ethylcarbamoyl}-2-pyridine-2-hylothyl) -acrylamida, 3- (2,4-difluorophenyl)-6-[2-(4-imidazol-1-ylmethylphenoxy)-ethoxy]-2-phenylpyridine, methyl ester of 3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]methyl}-4-(2-imidazol-1-yl-pyrimidine-4-yl)-piperazin-1-carbon, or (2-benzo[1,3]dioxol-5-yl-ethyl)-amide of (R)-1-(2-imidazol-1-yl-6-methylpyrimidine-4-yl)-pyrrolidine-2-carbon, optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. The preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate. Additional examples of preferred iNOS inhibitors that may be mentioned include antisense oligonucleotides,especially those antisense oligonucleotides that bind to nucleic acids encoding iNOS, examples of which are described in WO 01 / 52902, incorporated herein by reference in its entirety. In another embodiment, the additional therapeutic agent is a SYK inhibitor selected from 2-[(2-aminoethyl)amino]-4-[(3-bromofenil)amino]-5-pyrimidinacarboxamide; 2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidina-5-yl]amino]-3-pyridinecarboxamide; 6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one; N-[3-bromo-7-(4-methoxyphenyl)-1,6-naphthiridina-5-yl]-1,3-propanodiamina;7-(4-methoxyphenyl)-N-methyl-1,6-naphthiridina-5-amine; N-[7-(4-methoxyphenyl)-1, 6-naphthyridin-5-yl]-1, 3-propanediamina;N-[7-(2-thienyl)-1, 6-naphthyridin-5-yl-1, 3-propanediamina;N-[7-(4-(dimethylamino)phenyl]-1, 6-naphthyridin-5-yl]-1, 2-ethanediamina; N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1, 6-naphthyridin-5-yl]-1, 3-propanediamine;N-[7-(4-methoxyphenyl)-3-phenyl-1, 6-naphthyridin-5-yl]-1, 3-propanediamine;N- (7-phenyl-1, 6-naphthyridin-5-yl)-1, 3-propanediamine;N- [7-(3-fluorophenyl)-1, 6-naphthyridin-5-yl]-1, 3-propanediamine;N-[7-(3-chlorophenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[3-(trifluoromethoxy)phenyl]-1, 6-naphthyridine-5yl]-1, 3-propanediamine;N-[7-(4-fluorophenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(4-fluorophenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(4-chlorophenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(4'-methyl[1, 1'-biphenyl]-4-yl)-1, 6-naphthyridine-1, 3-propanediamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine;N-[7-[4-(diethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[4-(4-morpholinyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(4-bromophenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(4-methylphenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[4-(methylthio)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine;N-[7-[4-(1-methylethyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanodiamine; 7-[4-(dimethylamino)phenyl]-N-methyl-1, 6-naphthyridine-5-amine; 7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1,6-naphthyridine-5-amine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 4-butanediamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 5-pentanediamine; 3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]oxy]-1-propanol; 4-[5-(4-aminobutoxy)-1, 6-naphthyridine-7-yl]-N, N-dimethylbenzenamine; 4-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]amino]-1-butanol;N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-N-methyl-1, 3-propanodiamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-N'-methyl-1, 3-propanodiamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-N, N'-dimethyl-1, 3-propanodiamine; 1-amino-3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]amino]-2-propanol;N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-2, 2-dimethyl-1, 3-propanodiamine;7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1, 6-naphthyridin-5-amine; N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1, 6-naphthyridin-5-amine; N-[7-[6-(dimethylamino)[1, 1'-biphenyl]-3-yl]-1, 6-naphthyridin-5-yl]-1, 3-propanediamine; N-[7-[3-chloro-4-(diethylamino)phenyl]-1, 6-naphthyridin-5-yl]-1, 3-propanediamine; N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1, 6-naphthyridin-5-yl]-1, 3-propanediamine; N-[7-[4- (diethylamino) phenyl]-3-methyl-1, 6-naphthyridin-5-yl]-1, 3-propanediamine; N-[7- (3'-fluoro[1, 1'-biphenyl]-3-yl) -1, 6-naphthyridin-5-yl]-1, 2-ethanediamine; N-[7- (4-methoxyphenyl) -1, 6-naphthyridin-5-yl]-1, 6-naphthyridin-1, 3-propanediamine; N, N'-bis (3-aminopropyl) -7- (4-methoxyphenyl) -2, 5-diamina; N-[7- (4-methoxyphenyl) -2- (phenylmethoxy) -1, 6-naphthyridin-5-yl]-1, 6-naphthyridin-1, 3-propanediamine; N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamina; N-[7-(2-naphthalenyl)-1,6-naphthyridin-5yl]-1,3-propanediamina;N-[7-(2'-fluoro[1, 1'-biphenyl]-4-yl)-1, 6-naphthyridine-5-yl]-1, 3-propanodiamine;N-[7-(3, 4, 5-trimethoxyphenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanodiamine; N-[7-(3, 4-dimethylphenyl)-1, 6-naphthyridine-5-yl]-1, 3-propanodiamine; 1-amino-3-[[7-(2-naphthalenyl)-1, 6-naphthyridine-5-yl]amino]-2-propanol; 1-amino-3-[[7- (2'-fluoro[1, 1'-biphenyl]-4-yl) -1, 6-naphthyridine-5-yl]amino]-2-propanol; 1-amino-3-[[7- (4'-methoxy[1, 1'-biphenyl]-4-yl) -1, 6-naphthyridine-5-yl]amino]-2-propanol; 1-amino-3-[[7- (3, 4, 5-trimethoxyphenyl) -1, 6-naphthyridine-5-yl]amino]-2-propanol;1-amino-3-[[7- (4-bromophenyl) -1, 6-naphthyridine-5-yl]amino]-2-propanol; N-[7-(4'-methoxy[1, 1'-biphenyl]-4-yl)-1, 6-naphthyridine-5-yl]-2, 2-dimethyl-1, 3-propanodiamine; 1-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]amino]-2-propanol; 2-[[2-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]amino]-ethyl]thio]-ethanol; 7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1, 6-naphthyridine-5-amine;7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-1, 6-naphthyridin-5-amine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridin-5-yl]-1, 3-cyclohexane diamine; N, N-dimethyl-4-[5-(1-piperazinyl)-1, 6-naphthyridin-7-yl]-benzenamine; 4-[5-(2-methoxyethoxy)-1, 6-naphthyridin-7-yl]-N, N-dimethylbenzeneamine; 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridin-5-yl]-4-piperidinol; 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridin-5-yl]-3-pyrrolidinol; 7-[4-(dimethylamino)fenil]-N-(2-furanylmethyl)-1,6-naphthyridin-5-amine; 7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazole-1-yl)propyl]-1,6-naphthyridin-5-amine; 1-[7-[4-(dimethylamino) fenil]-1, 6-naphthiridina-5-yl]-4-piperidina carboxamida; 1-[3-[[7-[4-(dimethylamino) fenil]-1, 6-naphthiridina-5-yl]amino]propyl]-2-pyrrolidinone; N-[3'-[5-[(3-aminopropyl)amino]-1,6-naphthiridina-7-yl][1,1'-bifenil]-3-yl]-acetamide; N-[7-(4'-fluoro[1,1-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanodiamine;N-[4'-[5-[(3-aminopropyl)amino]-1, 6-naphthyridine-7-yl][1, 1'-biphenyl]-3-yl]-acetamida;N-[7-[4-(1, 3-benzodioxol-5-yl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[4-(2-thienyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanodiamine;N-[7-[4-(3-pyridinyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanodiamine; N-[7-(1,3-benzodioxol-5-yl)-1,6-naphthyridine-5-yl]-1,3-propanodiamine; N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanodiamine;7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridine-5-amine; 3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]methylamino]-propanonitrile; 7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1, 6-naphthyridine-5-amine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 2-cyclohexanediamine;N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 2-cyclohexanediamine, (1R, 2S)-rel-;N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 2-bencenodimethanamine; N-[7-[4-(diethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 4-butanediamine; N-[7-[3', 5'-bis(trifluoromethyl)[1, 1'-biphenyl]-4-yl]-1, 6-naphthyridine-5-yl]-, 3-propanediamine;N-[7-(3'-methoxy[1, 1'-biphenyl]-4-yl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(3'-fluoro[1, 1'-biphenyl]-4-yl)-1, 6-naphthyridine-5-yl]-1,3-propanodiamine; 4-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]oxy]-1-butanol;N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 4-cyclohexanediamine; 7-[4-(dimethylamino)phenyl]-N-(2, 2, 6, 6-tetramethyl-4-piperidinyl)-1, 6-nap-thyridine-5-amine; N-[7-[3-bromo-4-(dimethylamino)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-(1-methyl-1H-indol-5-yl)-1, 6-naphthyridine-5-yl]-1, 3-propanediamine;N-[7-[3-(trifluoromethyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine; N-[7-[4-(trifluoromethyl)phenyl]-1, 6-naphthyridine-5-yl]-1, 3-propanediamine;N-[7- (3-bromo-4-methoxyphenyl) -1, 6-naphthyridin-5-yl]-1, 3-propanediamine;N-[7-[4-[[3- (dimethylamino) propyl]methylamino]phenyl]-1, 6-naphthyridin-5-yl]-1, 4-cyclohexanediamine;N-[7-[4-[[2- (dimethylamino) ethyl]methylamino]phenyl]-1, 6-naphthyridin-5-yl]-1, 4-cyclohexanediamine;N-[7- [4- (dimethylamino) -3-methoxyphenyl]-1, 6-naphthyridin-5-yl]-1, 4-cyclohexanediamine;N-[7- [4- (dimethylamino) -3-methoxyphenyl]-1, 6-naphthyridin-5-yl]-1, 4-cyclohexanediamine;N-[7- [4- (4-morpholinyl) phenyl]-1, 6-naphthyridin-5-yl]-1, 4-cyclohexanediamine; N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexano-diamine; 4-[[7-[4-[[2-(dimethylamino)ethyl]metilamino]fenil]-1,6-naphthyridin-5-yl]oxy]-cyclohexanol; N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propano-diamine; N,Ndimethyl-4-[5-(4-methyl-1-piperazinyl)-1,6-naphthiridina-7-yl]-benzenamina; 4-[[7-[4-[[3-(dimethylamino)propyl]metilamino]fenil]-1, 6-naphthiridina-5-yl]oxi]-cyclohexanol; N-[7-[4-[[2-(dimethylamino)ethyl]metilamino]fenil]-1,6-naphthiridina-5-yl]-1,4-butanediamine;or 1,1-dimethylethyl ester of [3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridine-2-yl]-amino]propyl]carbamic acid, optionally in racemic form, as enantiomers, diastereomers, or as pharmaceutically acceptable salts, solvates, or hydrates. Preferred salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate. These pharmaceutical compositions are administered as oral formulations containing approximately 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg of a compound from Compound 1, Compound 2, or both. In this respect, the pharmaceutical compositions further comprise a filler, a disintegrant, or a lubricant, or combinations thereof. It will also be appreciated that the pharmaceutical compositions of the invention can be used in combination therapies; that is, the compositions can be administered concurrently, before, or after, one or more of other desired therapeutic agents or medical procedures. In some embodiments, the tablet comprises from approximately 25 mg to approximately 75 mg of Compound 1. In some embodiments, the tablet comprises approximately 100 mg to approximately 200 mg of Compound 2. In some embodiments, the tablet comprises one or more excipients selected from a bulking agent, a disintegrant, a lubricant, a binder, or any combination thereof. For example, the tablet comprises from approximately 100 mg to approximately 300 mg of a bulking agent. In some cases, the bulking agent comprises microcrystalline cellulose. In other examples, the tablet comprises from approximately 12 mg to approximately 36 mg of a disintegrant. In some cases, the disintegrant comprises croscarmellose sodium. In some examples, the tablet comprises from approximately 1 mg to approximately 5 mg of a lubricant. In some cases, the lubricant comprises magnesium stearate. And in some examples, the tablet comprises from approximately 25 mg to approximately 75 mg of a binder. In some cases, the binder comprises hydroxypropyl methylcellulose. In some embodiments, the pharmaceutical composition further comprises one or more excipients selected from a bulking agent, a disintegrant, a lubricant, a binder, or any combination thereof. For example, the pharmaceutical composition further comprises approximately 30% to approximately 50% by weight of a bulking agent. In some cases, the bulking agent comprises microcrystalline cellulose. In some embodiments, the pharmaceutical composition also comprises approximately 1% to approximately 10% by weight of a disintegrant. In some examples, the disintegrant comprises croscarmellose sodium. In some embodiments, the pharmaceutical composition further comprises less than approximately 1% by weight of a lubricant. In some examples, the lubricant comprises magnesium stearate. In some embodiments, the tablet comprises from approximately 30 mg to approximately 85 mg of the first agent. In some embodiments, the tablet comprises approximately 150 mg to approximately 250 mg of the second agent. In some embodiments, the tablet comprises one or more excipients selected from a bulking agent, a disintegrant, a lubricant, a binder, or any combination thereof. For example, the tablet comprises from approximately 100 mg to approximately 300 mg of a bulking agent. In some cases, the bulking agent comprises microcrystalline cellulose. In other examples, the tablet comprises from approximately 12 mg to approximately 36 mg of a disintegrant. In some cases, the disintegrant comprises croscarmellose sodium. In some examples, the tablet comprises from approximately 1 mg to approximately 5 mg of a lubricant. For example, the lubricant comprises magnesium stearate. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent (e.g., any of the additional APIs described herein). In some examples, the additional therapeutic agent is another CFTR corrector (e.g., any of the CFTR correctors described herein) other than Compound 1. In other examples, the additional therapeutic agent is another CFTR enhancer (e.g., any of the CFTR enhancers described herein) other than Compound 2. The tablets of the present invention can be produced by compacting or compressing a mixture or composition, for example, powder or granules, under pressure to form a stable three-dimensional shape (for example, a tablet). As used herein, "tablet" includes compressed pharmaceutical dosage unit forms of all shapes and sizes, whether coated or uncoated. Granulation and Compression In some embodiments, solid dosage forms, including powders comprising the active agents, amorphous Compound 1 and amorphous Compound 2, and pharmaceutically acceptable excipients (e.g., filler, diluent, disintegrant, surfactant, gluing agent, binder, lubricant, or any combination thereof), may be subjected to a dry granulation process. The dry granulation process causes the powder to agglomerate into larger particles of a suitable size for further processing. Dry granulation can improve the flowability of a mixture to produce tablets that meet requirements for mass variation or content uniformity. The formulations described herein can be produced using one or more dry mixing and granulation steps. The order and number of mixing and granulation steps do not appear to be critical. However, at least one of the excipients, as well as the amorphous Compound 1 and amorphous Compound 2, can be subjected to either dry granulation or wet high-shear granulation prior to tablet compression. Dry granulation of the amorphous Compound 1, amorphous Compound 2, and the excipients prepared together prior to tablet compression appears, surprisingly, to be a simple, economical, and efficient way to provide close physical contact between the ingredients of the present compositions and formulations, thereby resulting in a tablet formulation with good stability properties.Dry granulation can be carried out by a mechanical process, which transfers energy to the mixture without the use of any liquid substance (neither in the form of aqueous solutions, solutions based on organic solutes, nor mixtures thereof), unlike wet granulation processes, also discussed herein. Generally, the mechanical process requires compaction, such as that provided by roller compaction. An example of an alternative method for dry granulation is double compression. In some embodiments, roller compaction is a granulation process comprising highly intensive mechanical compaction of one or more substances. In some embodiments, a pharmaceutical composition comprising a mixture of powders is pressed between two counter-rotating rollers to form a solid sheet, which is subsequently ground on a sieve to form particulate matter. In this particulate matter, close mechanical contact between the ingredients can be achieved. An example of roller compaction equipment is the Minipactor® a Gerteis 3W-Polygran from Gerteis Maschinen+Processengineering AG. In some embodiments, the compression of tablets according to the invention can be carried out without the use of any liquid substance (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof), i.e., a dry granulation process. In a typical embodiment, the resulting core or tablet has a compressive strength in the range of approximately 1 kp to approximately 15 kp; such as 1.5 to 12.5 kp, preferably in the range of 2 to 10 kp. Brief Manufacturing Procedure In some embodiments, the ingredients are weighed according to the formula established herein. All intragranular ingredients are then sieved and thoroughly mixed. The ingredients may be lubricated with a suitable lubricant, for example, magnesium stearate. The next step may involve compacting / double-compressing the powder mixture and the sized ingredients. The compacted or double-compressed mixtures are then milled into granules and sieved to the desired size. The granules may then be further lubricated, for example, with magnesium stearate. The granular composition of the invention may then be compressed into suitable punches in various pharmaceutical formulations according to the invention. Optionally, the tablets may be coated with a film, a colorant, or another coating. A method for producing a pharmaceutical composition comprising a mixture of a composition comprising amorphous Compound 1 and amorphous Compound 2 and one or more excipients selected from: a filler, a diluent, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and the compression of the composition into a tablet having a dissolution of at least approximately 50% in approximately 30 minutes. In another embodiment, a wet granulation process is used to produce the pharmaceutical formulation of the invention from a mixture of powder and liquid ingredients. For example, a pharmaceutical composition comprising a mixture of amorphous Compound 1 and amorphous Compound 2 and one or more excipients selected from: a filler, a diluent, a binder, a glidant, a surfactant, a lubricant, or a disintegrant, is weighed according to the formula set forth herein. All the intragranular ingredients are then sieved and mixed in a high-shear or low-shear granulator using water, water with a surfactant, water with a binder, or water with both a surfactant and a binder to granulate the mixture into a powder. A fluid other than water, with or without a surfactant and / or binder, may also be used to granulate the powder mixture. The wet granules may then be optionally milled using a suitable mill.The water can then be optionally removed from the mixture by drying the ingredients in any suitable manner. The dried granules can then be optionally ground to the required size. Extra granular excipients can then be added by mixing (e.g., a filler, a diluent, and a disintegrant). The sized granules can then be further lubricated with magnesium stearate and a disintegrant, e.g., croscarmellose sodium. The granular composition of the invention can then be sieved for a sufficient time to obtain the correct size and then compressed in suitable punches into various pharmaceutical formulations according to the invention. Optionally, the tablets can be coated with a film, a colorant, or another coating. Each of the ingredients in this exemplary mixture is described above and in the following examples. In addition, the mixture may comprise optional additives, such as one or more colorants, one or more flavorings, and / or one or more fragrances, as described above and in the following examples. In some embodiments, the relative concentrations (e.g., wt.%) of each of these ingredients (and any optional additives) in the mixture are also presented above and in the following examples. The ingredients constituting the mixture may be provided sequentially or in any combination of additions; and the ingredients or combination of ingredients may be provided in any order. In one embodiment, the lubricant is the last component added to the mixture. In another embodiment, the mixture comprises a composition of amorphous Compound 1 and amorphous Compound 2, and any one or more of the following excipients: a binder, a glidant, a surfactant, a diluent, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in powder form (for example, provided as particles having a mean or 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)).For example, the mixture comprises a composition of amorphous Compound 1 and amorphous Compound 2, a diluent, a slip, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in powder form (for example, provided as particles having a mean diameter, 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)). In another example, the mixture comprises a composition of amorphous Compound 1, amorphous Compound 2, a diluent, a binder, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in powder form (e.g., provided as particles having a mean diameter, measured by light scattering, of 250 µm or less (e.g., 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). In another embodiment, the mixture comprises a composition of amorphous Compound 1, amorphous Compound 2, and any combination of a binder, a slide, a diluent, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is substantially free of water. Each of the ingredients comprises less than 5% by weight (e.g., less than 2% by weight, less than 1% by weight, less than 0.75% by weight, less than 0.5% by weight, or less than 0.25% by weight) of water by weight of the ingredient. For example, the mixture comprises a composition of amorphous Compound 1, amorphous Compound 2, a diluent, a slide, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is substantially free of water. In some embodiments, each of the ingredients comprises less than 5% by weight (e.g., less than 2% by weight, less than 1% by weight, less than 0.75% by weight, In another embodiment, compression of the mixture into a tablet is carried out by filling a mold (e.g., a die) with the mixture and applying pressure to mix it. This can be achieved using a stamping press or other similar apparatus. In some embodiments, the mixture of amorphous Compound 1, amorphous Compound 2, and excipients can first be processed into granular form. The granules can then be sized and compressed into tablets or formulated for encapsulation according to methods known in the pharmaceutical art. It is also noted that the application of pressure to the mixture in the mold can be repeated using the same pressure during each compression or using different pressures during the compressions.In another example, the mixture of powdered or granulated ingredients can be compressed using a stamping press that applies sufficient pressure to form a tablet that has a dissolution of approximately 50% or more in approximately 30 minutes (e.g., approximately 55% or more in approximately 30 minutes or approximately 60% or more in approximately 30 minutes). For example, the mixture is compressed using a stamping press to produce a tablet hardness of at least approximately 5 kP (at least approximately 5.5 kP, at least approximately 6 kP, at least approximately 7 kP, at least approximately 10 kP, or at least 15 kP). In some cases, the mixture is compressed to produce a tablet hardness between approximately 5 and 20 kP. In some embodiments, tablets comprising a pharmaceutical composition as described herein may be coated with approximately 3.0% by weight of a film coating comprising a colorant by weight of the tablet. In certain cases, the colorant suspension or solution used to coat the tablets comprises approximately 20% w / w solids by weight of the colorant suspension or solution. In further cases, the coated tablets may be labelled with a logo, other image, or text. In another embodiment, the method for producing a pharmaceutical composition comprises providing a solid mixture, for example, a mixture of powdered and / or liquid ingredients, the mixture comprising amorphous Compound 1, amorphous Compound 2, and one or more excipients selected from: a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and a filler; mixing the mixture until it is substantially homogeneous; and compressing or compacting the mixture into a granular form. The granular composition comprising amorphous Compound 1 and amorphous Compound 2 can then be compressed into tablets as described above or in the Examples below.Alternatively, methods for producing a pharmaceutical composition comprise providing a mixture of amorphous Compound 1, amorphous Compound 2, and one or more excipients, for example, a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and a filler; mixing the mixture until it is substantially homogeneous; and compressing / compacting the mixture into a granular form using a roller compactor with a dry granulation composition as set forth in the Examples below, or alternatively, compressing / compacting into granules using a high-shear wet granule compaction process as set forth in the Examples below. Pharmaceutical formulations, for example, a tablet as described herein, may be prepared using the prepared granules incorporating the amorphous Compound 1 and the amorphous Compound 2 in addition to the selected excipients described herein. In some embodiments, the mixture is mixed by stirring, mixing, shaking, or similar means using a hand mixer, a mixer, a beater, or any combination thereof. When ingredients or combinations of ingredients are added sequentially, mixing may occur between successive additions, continuously throughout the addition of ingredients, after the addition of all ingredients or combinations of ingredients, or any combination thereof. The mixture is mixed until it has a substantially homogeneous composition. A useful method for preparing the present invention comprises jet milling amorphous Compound 1 and amorphous Compound 2 in a suitable conventional milling apparatus using suitable air pressure to produce particles having a significant particle size fraction between 0.1 micrometers and 50 micrometers. In another embodiment, the particle size is between 0.1 micrometers and 20 micrometers. In another embodiment, the particle size is between 0.1 micrometers and 10 micrometers. In another embodiment, the particle size is between 1.0 micrometers and 5 micrometers. In yet another embodiment, the amorphous Compound 1 and amorphous Compound 2 have a D50 particle size of approximately 5 to approximately 100 micrometers. In yet another embodiment, the amorphous Compound 1 and amorphous Compound 2 have a D50 particle size of approximately 5 to approximately 30 micrometers.In yet another embodiment, the amorphous Compound 1 and the amorphous Compound 2 have a D50 particle size of approximately 15 micrometers. In several embodiments, an additional therapeutic agent(s) may be formulated together with the amorphous Compound 1 and the amorphous Compound 2 to form a unit dose or single-dose form, e.g., a tablet. Tablets prepared as described above may be subjected to in vitro dissolution evaluations in accordance with Test 711 "Dissolution" in the United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, MD, 2005 ("USP"), to determine the rate at which the active substance is released from the dosage forms. Active substance content and impurity levels are conveniently measured using techniques such as high-performance liquid chromatography (HPLC). Useful packaging materials include containers and closures made of high-density polyethylene (HDPE), low-density polyethylene (LDPE), and / or polypropylene and / or glass; aluminum foil; aluminum pouches; and blisters or strips made of aluminum or high-density polyvinyl chloride (PVC), optionally including a desiccant; polyethylene (PE); polyvinylidene dichloride (PVDC); PVC / PE / PVDC; and similar materials. These packaging materials can be used to store the various pharmaceutical compositions and formulations in a sterile manner after appropriate sterilization of the container and its contents using chemical or physical sterilization techniques commonly employed in pharmaceutical manufacturing. V. PHARMACEUTICAL COMPOSITION FOR USE IN METHODS FOR TREATING CYSTIC FIBROSIS The pharmaceutical compositions described above are useful for treating cystic fibrosis. Accordingly, one aspect of the present invention provides a method for treating cystic fibrosis in a patient comprising administering the composition to the patient. In some implementations, the pharmaceutical composition is administered orally to the patient. And, some implementations also include administering to the patient an additional therapeutic agent that is not found in the pharmaceutical composition, as claimed. In some implementations, the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition, as claimed. A. Mutations In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811 + 1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, y 621+3A->G. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R. In an implementation of this aspect, the invention provides a method for treating a CFTR-mediated disease wherein the patient has a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In another implementation of this aspect, the invention provides a method for treating a CFTR-mediated disease in which the patient possesses a human CFTR mutation selected from E193K, F1052V, and G1069R.In some implementations of this aspect, the method produces a greater than 10-fold increase in chloride transport relative to reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has a human CFTR mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H. In one implementation of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G. In one implementation of this aspect, the patient has a selected human CFTR mutation of 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T.In another implementation of this aspect, the patient has a selected human CFTR mutation of 2789+5G->A and 3272-26A->G. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811 + 1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, y 621+3A->G, y una mutación de CFTR humana seleccionada de AF508, R117H, y G551D. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTr-mediated disease in a patient comprising administering the pharmaceutical composition as claimed to the patient, wherein the patient has a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selected from AF508, R117H, and G551D. In an implementation of this aspect, the invention provides a method for treating a CFTR-mediated disease in which the patient possesses a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N, and a human CFTR mutation selected from AF508, R117H, and G551D.In another implementation of this aspect, the invention provides a method for treating a CFTR-mediated disease in which the patient possesses a human CFTR mutation selected from E193K, F1052V, and G1069R, and a human CFTR mutation selected from AF508, R117H, and G551D. In some implementations of this aspect, the method produces an increase of more than 10-fold in chloride transport relative to the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has a human CFTR mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G. In one implementation of this aspect, the patient possesses a selected human CFTR mutation of 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T, and a selected human CFTR mutation of AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses a selected human CFTR mutation of 2789+5G->A and 3272-26A->G. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, y 621+3A->G, y una mutación de CFTR humana seleccionada de AF508, R117H, y G551D. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has one or more human CFTR mutations selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R. In one implementation of this aspect, the patient has one or more human CFTR mutations selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of E193K, F1052V, and G1069R. In some implementations of this aspect, the method produces a greater than 10-fold increase in chloride transport relative to the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has one or more human CFTR mutations selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H. In one implementation of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G. In an implementation of this aspect, the patient possesses one or more selected human CFTR mutations of 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of 2789+5G->A and 3272-26A->G. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G, and a human CFTR mutation selected from AF508, R117H, and G551D, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In an implementation of this aspect, the patient possesses one or more selected human CFTR mutations of Gl78R, G551S, G970R, G1244E, Sl255P, G1349D, S549N, S549R, and S1251N, and one or more selected human CFTR mutations of AF508, R117H, and G551D.In another implementation of this aspect, the patient has one or more selected human CFTR mutations of G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In another implementation of this aspect, the patient has one or more selected human CFTR mutations of E193K, F1052V, and G1069R, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In some implementations of this aspect, the method produces a more than 10-fold increase in chloride transport relative to the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has one or more human CFTR mutations selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In one implementation of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811 + 1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G, and one or more selected human CFTR mutations from AF508, R117H, and G551D.In one implementation of this aspect, the patient possesses one or more selected human CFTR mutations of 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of 2789+5G->A and 3272-26A->G, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In another aspect, the invention provides a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In one implementation, the human CFTR mutation is selected from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q. In one implementation, the human CFTR mutation is selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In a further implementation, the human CFTR mutation is selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P. In another aspect, the patient possesses a selected human CFTR mutation of R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and a selected human CFTR mutation of AF508, R117H, and G551D. In one implementation, the patient possesses a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation, the patient has a human CFTR mutation selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and a human CFTR mutation selected from AF508, R117H, and G551D. In a further implementation, the patient possesses a human CFTR mutation selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P, and a human CFTR mutation selected from AF508, R117H, and G551D. In another aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to a patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In one implementation, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q. In one implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In a further implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P. In another aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from 74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one implementation, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, Kl060T, A1067T, and R1070Q, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In a further implementation, the patient possesses one or more selected human CFTR mutations from Rl066H, T338I, R334W, I336K, H1054D, MlV, E92K, and L927P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In one implementation, the human CFTR mutation is selected from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q. In one implementation, the human CFTR mutation is selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In a further implementation, the human CFTR mutation is selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P. In another aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation, the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, Kl060T, A1067T and R1070Q, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation, the patient has a human CFTR mutation selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and a human CFTR mutation selected from AF508, R117H, and G551D. In a further implementation, the patient possesses a human CFTR mutation selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P, and a human CFTR mutation selected from AF508, R117H, and G551D. In another aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In one implementation, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q. In one implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In another implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P. In another aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one implementation, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, Kl060T, A1067T, and R1070Q, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In a further implementation, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K and L927P, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In one aspect, the invention includes a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In one implementation, the human CFTR mutation is selected from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q. In one implementation, the human CFTR mutation is selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In a further implementation, the human CFTR mutation is selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P. In another aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation, the patient possesses a human CFTR mutation selected from R74W, R668C, S977F, L997F, Kl060T, A1067T, and R1070Q, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation, the patient has a human CFTR mutation selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation, the patient has a human CFTR mutation selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P, and a human CFTR mutation selected from AF508, R117H, and G551D. In another aspect, the invention includes a method for treating a CFTR-mediated disease in a patient by administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above, wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In one implementation, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, K1060T, A1067T, and R1070Q. In one implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P. In a further implementation, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, and L927P. In another aspect, the invention includes a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one implementation, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, Kl060T, A1067T, and R1070Q, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one implementation, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, and S341P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In a further implementation, the patient possesses one or more selected human CFTR mutations from Rl066H, T338I, R334W, I336K, H1054D, MlV, E92K, and L927P, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, y2184InsA. In one implementation of this aspect, the human CFTR mutation is selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the human CFTR mutation is selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In yet another implementation of this aspect, the human CFTR mutation is selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184 InsA. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation of this aspect, the patient possesses a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses a human CFTR mutation selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient has a selected human CFTR mutation of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a selected human CFTR mutation of AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In an implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In an implementation of this aspect, the patient possesses one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one implementation of this aspect, the human CFTR mutation is selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the human CFTR mutation is selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In yet another implementation of this aspect, the human CFTR mutation is selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation of this aspect, the patient possesses a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses a human CFTR mutation selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient has a selected human CFTR mutation of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a selected human CFTR mutation of AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In an implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In an implementation of this aspect, the patient possesses one or more selected human CFTR mutations of R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations of AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one implementation of this aspect, the human CFTR mutation is selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the human CFTR mutation is selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In yet another implementation of this aspect, the human CFTR mutation is selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In one implementation of this aspect, the patient possesses a human CFTR mutation selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses a human CFTR mutation selected from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient has a human CFTR mutation selected from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA, and a human CFTR mutation was selected from AF508, R117H, and G551D. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In an implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations of R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA. In one aspect, the invention includes a pharmaceutical composition for use in a method for treating a CFTR-mediated disease in a patient comprising administering to the patient any of the spray-dried dispersions or pharmaceutical compositions described above wherein the patient has one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In an implementation of this aspect, the patient possesses one or more human CFTR mutations selected from R74W, R668C, S977F, L997F, K1060T, A1067T, R1070Q, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, G85E, A46D, I336K, H1054D, M1V, E92K, V520F, H1085R, R560T, L927P, R560S, N1303K, M1101K, L1077P, R1066M, R1066C, L1065P, Y569D, A561E, A559T, S492F, L467P, R347P, S341P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In another implementation of this aspect, the patient possesses one or more selected human CFTR mutations from R1066H, T338I, R334W, I336K, H1054D, M1V, E92K, L927P, I507del, G1061R, G542X, W1282X, and 2184InsA, and one or more selected human CFTR mutations from AF508, R117H, and G551D. In one aspect, the invention also provides a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating a disease in a patient, the method comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the disease is selected from cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary angioedema type 1, lipid processing deficiencies,such as familial hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia, lysosomal storage diseases such as I-cell / pseudo-Hurler disease, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG glycanosis type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie-Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neurological disorders such as Huntington's disease, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dento-rubal pallidoloisian dystrophy, and myotonic dystrophy,as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to defects in prion protein processing), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjögren's disease, osteoporosis, osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reduced bone resorption, and increased bone deposition), Gorham's syndrome, chloride channelopathies such as congenital myotonia (Thomson and Becker forms), Bartter syndrome type III, Dent disease, hyperekplexia, epilepsy, lysosomal storage disease, Angelman syndrome, and primary ciliary dyskinesia (PCD), a term for inherited disorders of ciliary structure and / or function, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia. In one aspect, the invention also provides a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating a disease in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the disease is selected from generalized epilepsy with febrile seizures plus (GEFS+), generalized epilepsy with febrile and afebrile seizures, myotonia, congenital paratolonia, potassium-aggravated myotonia, hyperkalemic periodic paralysis, LQTS, LQTS / Brugada syndrome, autosomal dominant LQTS with deafness, autosomal recessive LQTS, LQTS with dysmorphic features, congenital and acquired LQTS, Timothy syndrome, persistent hyperinsulinemic hypoglycemia of infancy, dilated cardiomyopathy, autosomal dominant LQTS, Dent disease, osteopetrosis, Bartter syndrome type III,central core disease, malignant hyperthermia, and catecholaminergic polymorphic tachycardia. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation N1303K, AI507, or R560T. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR G551D genetic mutation. In another embodiment, the patient is homozygous for G551D. In another implementation, the patient is heterozygous for G551D where the other CFTR genetic mutation is any of AF508, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, AI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR AF508 genetic mutation. In another embodiment, the patient is homozygous for AF508. In another implementation, the patient is heterozygous for AF508 where the other CFTR genetic mutation is any of G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, AI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341 + 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, y621+3A->G. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R. In an implementation of this aspect, the invention provides a method for treating a CFTR-mediated disease comprising administering a spray-dried dispersion, as described above, to a patient possessing a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N.In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from E193K, F1052V, and G1069R. In some implementations of this aspect, the method produces an increase of more than 10-fold in chloride transport relative to the reference chloride transport. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H. In one embodiment of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+ 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341 + 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, y 621+3A->G, y una mutación de CFTR humana seleccionada de AF508, R117H, y G551D. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R, and a human CFTR mutation selected from AF508, R117H, and G551D.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N, and a human CFTR mutation selected from AF508, R117H, and G551D.In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from E193K, F1052V, and G1069R, and a human CFTR mutation selected from AF508, R117H, and G551D. In some embodiments of this aspect, the method produces an increase of more than 10-fold in chloride transport relative to the reference chloride transport. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient has the CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H, and a human CFTR mutation selected from AF508, R117H, and G551D. In one embodiment of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+ 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G, and a human CFTR mutation selected from AF508, R117H, and G551D.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T, and a human CFTR mutation selected from AF508, R117H, and G551D.In one aspect, the present invention relates to a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G, and a human CFTR mutation selected from AF508, R117H. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341 + 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, y 621+3A->G, y una mutación de CFTR humana seleccionada de AF508, R117H, y G551D. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N.In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from E193K, F1052V, and G1069R. In some embodiments of this aspect, the method produces an increase of more than 10-fold in chloride transport relative to the reference chloride transport. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H. In one embodiment of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+ 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621 + 1G->T, 3120+1G->A, 1898+1G->A, 711 + 1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341 + 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G, and a human CFTR mutation selected from AF508, R117H, and G551D, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient has the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R, and one or more human CFTR mutations selected from AF508, R117H, and G551D.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N, and one or more human CFTR mutations selected from AF508, R117H, and G551D.In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from E193K, F1052V, and G1069R, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In some embodiments of this aspect, the method produces an increase of more than 10z-fold in chloride transport relative to reference chloride transport. In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H, and one or more human CFTR mutations selected from AF508, R117H, and G551D. In one embodiment of this aspect, the method produces an increase in chloride transport that is greater than or equal to 10% above the reference chloride transport. In one aspect, the present invention relates to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+ 1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811 + 1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G, and one or more selected human CFTR mutations from AF508, R117H, and G551D.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 1717-1G->A, 1811 + 1.6kbA->G, 2789+5G->A, 3272-26A->G, and 3849+10kbC->T, and one or more human CFTR mutations selected from AF508, R117H, and G551D.In one aspect, the present invention is directed to a pharmaceutical composition for use in a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the spray-dried dispersion or pharmaceutical composition of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation selected from 2789+5g->A and 3272-26A->G, and one or more human CFTR mutations selected from AF508, R117H, and G551D. 1. Homozygous Mutations In some implementations, the patient is homozygous for any of the mutations listed above. In some implementations, the patient is homozygous for the human CFTR AF508 mutation. In some implementations, the patient is homozygous for a human mutation other than the CFTR AF508 mutation. 2. Heterozygous Mutations In some implementations, the patient is heterozygous for any of the mutations listed above. In some implementations, the patient is heterozygous for the human CFTR AF508 mutation. For example, the patient is heterozygous for the human CFTR AF508 mutation and a selected activation mutation of G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. In some implementations, the patient is heterozygous for the human CFTR AF508 mutation and a selected residual function mutation from R117H, A455E, D1152H, L206W, R347H, P67L, R117C, S945L, S1235R, I1027T, R668C, R352Q, G576A, M470V, D110H, D1270N, L997F, R75Q, R74W, D579G, R1070Q, F1052V, R1070W, R31C, D614G, S977F, G1069R, R1162L, E56K, F1074L, D110E, F1074L, E56K, D110E, A1067T, E193K, or K1060T. In some implementations, the patient is heterozygous for the human CFTR AF508 mutation and the residual R117H mutation. In some implementations, the patient is heterozygous for the human CFTR mutation AF508 and a selected splicing mutation of 2789+5G->A, 3120G->A, 5T, 711+3A->G, 711+5G->A, 7T, 1717-8G->A, 1898+3A->G, 1811+1.6kbA->G, 3272-26A->G, and 3849+10kbC->T. In some implementations, the patient is heterozygous for a mutation other than AF508 and a selected activation mutation of G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. In some implementations, the patient is heterozygous for a mutation other than AF508 and a selected residual function mutation from R117H, A455E, D1152H, L206W, R347H, P67L, R117C, S945L, S1235R, I1027T, R668C, R352Q, G576A, M470V, D110H, D1270N, L997F, R75Q, R74W, D579G, R1070Q, F1052V, R1070W, R31C, D614G, S977F, G1069R, R1162L, E56K, F1074L, D110E, F1074L, E56K, D110E, A1067T, E193K, or K1060T. For example, the patient is heterozygous for a mutation other than AF508 and the residual mutation R117H. In some implementations, the patient is heterozygous for a mutation other than AF508 and a selected splicing mutation of 2789+5G->A, 3120G->A, 5T, 711+3A->G, 711+5G->A, 7T, 1717-8G->A, 1898+3A->G, 1811+1.6kbA->G, 3272-26A->G, or 3849+10kbC->T. B. Dosage Regimen In one embodiment, 50 mg of substantially amorphous Compound 1 and 150 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof. In these embodiments, the dosage amounts may be achieved by administering one or more tablets of the invention. For example, the administration of 50 mg of substantially amorphous Compound 1 and 150 mg of substantially amorphous Compound 2 may be achieved by administering one tablet containing 50 mg of substantially amorphous Compound 1 and 150 mg of substantially amorphous Compound 2. The duration of administration may continue until improvement of the condition is achieved or until advised otherwise by the subject's physician; for example, the duration of administration may be less than one week, one week, two weeks, three weeks, four weeks (28 days), or one month or more.In one embodiment, two tablets, each comprising 50 mg of substantially amorphous Compound 1 and 150 mg of substantially amorphous Compound 2, may be administered to the patient daily. In a further embodiment, the two tablets may be administered at the same time or at different times throughout the day. In a further embodiment, one tablet is administered daily (qd). In a further embodiment, one tablet is administered twice daily (bid). In a further embodiment, one tablet is administered every 12 hours (q12h). In a further embodiment, two tablets are administered daily (qd). In a further embodiment, two tablets are administered twice daily (bid). In a further embodiment, two tablets are administered every 12 hours (q12h). In another embodiment, the administration of a pharmaceutical composition of the present invention, such as a tablet, may be supplemented by the addition of Compound 1 or Compound 2 before, after, or concurrently with the pharmaceutical composition. For example, a tablet of the present invention may be administered followed by the administration of Compound 1 or Compound 2 alone. In one embodiment, a tablet of the present invention is administered once daily (qd) followed by the administration of 150 mg of Compound 2 once daily (qd). In another embodiment, a tablet of the present invention is administered once daily (qd) followed by the administration of a Kaly deco™ tablet once daily (qd). In another embodiment, an effective amount of the compositions of the present invention may be administered to a patient aged 1 to 5 years. In another embodiment, the patient is aged 6 to 11 years. In another embodiment, the patient is aged 12 to 18 years. In another embodiment, the patient is 18 years of age or older. In another embodiment, the patient in the preceding embodiments is taking an effective amount of the compositions of the present invention for the treatment of cystic fibrosis. VI. KITS A useful form of the pharmaceutical composition is a kit comprising a pharmaceutical composition of the present invention and instructions for its use. In some embodiments, the kit also includes an additional therapeutic agent that is not found in the pharmaceutical composition described above. In some embodiments, the additional therapeutic agent is selected from any of the additional therapeutic agents described above. In some embodiments, the additional therapeutic agent is another CFTR corrector different from the first agent. In some embodiments, the additional therapeutic agent is a different CFTR enhancer than the second agent. And, in some embodiments, the additional therapeutic agent is selected from In some embodiments, the additional therapeutic agent and the pharmaceutical composition of the present invention are stored in the same container. In some examples, the pharmaceutical composition of the present invention and the additional therapeutic agent are stored in the same container, and the container is a bottle, vial, or blister pack. In other embodiments, the additional therapeutic agent and the pharmaceutical composition of the present invention are stored in separate containers. For example, the pharmaceutical composition of the present invention is stored in a bottle, vial, or blister pack, and the additional therapeutic agent is stored in a separate bottle, vial, or blister pack. VII. GENERAL SYNTHETIC SCHEMES Compound 1 can be prepared by coupling the acid halide fraction 1-1 with the amine fraction 1-2 to form compound 1-3 followed by deprotection according to Scheme 1. Scheme 1: Preparation of Compound 1. Compound 1-1 is prepared according to Scheme 2. Scheme 2: Preparation of Compound 1-1. Compound 1-2 is prepared according to scheme 3. Scheme 3: Preparation of Compound 1-2. Compound 2 can be prepared by coupling a 4-oxo-dihydroquinoline carboxylic acid fraction with an amine fraction according to schemes 4-6. Scheme 4: Synthesis of the 4-oxo-dihydroquinoline carboxylic acid fraction. Scheme 5: Synthesis of the amine fraction. Scheme 6: Coupling of the 4-oxo-dihydroquinoline carboxylic acid fraction with the amine fraction. VIII. EXAMPLES Analytical methods 1. Differential Scanning Calorimetry (DSC) Referring to Figures 2 and 7, differential scanning calorimetry (DSC) data of the spray-dried dispersions were collected using a Q2000 DSC (TA Instruments, Newcastle, DE). Temperature was calibrated with indium and heat capacity with sapphire. Samples of 8–15 mg were weighed into T-zero aluminum trays, which were sealed using lids with a single-bolt hole. The samples were scanned from 20°C to 250°C at a heating rate of 2°C / min with a nitrogen purge of 50 mL / min. The reported numbers represent individual analyses. 2. Thermogravimetric Analysis (TGA) Thermal gravimetric analysis (TGA) was performed using a TGA Q500 V6.3 Build 189 (TA Instruments, Newcastle, DE). The temperature was equilibrated to the Curie point with nickel. Samples of 10–20 mg were scanned from 25°C to 350°C at a heating rate of 10°C / min. A nitrogen gas equilibration purge of 10 mL / min and a sample purge of 90 mL / min were used. Data were collected using Thermal Advantage Q Series™ software version 2.2.0.248 and analyzed using Universal Analysis software version 4.1D (TA Instruments, Newcastle, DE). Reported numbers represent individual analyses. 3. XRPD (X-ray Powder Diffraction) With reference to Figures 1 and 6, X-ray diffraction (XRD) data of the spray-dried dispersions of the present invention were collected on a Bruker Advance detector with Vantec-1. A copper-sealed tube was used with Ka radiation at 40 kV, 40 mA. The samples were placed on zero-background silicon wafers at 25°C. For each sample, the 20° angles varied from 3° to 40° for a total scan time of 12 minutes. Example 1: Synthesis of Compound 1: (R) -1- (2, 2-difluorobenzo[d][1, 3]dioxol-5-yl) -N- (1- (2, 3-dihydroxyproM) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cidopropanecarboxamide. Acid fraction Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile A reactor was purged with nitrogen and charged with 900 mL of toluene. The solvent was degassed by bubbling nitrogen through it for at least 16 h. The reactor was then charged with Na3PO4 (155.7 g, 949.5 mmol), followed by bis(dibenzylideneacetone) palladium(0) (7.28 g, 12.66 mmol). A 10% w / w solution of tert-butylphosphine in hexanes (51.23 g, 25.32 mmol) was charged for 10 min at 23°C from a nitrogen-purged addition funnel. The mixture was allowed to stir for 50 min, at which point 5-bromo-2,2-difluoro-1,3-benzodioxol (75 g, 316.5 mmol) was added for 1 min. After stirring for an additional 50 minutes, the mixture was loaded with ethyl cyanoacetate (71.6 g, 633.0 mmol) for 5 minutes, followed by water (4.5 mL) in one portion. The mixture was heated to 70°C for 40 minutes and analyzed by HPLC every 1–2 hours for the percent conversion of the reagent to the product.After complete conversion was observed (typically 100% conversion after 5–8 h), the mixture was cooled to 20–25°C and filtered through a Celite pad. The Celite pad was rinsed with toluene (2 x 450 mL) and the combined organics were concentrated to 300 mL under vacuum at 60–65°C. The concentrate was loaded with 225 mL of DMSO and concentrated under vacuum at 70–80°C until active distillation of the solvent ceased. The solution was cooled to 20-25 °C and diluted to 900 ml with DMSO in preparation for Step 2. 1H NMR (500 MHz, CDCh) 87.16-7.10 (m, 2H) , 7.03 (d, J = 8.2 Hz, 1H) , 4.63 (s, 1H) , 4.19 (m, 2H) , 1.23 (t, J = 7.1 Hz, 3H) . Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile. The DMSO solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile above was loaded with 3 N HCl (617.3 mL, 1.85 mol) for 20 min while maintaining an internal temperature of <40°C. The mixture was then heated to 75°C for 1 h and analyzed by HPLC every 1–2 h for percent conversion. When a conversion of >99% was observed (typically after 5–6 h), the reaction was cooled to 20–25°C and extracted with MTBE (2 x 525 mL), allowing sufficient time for complete phase separation during the extractions. The pooled organic extracts were washed with 5% NaCl (2 x 375 mL). The solution was then transferred to a suitable 1.5–2.5 Torr vacuum distillation apparatus equipped with a refrigerated receiving flask. The solution was concentrated under vacuum at <60°C to remove the solvents.(2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was then distilled from the resulting oil at 125-130°C (furnace temperature) and 1.5-2.0 Torr. (2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was isolated as a clear oil with a 66% yield from 5-bromo-2,2-difluoro-1,3-benzodioxol (2 steps) and with an HPLC purity of 91.5% AUC (corresponding to a 95% w / w assay). 1H NMR (500 MHz, DMSO) 67.44 (br s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 4.07 (s, 2H). Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-ddopropanecarbonitrile. A 50% w / w NaOH stock solution was degassed by bubbling nitrogen through it for at least 16 h. An appropriate amount of MTBE was similarly degassed for several hours. A nitrogen-purged reactor was charged with degassed MTBE (143 mL), followed by (2,2-difluoro-1,3-benzodioxol-5-yl)acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was recorded, and the mixture was degassed by bubbling nitrogen through it for 30 min. Sufficient degassed MTBE was added to return the mixture to its original volume before degassing. The mixture, stirred at 23°C, was charged with 50% w / w NaOH (143 mL) for 10 minutes, followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) for 30 minutes. The reaction was analyzed by HPLC at 1-hour intervals for % conversion. Before sampling, stirring was stopped and the phases were allowed to separate.The upper organic phase was sampled for analysis. When a percent conversion of >99% was observed (typically after 2.5–3 h), the reaction mixture was cooled to 10°C and charged with water (461 mL) at a rate that maintained a temperature <25°C. The temperature was then adjusted to 20–25°C, and the phases were separated. Note: Sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1N HCl (163 mL) and 5% NaCl (163 mL). The (2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonitrile solution in MTBE was concentrated to 164 mL under vacuum at 40–50°C. The solution was loaded with ethanol (256 ml) and concentrated again to 164 ml under vacuum at 50-60°C. The resulting mixture was cooled to 20-25°C and diluted with ethanol to 266 ml in preparation for the next step. 1H NMR (500 MHz, DMSO) 67.43 (d, J = 8.4 Hz, 1H) , 7.40 (d, J = 1.9 Hz, 1H) , 7.30 (dd, J = 8.4, 1.9 Hz, 1H) , 1.75 (m, 2H) , 1.53 (m, 2H) . Synthesis of Acid 1- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -ddopropanocarboxWco. The (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile solution in ethanol from the previous step was loaded with 6N NaOH (277 mL) for 20 min and heated to an internal temperature of 77–78°C for 45 min. The progress of the reaction was monitored by HPLc after 16 h. Note: Both the consumption of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile and the primary amide resulting from the partial hydrolysis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile were monitored. When a conversion of >99% was observed (typically 100% conversion after 16 h), the reaction mixture was cooled to 25°C and charged with ethanol (41 mL) and DCM (164 mL). The solution was then cooled to 10°C and charged with 6 N HCl (290 mL) at a rate such that a temperature of <25°C was maintained. After heating to 20–25°C, the phases were allowed to separate.The lower organic phase was collected, and the upper aqueous phase was re-extracted with DCM (164 mL). Note: The aqueous phase was somewhat turbid before and after extraction due to a high concentration of inorganic salts. The organic compounds were combined and concentrated under vacuum to 164 mL. Toluene (328 mL) was added, and the mixture was condensed to 164 mL at 70–75°C. The mixture was cooled to 45°C, charged with MTBE (364 mL), and stirred at 60°C for 20 minutes. The solution was cooled to 25°C and polished to remove residual inorganic salts. MTBE (123 mL) was used to rinse the reactor and the collected solids. The combined organic compounds were transferred to a clean reactor in preparation for the next step. Isolation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-ddoppanocarboxWco acid. The 1-(2,2-difluoro-1,3-benzodioxol-5-N)-propanecarboxylic acid solution from the previous step was concentrated under vacuum to 164 mL, loaded with toluene (328 mL), and further concentrated to 164 mL at 70–75°C. The mixture was then heated to 100–105°C to obtain a homogeneous solution. After stirring at this temperature for 30 min, the solution was cooled to 5°C for 2 hours and held at 5°C for 3 hours. The mixture was then filtered, and the collected solid was washed with cold 1:1 toluene / n-heptane (2 x 123 mL). The material was vacuum dried at 55°C for 17 hours to yield 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid as a whitish crystalline solid. The 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (3 steps including isolation) with a purity by HLC of 99.0% AUC. ESI-MS m / z calculated for 242.04, found 241.58 (M+1) + ; 1H NMR (500 MHz, DMSO) 612.40 (s, 1H) , 7.40 (d, J = 1.6 Hz, 1H) , 7.30 (d, J = 8.3 Hz, 1H) , 7.17 (dd, J = 8.3, 1.7 Hz, 1.6 Hz, 1.6 Hz). 2H) , 1.17 (m, 2H) . Alternative Synthesis of the Acid Fraction Synthesis of (2, 2-difluoro-1, 3-benzodioxol-5-yl) -methanol. Commercially available 2,2-difluoro-1,3-benzodioxo-5-carboxylic acid (1.0 eq) is suspended in toluene (10 vol). Vitride® (2 eq) is added via an addition funnel at a rate sufficient to maintain the temperature at 15–25°C. At the end of the addition, the temperature is raised to 40°C for 2 h, then 10% (w / w) aqueous NaOH (4.0 eq) is carefully added via an addition funnel, maintaining the temperature at 40–50°C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40°C. The organic phase is cooled to 20°C, then washed with water (2 x 1.5 vol), dried (Na₂SO₄), filtered, and concentrated to provide crude 2,2-difluoro-1,3-benzodioxol-5-yl)-methanol, which is used directly in the next step. Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxol. (2,2-Difluoro-1,3-benzodioxol-5-yl)methanol (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol%) is added, and SOCh (1.2 eq) is added via an addition funnel. The SOCh is added at a rate sufficient to maintain the reactor temperature at 15–25°C. The temperature is then raised to 30°C for 1 hour and cooled to 20°C. Water (4 vol) is then added via an addition funnel, maintaining the temperature below 30°C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred, and 10% (w / v) aqueous NaOH (4.4 vol) is added. After stirring for 15–20 minutes, the layers are allowed to separate. The organic phase (Na2SO4) is then dried, filtered and concentrated to provide crude 5-chloromethyl-2,2-difluoro-1,3-benzodioxol which is used directly in the next step. Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile. A solution of 5-chloromethyl-2,2-difluoro-1,3-benzodioxol (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) while maintaining the temperature between 30-40°C. The mixture is stirred for 1 hour, and then water (6 vol) followed by MTBE (4 vol) is added. After stirring for 30 minutes, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried with Na₂SO₄, filtered, and concentrated to yield crude (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (95%), which is used directly in the next step. The remaining steps are the same as those described above for the synthesis of the acid fraction. Amine Fraction Synthesis of 2-bromo-5-fluoro-4-nitroaniline. A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and shaken to dissolve all solids. N-bromosuccinimide (1.0 equiv) was added in portions to maintain an internal temperature of 22°C. At the end of the reaction, the reaction mixture was concentrated under vacuum in a rotary evaporator. The residue was suspended in distilled water (5 vol) to dissolve and remove the succinimide. (The succinimide can also be removed by the water treatment procedure.) The water was decanted, and the solid was suspended in 2-propanol (5 vol) overnight. The resulting suspension was filtered, and the wet cake was washed with 2-propanol and dried in a vacuum oven at 50°C overnight with N2 diffusion until a constant weight was achieved. A yellowish-tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO) 8 8.19 (1 H, d, J = 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J = 14.3 Hz). Synthesis of p-toluenesulfonic acid salt of (R) -1- ( (4-amino-2-bromo-5-fluorophenyl) amino) -3- (benzyloxy) propan-2-ol. A flask thoroughly dried under N2 was charged with the following: powdered activated molecular sieve 4A (50 wt% based on 2-bromo-5-fluoro-4-nitroaniline), 2-bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 mol%), and toluene (8 vol). The mixture was stirred at room temperature for 30 min under NMT. ​​Finally, (R)-benzylglycidyl ether (2.0 equiv) was added to toluene (2 vol) in a steady stream. The reaction was heated to 80°C (internal temperature) and stirred for approximately 7 hours or until the 2-bromo-5-fluoro-4-nitroaniline concentration was <5% AUC. The reaction was cooled to room temperature, and Celite (50 wt%) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove the Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20% w / v). The organic layer was washed with sodium bicarbonate solution (4 vol x 2.5% w / v). The organic layer was concentrated under vacuum in a rotary evaporator. The resulting slurry was dissolved in isopropyl acetate (10 vol), and this solution was transferred to a Buchi hydrogenator. The hydrogenator was charged with 5 wt% Pt(S) / C (1.5 mol%) and the mixture was stirred under N2 at 30°C (internal temperature). The reaction was scrubbed with N2 followed by hydrogen. The hydrogenator pressure was set to 1 bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a Celite pad and washed with 10 vol dichloromethane. The filtrate was concentrated under vacuum. Any remaining isopropyl acetate was heated with 2 vol dichloromethane and concentrated to dryness using a rotary evaporator. The resulting residue was dissolved in dichloromethane (10 vol). Ptoluenesulfonic acid monohydrate (1.2 equiv) was added, and the mixture was stirred overnight. The product was filtered, washed with dichloromethane (2 vol), and dried by suction. The wet cake was transferred to drying trays and a vacuum oven and dried at 45°C with N₂ diffusion until a constant weight was achieved. The p-toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol was isolated as a whitish solid. The chiral purity was determined to be >97% ee. Synthesis of (3-doro-3-methylbut-1-ynyl)trimethylsilane. Propargylic alcohol (1.0 equiv) was charged into a vessel. Aqueous hydrochloric acid (37%, 3.75 vol) was added, and stirring began. Modest endothermy (5–6°C) was observed during the dissolution of the solid alcohol. The resulting mixture was stirred overnight (16 h), slowly turning dark red. A 30 L jacketed vessel was charged with water (5 vol), which was then cooled to 10°C. The reaction mixture was slowly transferred into the water under vacuum, maintaining the internal temperature of the mixture below 25°C. Hexanes (3 vol) were added, and the resulting mixture was stirred for 0.5 h. The phases settled, and the aqueous phase (pH <1) was drained off and discarded. The organic phase was concentrated under vacuum using a rotary evaporator, yielding the product as a red oil. Synthesis of (4-(benzyloxy)-3,3-dimethylbut-1-ynyl)trimethylsilane. Method 1A. All equivalent and volume descriptors in this part are based on a 250 g reaction. Magnesium flakes (69.5 g, 2.86 mol, 2.0 equiv) were loaded into a 3 L, 4-hole reactor and stirred with a magnetic stirrer under a nitrogen atmosphere for 0.5 h. The reactor was then immersed in an ice-water bath. A solution of propargyl chloride (250 g, 1.43 mol, 1.0 equiv) in THF (1.8 L, 7.2 vol) was slowly added to the reactor, with stirring, until an initial exothermic reaction was observed (~10°C). Grignard reagent formation was confirmed by IPC using 1H-NMR spectroscopy. Once the exothermic reaction ceased, the remainder of the solution was slowly added, maintaining the batch temperature at <15°C. The addition took approximately 3.5 hours. The resulting dark green mixture was decanted into a capped 2-liter bottle. All equivalent and volume descriptors in this part are based on a 500 g reaction. A 22 L reactor was charged with a solution of benzyl chloromethyl ether (95%, 375 g, 2.31 mol, 0.8 equiv) in THF (1.5 L, 3 vol). The reactor was cooled in an ice-water bath. Two batches of Grignard reagent prepared as described above were combined and then slowly added to the benzyl chloromethyl ether solution through an addition funnel, maintaining the batch temperature below 25°C. The addition required 1.5 h. The reaction mixture was stirred overnight (16 h). All equivalent and volume descriptors in this part are based on a 1 kg reaction. A 15% ammonium chloride solution was prepared in a 30 L jacketed reactor (1.5 kg in 8.5 kg of water, 10 vol). The solution was cooled to 5°C. Two Grignard reaction mixtures, prepared as described above, were then transferred to the ammonium chloride solution via a header vessel. An exothermic reaction was observed during this neutralization, which was carried out at a rate sufficient to maintain the internal temperature below 25°C. Once the transfer was complete, the jacket temperature was adjusted to 25°C. Hexanes (8 L, 8 vol) were added, and the mixture was stirred for 0.5 h. After settling of the phases, the aqueous phase (pH 9) was drained and discarded. The remaining organic phase was washed with water (2 L, 2 vol).The organic phase was concentrated under vacuum using a 22 l rotary evaporator, yielding the crude product as an orange oil. Method 1B. Magnesium shavings (106 g, 4.35 mol, 1.0 eq) were loaded into a 22 L reactor and then suspended in THF (760 mL, 1 vol). The vessel was cooled in an ice-water bath so that the batch temperature reached 2°C. A solution of propargyl chloride (760 g, 4.35 mol, 1.0 eq) in THF (4.5 L, 6 vol) was slowly added to the reactor. After 100 mL had been added, the addition was stopped and the mixture was stirred until an exothermic reaction of 13°C was observed, indicating the onset of the Grignard reaction. Once the exothermic reaction had subsided, another 500 mL of propargyl chloride solution was slowly added, maintaining the batch temperature at <20°C. The formation of the Grignard reagent was confirmed by IPC using 1H-NMRR spectroscopy. The remaining propargyl chloride solution was added slowly, maintaining the batch temperature at <20°C. The addition took approximately 1.5 hours.The resulting dark green solution was stirred for 0.5 h. Grignard reagent formation was confirmed by IPC using 1H-NMR spectroscopy. Benzyl chloromethyl ether was loaded into the reactor's addition funnel and then added dropwise to the reactor, maintaining the batch temperature below 25°C. The addition required 1.0 h. The reaction mixture was stirred overnight. Aqueous treatment and concentration were carried out using the same procedure and relative amounts of materials as in Method A to give the product in the form of an orange oil. Synthesis of 4-benzyloxy-3,3-dimethylbut-1-yne. A 30 L jacketed reactor was charged with methanol (6 vol) and then cooled to 5°C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. An exothermic reaction of 15–20°C was observed upon dissolution of the potassium hydroxide. The jacket temperature was adjusted to 25°C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv) in methanol (2 vol) was added, and the resulting mixture was stirred until the reaction was complete, as monitored by HPLC. The typical reaction time at 25°C is 3–4 h. The reaction mixture was diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) were added, and the resulting mixture was stirred for another 0.5 h. The phases were allowed to settle, and then the aqueous phase (pH 10-11) was drained and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol).The organic phase was then concentrated using a rotary evaporator, producing the title material as a yellow-orange oil. The typical purity of this material is in the range of 80% with only one impurity present. 1H NMR (400 MHz, C6D6) 67.28 (d, 2 H, J = 7.4 Hz) , 7.18 (t, 2 H, J = 7.2 Hz) , 7.10 (d, 1H, J = 7.2 Hz) , 4.35 (s, 2 H) , 3.24 (s, 2 H) , 1.91 (s, 1 H) , 1.25 (s, 6 H) . Synthesis of N-benzylglycoadol-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole. Method 1C. Synthesis of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol. The p-toluenesulfonic acid salt of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol was made freebase by stirring the solid in dichloromethane (5 vol.) and a saturated solution of NaHCO3 (5 vol.) until a clear organic layer was obtained. The resulting layers were separated, and the organic layer was washed with saturated solution of NaHCO3 (5 vol.) followed by brine and concentrated under vacuum to obtain freebase (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol as an oil. Palladium acetate (0.01 eq), dppb (0.015 eq), Cul (0.015 eq), and potassium carbonate (3 eq) were suspended in acetonitrile (1.2 vol). After stirring for 15 minutes, a solution of 4-benzyloxy-3,3-dimethylbut-1-yne (1.1 eq) in acetonitrile (0.2 vol) was added. The mixture was bubbled through with nitrogen gas for 1 hour, and then a free-base solution of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol (1 eq) in acetonitrile (4.1 vol) was added. The mixture was bubbled through with nitrogen gas for another hour and then heated to 80°C. The progress of the reaction was monitored by HPLC, and the reaction typically completed in 3–5 h. The mixture was cooled to room temperature and then filtered through Celite. The cake was washed with 4 vol acetonitrile. The combined filtrates were azeotropically distilled to dryness, and then the mixture was further polished into the next reactor.The acetonitrile solution of (R) -1- ( (4-amino-2- (4- (benzyloxy) -3, 3-dimethylbut-1-yn-1-yl) -5-fluorophenyl) amino) -3- (benzyloxy) propan-2-ol thus obtained is used directly in the following procedure (cyclization) without further manipulation. Synthesis of N-bendlglycoadol-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole. Sis-acetonitriledichloropalladium (0.1 eq) and Cul (0.1 eq) are loaded into the reactor and then suspended in a previously prepared solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol (1 eq) in acetonitrile (9.5 vol total). The mixture is bubbled through with nitrogen gas for 1 hour and then heated to 80°C. The progress of the reaction is monitored by HPLC, and the reaction is typically completed in 1–3 hours. The mixture is filtered through Celite, and the cake is washed with acetonitrile. A solvent exchange is performed in ethyl acetate (7.5 vol). The ethyl acetate solution is washed with aqueous NH3-NH4 solution (2 x 2.5 vol) followed by 10% brine (2.5 vol). The ethyl acetate solution is then stirred with silica gel (1.8 eq) and Si-TMT (0.1 wt eq) for 6 h. After filtration, the resulting solution is concentrated downstream.The residual oil is dissolved in DCM / heptane (4 vol) and then purified by column chromatography. The oil thus obtained is then crystallized in 25% EtOAc / heptane (4 vol). Typically, crystalline (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol is obtained in a yield of 27-38%. 1H NMR (400 MHz, DMSO) 87.38-7.34 (m, 4 H), 7.32-7.23 (m, 6 H), 7.21 (d, 1 H, J = 12.8 Hz), 6.77. (d, 1H, J = 9.0 Hz) , 6.06 (s, 1 H) , 5.13 (d, 1H, J = 4.9 Hz) , 4.54 (s, 2 H) , 4.46 (br. s, 2 H) , 4.45 (s, 2 H) , 4.33 (d, 1 H, J = 12.4 Hz), 4.09-4.04 (m, 2 H), 3.63 (d, 1H, J = 9.2 Hz), 3.56 (d, 1H, J = 9.2 Hz), 3.49 (dd, 1H, J = 9.8, 4.4 Hz), 3.43 (dd, 1H, J = 9.8, 5.7 Hz), 1.40 (s, 6 H) . Synthesis of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole. Method 1D. Palladium acetate (33 g, 0.04 eq), dppb (94 g, 0.06 eq), and potassium carbonate (1.5 kg, 3.0 eq) are loaded into a reactor. Benzylglycolized 4-ammonium-2-bromo-5-fluorouaniline on a free basis (1.5 kg, 1.0 eq) is dissolved in acetonitrile (8.2 L, 4.1 vol) and then added to the reactor. The mixture is bubbled through with nitrogen gas for 1 h NLT. A solution of 4-benzyloxy-3,3-dimethylbut-1-yne (70%, 1.1 kg, 1.05 eq) in acetonitrile is added to the mixture, which is then bubbled through with nitrogen gas for 1 h NLT. The mixture is heated to 80°C and then stirred overnight. IPC is carried out by HPLC and the reaction is determined to be complete after 16 h. The mixture is cooled to room temperature and then filtered through a Celite pad (228 g). The reactor and the Celite pad were washed with acetonitrile (2 x 2 l, 2 vol).The combined phases are concentrated in a 22l rotary evaporator until 8l of solvent have been collected, leaving the crude product in 7l (3.5 vol) of acetonitrile. Bis-acetonitriledichloropalladium (144 g, 0.15 eq) was loaded into the reactor. The crude solution was transferred back to the reactor, and the rotary evaporator head was washed with acetonitrile (4 L, 2 vol). The combined solutions were bubbled through with nitrogen gas for n L 1 h. The reaction mixture was heated to 80°C for NLT 16 h. HPLC process control showed complete consumption of the starting material. The reaction mixture was filtered through Celite (300 g). The reactor and filter cake were washed with acetonitrile (3 L, 1.5 vol). The combined filtrates were concentrated into an oil by rotary evaporation. The oil was dissolved in ethyl acetate (8.8 L, 4.4 vol). The solution was washed with 20% ammonium chloride (5 L, 2.5 vol) followed by 5% brine (5 L, 2.5 vol). Silica gel (3.5 kg, 1.8 wt e) was added to the organic phase, which was stirred overnight.Deloxan THP II metal scrubber (358 g) and heptane (17.6 L) were added, and the resulting mixture was stirred for 3 h NLT. The mixture was filtered through a sintered glass funnel. The filter cake was washed with 30% ethyl acetate in heptane (25 L). The combined filtrates were concentrated under reduced pressure to give N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole as a brown paste (1.4 kg). Synthesis of Compound 1 protected with benzyl. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was suspended in toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol)-5-yl)-cyclopropanecarboxylic acid). Thionyl chloride (SOCl2, 1.7 equiv) was added via an addition funnel, and the mixture was heated to 60°C. The resulting mixture was stirred for 2 h. The toluene and excess SOCl2 were distilled using a rotary evaporator. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added, and the mixture was distilled to 1 vol of toluene. A solution of (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol (1 eq) and triethylamine (3 eq) was cooled in DCM (4 vol) at 0° C. Acid chloride solution in toluene (1 vol) was added while maintaining the batch temperature below 10° C.The progress of the reaction is monitored by HPLC, and the reaction is usually completed in minutes. After heating to 25°C, the reaction mixture is washed with 5% (3.5 vol) NaHCO3, 1M (3.5 vol) NaOH, and 1M (5 vol) HCl. A solvent exchange is performed in methanol (2 vol), and the resulting (R)-N-(1-(3-(benzyloxy)-2-hydroxypropyl)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide solution in methanol is used without further manipulation in the next step (hydrogenolysis). Synthesis of Compound 1. Five percent palladium on carbon (~50% wet, 0.01 eq) is loaded into a suitable hydrogenation vessel. The previously obtained (R)-N-(1-(3-(benzyloxy)-2-hydroxypropyl)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide solution in methanol (2 vol) is carefully added, followed by a 3M solution of HCl in methanol. The vessel is purged with nitrogen gas and then with hydrogen gas. The mixture is stirred vigorously until the reaction is complete, as determined by HPLC analysis. The typical reaction time is 3–5 h. The reaction mixture is filtered through Celite, and the cake is washed with methanol (2 vol). A solvent exchange is performed in isopropanol (3 vol).Crude compound 1 is crystallized in 75% IPA-heptane (4 vol, i.e., 1 vol of heptane added to 3 vol of IPA), and the resulting crystals are matured in 50% IPA-heptane (i.e., 2 vol of heptane added to the mixture). Typical yields of compound 4 from the two-step acylation / hydrogenolysis procedure range from 68% to 84%. Compound 4 can be recrystallized from IPA-heptane following the same procedure just described. Compound 1 can also be prepared by one of several synthetic routes described in published patent application US20090131492, incorporated herein by reference. T l 7. D fí irlm 1. Example 2: Synthesis of Compound 2: N-r2.4-bis(1.1-dimethylethyl)-5-hydroxyphenyl-1.4-dihydro-4-oxoquinolin-3-carboxamide. Synthesis of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (26) . Procedure for the preparation of ethyl 4-oxo-1,4-dihydroquinolin-3-carboxylate (25). Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to expel ethanol below 30°C for 0.5 hours. The solution was then heated to 100–110°C and stirred for 2.5 hours. After cooling the mixture to below 60°C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228–232°C for 1.5 hours with subsurface N2 flow to expel ethanol. The mixture was stirred at 228–232°C for another 2 hours, cooled to below 100°C, and then heptane was added to precipitate the product. The resulting slurry was stirred at 30°C for 0.5 hours. The solids were then filtered out, and the cake was washed with heptane and vacuum dried to give compound 25 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) 812.25 (s) , 88.49 (d) , 88.10 (m) , 87.64 (m) , 87.55 (m) , 87.34 (m) , 84.16 (q) , 81.23 (t) . Procedure for the preparation of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (26) . Method 2A. Compound 25 (1.0 eq) was suspended in a solution of HCl (10.0 eq) and H₂O (11.6 vol). The slurry was heated to 85–90°C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can be carried out at approximately 75 to approximately 100°C. In some cases, the hydrolysis is carried out at approximately 80 to approximately 95°C. In others, the hydrolysis step is carried out at approximately 82 to approximately 93°C (e.g., approximately 82.5 to approximately 92.5°C or approximately 86 to approximately 89°C). After stirring at 85–90°C for approximately 6.5 hours, the reaction was sampled to determine its completion. Stirring can be carried out at any of the temperatures suitable for hydrolysis. The solution was then cooled to 20-25°C and filtered. The reactor / cake was rinsed with H2O (2 vol x 2).The cake was then washed with 2 vols of H2O until pH > 3.0. The cake was then dried under vacuum at 60°C to give compound 26. Method 2B. Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aqueous) (10 mL) and ethanol (100 mL). The solution was heated under reflux for 16 hours, cooled to 20–25°C, and then the pH was adjusted to 2–3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The filter cake was washed with water (50 mL) and then vacuum dried to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) 8 15.33 (s), 8 13.39 (s), 8 8.87 (s), 88.26 (m), 87.87 (m), 87.80 (m), 87.56 (m). Total synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinolin-3-carboxamide (Compound 2). Method 2C To a solution of 2,4-di-tert-butylphenol (10 g, 48.5 mmol) in diethyl ether (100 mL) and triethylamine (10.1 mL, 72.8 mmol), methyl chloroformate (7.46 mL, 97 mmol) was added dropwise at 0°C. The mixture was then allowed to warm to room temperature and stirred for an additional 2 hours. An additional 5 mL of triethylamine and 3.7 mL of methyl chloroformate were then added, and the reaction was stirred overnight. The reaction was then filtered, the filtrate was cooled to 0°C, and an additional 5 mL of triethylamine and 3.7 mL of methyl chloroformate were added. The reaction was allowed to warm to room temperature and then stirred for an additional 1 hour. At this stage, the reaction was almost complete and was treated by filtration, then washing with water (2x), followed by brine. The solution was then concentrated to produce a yellow oil and purified using column chromatography to give the compound 30.1H NMR (400 MHz, DMSO-d6) 87.35 (d, J = 2.4 Hz, 1H) , 7.29 (dd, J = 8.4, 2.4 Hz, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 3.85 (s, 3H) , 1.30 (s, 9H) , 1.29 (s, 9H) . Método 2D. To a reactor vessel charged with 4-dimethylaminopyridine (DMAP, 3.16 g, 25.7 mmol) and 2,4-di-tert-butylphenol (compound 29, 103.5 g, 501.6 mmol), methylene chloride (415 g, 313 mL) was added, and the solution was stirred until all solids dissolved. Triethylamine (76 g, 751 mmol) was then added, and the solution was cooled to 0-5°C. Methyl chloroformate (52 g, 550.3 mmol) was then added dropwise over 2.5-4 hours while the solution was maintained at a temperature between 0-5°C. The reaction mixture was then heated slowly to 23-28°C and stirred for 20 hours. The reaction was then cooled to 10–15°C and loaded with 150 mL of water. The mixture was stirred at 15–20°C for 35–45 minutes, and then the aqueous layer was separated and extracted with 150 mL of methylene chloride. The organic layers were combined and neutralized with 2.5% HCl (aqueous) at a temperature of 5–20°C to give a final pH of 5–6.The organic layer was then washed with water and concentrated under vacuum at a temperature below 20°C to 150 ml to give compound 30 in methylene chloride. Procedure for the preparation of 5 -n itro -2, 4 -di- te rc -bu tylphenyl methyl carbonate (31) . Method 2E. To a stirred solution of compound 30 (6.77 g, 25.6 mmol), 6 mL of a 1:1 mixture of sulfuric acid and nitric acid were added dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The product was purified using liquid chromatography (ISCO, 120 g, 0–7% EtOAc / Hexanes, 38 min), yielding approximately an 8:1–10:1 mixture of regioisomers of compound 31 as a white solid. 1H NMR (400 MHz, DMSO-d6): 87.63 (s, 1H), 7.56 (s, 1H), 3.87 (s, 3H), 1.36 (s, 9H), 1.32 (s, 9H). HPLC retention time 3.92 min 10-99% CH3CN, 5 min run time; ESI-MS 310 m / z (MH) +. Method 2F. To compound 30 (100 g, 378 mmol) was added DCM (540 g, 408 mL). The mixture was stirred until all the solids dissolved, and then cooled to -5 to 0°C. Concentrated sulfuric acid (163 g) was then added dropwise, while maintaining the initial reaction temperature, and the mixture was stirred for 4.5 hours. Nitric acid (62 g) was then added dropwise for 2–4 hours while maintaining the initial reaction temperature, and the mixture was stirred at this temperature for an additional 4.5 hours. The reaction mixture was then slowly added to cold water, maintaining a temperature below 5°C. The neutralized reaction was then heated to 25°C, and the aqueous layer was removed and extracted with methylene chloride. The combined organic layers were washed with water, dried using Na2SO4, and concentrated to 124–155 ml. Hexane (48 g) was added, and the resulting mixture was concentrated again to 124–155 ml. Subsequently, more hexane (160 g) was added to the mixture.The mixture was then stirred at 23–27°C for 15.5 hours and subsequently filtered. Hexane (115 g) was added to the filter cake, the resulting mixture was heated under reflux and stirred for 2–2.5 hours. The mixture was then cooled to 3–7°C, stirred for an additional 1–1.5 hours, and filtered to give compound 31 as a pale yellow solid. Process for the preparation of 5-amino-2,4-di-tert-butylphenyl methyl carbonate (32) . 2,4-Di-tert-butyl-5-nitrophenyl methyl carbonate (1.00 eq) was charged into a suitable hydrogenation reactor, followed by 5% Pd / C (2.50 wt. dry basis, Johnson-Matthey type 37). MeOH (15.0 vol) was charged into the reactor, and the system was closed. The system was purged with N2 (g) and then pressurized to 2.0 bar with H2 (g). The reaction was carried out at a reaction temperature of 25°C ± 5°C. When complete, the reaction was filtered, and the reactor / cake was washed with MeOH (4.00 vol). The resulting filtrate was vacuum distilled at no more than 50°C to 8.00 vol. Water (2.00 vol) was added at 45°C ± 5°C. The resulting slurry was cooled to 0°C ± 5°C. The slurry was held at 0°C ± 5°C for at least 1 hour and filtered. The cake was washed once with 0°C ± 5°C MeOH / H2O (8:2) (2.00 vol). The cake was vacuum dried (-0.90 bar and -0.86 bar) at 35°C - 40°C to give compound 32. 1H NMR (400 MHz, DMSO-d6) 67.05 (s, 1H), 6.39 (s, 1H), 4.80 (s, 2H), 3.82 (s, 3H), 1.33 (s, 9H) , 1.23 (s, 9H) . Once the reaction was completed, the resulting mixture was diluted with approximately 5 to 10 volumes of MeOH (e.g., from approximately 6 to approximately 9 volumes of MeOH, from approximately 7 to approximately 8.5 volumes of MeOH, from approximately 7.5 to approximately 8 volumes of MeOH, or to approximately 7.7 volumes of MeOH), heated to a temperature of approximately 35 ± 5° C, filtered, washed, and dried, as described above. Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinolin-3-carboxamide (Compound 2). 4-oxo-1,4-dihydroquinolin-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were loaded into a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added, followed by a 50% T3P® solution in 2-MeTHF (1.7 eq). The vessel loaded with T3P was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 ± 5.0°C and held at this temperature for 8 hours. A sample was taken and its completion was verified by HPLc. Once complete, the resulting mixture was cooled to 25.0°C ± 2.5°C. 2-MeTHF (12.5 vol) was added to dilute the mixture. The reaction mixture was washed twice with water (10.0 vol). 2-MeTHF was added to bring the total reaction volume to 40.0 vol (~16.5 vol loaded). NaOMe / MeOH (1.7 equivalents) was added to this solution to carry out the methanolysis. The reaction was stirred for at least 1.0 hour, and its completion was verified by HPLC.Once the reaction was complete, it was neutralized with 1N (10.0 vol) HCl and washed with 0.1N (10.0 vol) HCl. The organic solution was polished to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35°C (jacket temperature) and no less than 8.0°C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added at 40 vol, and the solution was concentrated at no more than 35°C (jacket temperature) and no less than 8.0°C (internal reaction temperature) to 20 vol. The addition of CH3CN and the concentration cycle were repeated two more times for a total of three CH3CN additions and four concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added, followed by 4.0 vol of H2O, to make a final concentration of 40 vol of H2O / CH3CN at 10% relative to the starting acid. This slurry was heated to 78.0°C ± 5.0°C (reflux). The slurry was stirred for at least 5 hours.The suspension was cooled to 0.0°C + / - 5°C for 5 hours and filtered. The cake was washed with CH3CN at 0.0°C + / - 5.0°C (5 vol) 4 times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0° C + / - 5.0° C. 1H NMR (400 MHz, DMSO-cfe) 812.8 (s, 1H) , 11.8 (s, 1H) , 9.2 (s, 1H) , 8.9 (s, 1H) , 8.3 (s, 1H) , 7.2 (s, 1H) , 7.9 (t, 1H) , 7.8 (d, 1H) , 7.5 (t, 1H) , 7.1 (s, 1H) , 1.4 (s, 9H) , 1.4 (s, 9H) . Alternative preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinolin-3-carboxamide (Compound 2). 4-oxo-1,4-dihydroquinolin-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were loaded into a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added, followed by a 50% T3P® solution in 2-MeTHF (1.7 eq). The vessel loaded with T3P was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 ± 5.0°C and held at this temperature for 8 hours. A sample was taken and its completion was verified by HPLc. Once complete, the resulting mixture was cooled to 20°C ± 5°C. 2-MeTHF (12.5 vol) was added to dilute the mixture. The reaction mixture was washed twice with water (10.0 vol) and charged with 2-MeTHF (16.5 vol) into the reactor. This solution was charged with 30% w / w NaOMe / MeOH (1.7 equiv) to carry out the methanolysis. The reaction was stirred at 25.0°C ± 5.0°C for at least 1.0 hour, and its completion was verified by HPLC.Once completed, the reaction was neutralized with 1.2N (10.0 vol) HCl / H2O, and washed with 0.1N (10.0 vol) HCl / H2O. The organic solution was polished to remove any particulate matter and placed in a second reactor. The filtered solution was concentrated at no more than 35°C (jacket temperature) and no less than 8.0°C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added at 40 vol, and the solution was concentrated at no more than 35°C (jacket temperature) and no less than 8.0°C (internal reaction temperature) to 20 vol. The addition of CH3CN and the concentration cycle were repeated two more times for a total of three additions of CH3CN and four concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was charged, followed by 4.0 vol of H2O, to make a final concentration of 40 vol H2O / CH3CN at 10% relative to the starting acid. This slurry was heated to 78.0°C ± 5.0°C (reflux). The slurry was stirred for at least 5 hours. The slurry was cooled to 20–25°C for 5 hours and filtered. The cake was washed with CH3CN (5 vol) heated to 20–25°C four times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0°C ± 5.0°C.1H NMR (400 MHz, DMSO-cfe) 812.8 (s, 1H) , 11.8 (s, 1H) , 9.2 (s, 1H) , 8.9 (s, 1H) , 8.3 (s, 1H) , 7.2 (s, 1H) , 7.9 (t, 1H) , 7.8 (d, 1H) , 7.5 (t, 1H) , 7.1 (s, 1H) , 1.4 (s, 9H) , 1.4 (s, 9H) . Procedure for the recrystallization of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinolin-3-carboxamide (Compound 2). Compound 2 (1.0 eq) was loaded into a reactor. 2-MeTHF (20.0 vol) was added, followed by 0.1 N HCl (5.0 vol). The two-phase solution was stirred and separated, and the upper organic phase was washed twice more with 0.1 N HCl (5.0 vol). The organic solution was polished to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35°C (jacket temperature) and no more than 8.0°C (internal reaction temperature) under reduced pressure to 10 vol. Isopropyl acetate (IPAc) (10 vol) was added, and the solution was concentrated at no more than 35°C (jacket temperature) and no more than 8.0°C (internal reaction temperature) to 10 vol. The addition of IPAc and the concentration were repeated 2 more times for a total of 3 IPAc additions and 4 concentrations to 10 vol. After the final concentration, 10 vol of IPAc was loaded and the slurry was heated under reflux and held at this temperature for 5 hours.The suspension was cooled to 0.0°C ± 5°C for 5 hours and filtered. The cake was washed once with IPAc (5 vol). The resulting solid was dried in a vacuum oven at 50.0°C ± 5.0°C. Example 3: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (1:1) Substantially Free of Polymer. 56.5 g of Compound 1 and 56.5 g of Compound 2 were added to 895.9 g of 90:0 methyl ethyl ketone (MEK):water in a 2 L amber bottle. The material was stirred until both compounds had dissolved and spray-dried using a Buchi Mini Spray Dryer set to the parameters described below in Table 8: Tabl: P rmrr mi nirinr lv riz tion. The material was secondarily dried in a vacuum oven with nitrogen purging for 2 hours at 60°C and overnight at 80°C. Figure 5 shows an SEM image of this spray-dried dispersion. With reference to Figures 1 and 2, the amory form was confirmed by XRPD and DSC, showing a glass transition temperature of 124°C. With reference to Figure 3, the spray-dried dispersion was subjected to solid-state NMR analysis for 1H-1H spin diffusion in Compound 1 and Compound 2. For the NMR spectrum in Figure 3, the following solid-state NMR parameters were used: 19F T 1 (spin structure relaxation time): 7-9 seconds Rotation: 12.5kHz Temp (K): 275 Reference: 29.5 ppm adamantane D20: 0.1 -50 ms As illustrated in the solid-state NMR spectrum in Figure 3, Compound 1 and Compound 2 make contact at the molecular level. With reference to Figure 4, the 19F and 13C solid-state NMR spectra were recorded for the spray-dried dispersion of Compound 1 and Compound 2. Figure 4 (top) is a superposition of Peak A and Peak B. Figure 4 (bottom) is Peak C. PEAK A: 13C CPMAS Sample preparation: Compound 1 and Compound 2 were cryo-ground / cryo-crushed for 100 min. 1H T1: 0.85 s Rotation: 12.0 kHz Reference: 29.5 ppm adamantane Temp (K): 275 PEAK B: 13C CPMAS Sample preparation: The spray-dried dispersion was dried for 72 hours. 1H T1: 0.85 s Rotation: 12.0 kHz Reference: 29.5 ppm adamantane Temp (K): 275 PEAK C: 19F PLUS Sample preparation: The spray-dried dispersion was dried for 72 hours. 19F T1 : 7-9 s Rotation: 12.5 kHz Reference: 29.5 ppm adamantane Temp (K): 275 RD: 2 s Thermogravimetric analyses were performed on the spray-dried dispersion that underwent the following processing: Sample A: 3 days at 90°C under vacuum, followed by N2 purging. Sample B: 3 days at 40° C. Figure 5 presents an SEM image of this spray-dried dispersion. Example 4: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (1:3) Substantially Free of Polymer. 29.94 g of Compound 1 and 90.01 g of Compound 2 were added to 955.7 g of 90:0 methyl ethyl ketone (MEK):water in a 2 L amber bottle. The material was stirred until both compounds had dissolved and spray-dried using a Buchi mini spray dryer set to the parameters described below in Table 9: Table 9: 25 / 75 Processing parameters of dried dispersion by spraying. 700 g of solution were spray-dried. The material was secondarily dried in a vacuum oven with nitrogen purging overnight at 80°C. Approximately 20 g of amorphous Compound 1 and Compound 2 were recovered (26% yield). Figure 8 shows an SEM image of this spray-dried dispersion. With reference to Figures 6 and 7, the amorphous form was confirmed by XRP and DSC, showing a glass transition temperature of 155°C. Example 5: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (1:10) Substantially Free of Polymer. 2.03 g of Compound 1 and 20.08 g of Compound 2 were added to 234.1 g of 90:10 methyl ethyl ketone (MEK):water in a 0.5 L amber bottle. The material was stirred until both compounds had dissolved and spray-dried using a Buchi mini spray dryer set to the parameters described below in Table 10: Table 10: 9 / 91 Processing parameters of dried dispersion by spraying. Approximately 15 g of amorphous Compound 1 and Compound 2 were recovered (68% yield). The material was secondarily dried in a vacuum oven at 60°C for 3 days. Example 6: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (10:1) Substantially Free of Polymer. 20.03 g of Compound 1 and 2.04 g of Compound 2 were added to 231.1 g of 90:10 methyl ethyl ketone (MEK):water in a 0.5 L amber bottle. The material was stirred until both compounds had dissolved and spray-dried using a Buchi mini spray dryer set to the parameters described below in Table 11: Table 11: 9 / 91 Drying dispersion processing parameters spraying. Approximately 11 g of amorphous Compound 1 and Compound 2 (50% yield) were recovered. The material was secondarily dried in a vacuum oven at 60°C for 3 days. The amorphous form was confirmed by XRPD and DSC. Example 7: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (1:3) by the hot pressure / hot temperature method. Compound 1 and Compound 2 were spray-dried in a 1:3 ratio (25 wt% Compound 1 / 75 wt% Compound 2) using a solvent system consisting of methanol. The resulting mixture contained a 5% solids loading. The actual quantities of materials used in this process are listed in Table 12. Table 12: Materials and quantities of r lv riz i n. Compound 1 and Compound 2 were added to methanol to form a suspension at room temperature in an appropriately sized vessel. This suspension was then transferred to a heat exchanger via a high-pressure pump. The solids were subsequently dissolved at the target temperature in the heat exchanger before entering the nozzle. The resulting suspension was spray-dried in a PSD1 spray dryer using a Bend research flash atomizer. The operating parameters of the spray dryer are listed in Table 13. T l 1: P rmrfnin mi nlrr lv riz i n. The wet SDD was collected and placed in a vacuum tray dryer with nitrogen purging gas due to potential oxidation risks. Residual methanol levels were tested for over 24 hours until low levels (<10 ppm) were detected. The dried material was analyzed for bulk density and particle size, resulting in values ​​of 0.24 g / ml and a D50 of 6 µm, respectively. Example 8: Preparation of a Solid Dispersion Comprising Substantially Amorphous Compound 1 and HPMC Polymer. A dichloromethane (DCM) and methanol (MeOH) solvent system was formulated in an 80 wt% DCM / 20 wt% MeOH ratio in an appropriately sized vessel equipped with a magnetic stirrer and stirring plate. Hypromellose polymer (HPMC, grade E15) and Compound 1 were added to this solvent system in a 20 wt% hypromellose / 80 wt% Compound 1 ratio. The resulting mixture contained 12.5 wt% solids. The actual quantities of ingredients and solvents used to generate this mixture are listed in Table 14 below. T l 14: in r in i rin lvriz in li rm 1 m rf . The mixture was mixed until it was substantially homogeneous and all components had substantially dissolved. An Anhydro MS-35 Spray Drier, equipped with two 0.8 mm fluid nozzles (Schlick 970 / 0 S4 series) was used in normal spray drying mode, following the dry spray process parameters listed in Table 15 below. Table 15: Spray drying dispersion processing parameters for nrrnirin lv riz in li lm 1 m rf . A high-efficiency cyclone separated the wet product from the spray gas and solvent vapors. The wet product was transferred to trays and placed in a vacuum dryer to reduce the residual solvents to a level of less than approximately 3000 ppm for MeOH and less than 600 ppm for DCM, and to generate a dry spray-dried dispersion of amorphous Compound 1, containing <0.02% MeOH and <0.06% DCM. Example 9: Preparation of a Solid Dispersion Comprising Substantially Amorphous Compound 2 and HPMCAS Polymer. A solvent system of MEK and DI water, formulated in a 90 wt% MEK / 10 wt% DI water ratio, was heated to 2–30°C in a reactor equipped with a magnetic stirrer and a thermal circuit. Hypromellose acetate succinate polymer (HPMCAS) (HG grade), SLS, and Compound 2 were added to this solvent system in a 19.5 wt% hypromellose acetate succinate / 0.5 wt% SLS / 80 wt% Compound 2 ratio. The resulting mixture contained 10.5 wt% solids. The actual quantities of ingredients and solvents used to generate this mixture are listed in Table 16 below. Table 16: Solid Spray Dispersion Ingredients for Compound 2 amorphous. The temperature of the mixture was adjusted to a range of 20-45°C and mixed until it was substantially homogeneous and all components had substantially dissolved. A commercial Niro PSD4 spray dryer was used, equipped with a pressure nozzle (Spray Systems Maximum Passage SK-MFP series having a hole / core size of 54 / 21) fitted with an anti-barb plug, in normal spray drying mode, following the spray drying process parameters listed in Table 17 below. Table 17: Spray drying dispersion processing parameters to generate nirin lv riz i nº li lm 2 m rf . A high-efficiency cyclone separated the wet product from the spray gas and solvent vapors. The wet product contained 8.5–9.7% MEK and 0.5–0.83% water and had an average particle size of 1–19 µm and a bulk density of 0.2–0.33 g / cc. The wet product was transferred to a 4000 L stainless steel double-cone vacuum dryer for drying to reduce the residual solvents to a level of less than approximately 5000 ppm and to generate a dry spray-dried dispersion of amorphous Compound 2, containing <0.03% MEK and 0.3% water. Example 10: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (1:1). Compound 1 and Compound 2 were spray-dried in a 1:1 ratio (40 wt. Compound 1 / 40 wt. Compound 2) along with 20 wt. hypromellose acetate succinate polymer (HPMCAS, HG grade) using a solvent system consisting of 90 wt. methyl ethyl ketone (MEK) / 10 wt. water DI. The resulting mixture contained an 11% solids loading. The actual quantities of materials used in this process are listed in Table 18. Table 18: Dried Materials by spraying and quantities. MEK and water were mixed at room temperature in an appropriately sized container using a magnetic stir bar. Compound 2 was added to the MEK / water mixture and stirred until dissolved. Compound 1 was then added and stirred until dissolved. Finally, HPMCAS-HG was added and stirred until dissolved. The resulting mixture was spray dried in a Buchi B-290 spray dryer using a 2-fluid, 1.5 mm nozzle. The operating parameters of the spray dryer are listed in Table 19. T l 1 : P rmrfnin mi nlrr lv riz i n. The wet SDD was collected and placed in a vacuum oven at room temperature and allowed to dry until residual MEK levels were <5000 ppm. The dried material was analyzed for bulk density and particle size, resulting in values ​​of 0.33 g / ml and a D50 of 4.092 µm, respectively. Example 11: Preparation of Solid Dispersion of Amorphous Compound 1 and Amorphous Compound 2 (2:1). Compound 1 and Compound 2 were spray-dried in a 2:1 ratio (53 wt% Compound 1 / 27 wt% Compound 2) along with 20 wt% hypromellose acetate succinate polymer (HPMCAS, HG grade) using a solvent system consisting of 90 wt% methyl ethyl ketone (MEK) / 10 wt% water DI. The resulting mixture contained an 11% solids loading. The actual quantities of materials used in this process are listed in Table 20. Table 20: Materials dried by lv riz in ni . MEK and water were mixed at room temperature in an appropriately sized container using a magnetic stir bar. Compound 2 was added to the MEK / water mixture and stirred until dissolved. Compound 1 was then added and stirred until dissolved. Finally, HPMCAS-HG was added and stirred until dissolved. The resulting mixture was spray dried in a Buchi B-290 spray dryer using a 2-fluid, 1.5 mm nozzle. The operating parameters of the spray dryer are listed in Table 21. Tal 21: P rmrfnin mi nlrr lv riz ion. The wet SDD was collected and placed in a vacuum oven at room temperature and allowed to dry until residual MEK levels were <5000 ppm. The dried material was analyzed for bulk density and particle size, resulting in values ​​of 0.35 g / ml and a D50 of 4.682 µm, respectively. Example 12: Preparation of a Tablet Formulation from a Dry Granulation Roller Compaction. Equipment: Turbula Mixer, V-shell Mixer or a container mixer, Gerteis Roller Compactor, Piccola Tablet Press. Selection / Weigh-in: The solid dispersion comprising substantially amorphous Compound 1, the solid dispersion comprising substantially amorphous Compound 2, and the excipients can be selected before or after weighing. Appropriate screen sizes are 30 mesh or 60 mesh. Mixed: The solid dispersion comprising substantially amorphous Compound 1, the solid dispersion comprising substantially amorphous Compound 2, and the excipients may be added to the mixer in a different order. An additional lubrication step may be required. Mixing and lubrication may be performed in a Turbula mixer, a V-shell mixer, or a container mixer. The components may be mixed for 10 minutes or lubricated for 4 minutes. Dry granulation: The mixture can be granulated using a Gerteis roller compactor. The mixture can be granulated using combined smooth / smooth rollers with an integrated 0.8 mm mesh grinding screen, a bagged rotor, and a paddle agitator. The Gerteis roller compactor can operate with a 2 mm roller spacing, a roller pressure of 4 kNcm, a roller speed of 2 rpm, an agitator speed of 15 rpm, a clockwise / counterclockwise granulation speed of 80 / 80 rpm, and a clockwise / counterclockwise oscillation of 330 / 360 degrees. The resulting strips can be ground using an integrated mill equipped with a 0.8 mm mesh screen. Mixed: Roller-compacted granules can be mixed with extragranular excipients such as filler, disintegrant, and, if necessary, lubricant using a Turbula mixer, a V-shell mixer, or a container mixer. The mixing time can be 10 minutes, or lubrication can be provided for 4 minutes. The compression mixture can be compressed into tablets using a single-station or rotary tablet presses, such as the Piccola press, using Size D Caplet Tooling (0.568" x 0.2885"). The tablet weight for a dose of 50 mg of substantially amorphous Compound 1 and 150 mg of substantially amorphous Compound 2 can be approximately 400 or 600 mg. T l 22. m rimi mrnmm 1 1 mm 2 Example 13: Preparation of a Tablet Formulation of Compound 1 and 150 mg of Compound 2 formulation from Dry Granulation Roller Compaction - Equipment: Turbula mixer, V-shell mixer or container mixer, Gerteis roller compactor, MTS Universal Testing System Selection / Weigh-in: The solid dispersion comprising the substantially amorphous Compound 1, the solid dispersion comprising the substantially amorphous Compound 2, and the excipients may be selected before or after weighing. Appropriate screen sizes are 30 mesh or 60 mesh. Mixed: The solid dispersion comprising the substantially amorphous Compound 1, the solid dispersion comprising the substantially amorphous Compound 2...

Claims

1. A pharmaceutical composition comprising: a first spray-dried dispersion and a second spray-dried dispersion, wherein the first spray-dried dispersion comprises from approximately 70 wt% to approximately 90 wt% of an amorphous form of (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 (Compound 1) and from approximately 10 wt% to approximately 30 wt% of a polymer, and wherein the second spray-dried dispersion comprises an amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) 2) ; and wherein the pharmaceutical composition is a tablet.

2. The pharmaceutical composition of claim 1, wherein the polymer comprises a cellulose polymer. 3.The pharmaceutical composition of claim 1 or claim 2, wherein the polymer comprises hydroxypropyl methylcellulose.

4. The pharmaceutical composition of any of claims 1-3, wherein the second spray-dried dispersion further comprises a polymer.

5. The pharmaceutical composition of claim 4, wherein the second spray-dried dispersion comprises from approximately 70 wt% to approximately 90 wt% of Compound 2 and from approximately 10 wt% to approximately 30 wt% of polymer.

6. The pharmaceutical composition of any of claims 1-5, comprising from approximately 5 wt% to approximately 20 wt% of the first spray-dried dispersion.

7. The pharmaceutical composition of any of claims 1-6, comprising from approximately 15 wt% to approximately 60 wt% of the second spray-dried dispersion. 8.The pharmaceutical composition of any of claims 1-7, wherein the tablet comprises approximately 25 mg to 125 mg of Compound 1.

9. The pharmaceutical composition of any of claims 1-8, wherein the tablet comprises approximately 100 mg to 200 mg of Compound 2.

10. The pharmaceutical composition of any of claims 1-9, wherein the pharmaceutical composition comprises one or more excipients selected from a filler, a disintegrant, a lubricant, or any combination thereof.

11. The pharmaceutical composition of any of claims 1-7, comprising approximately 30% by weight to approximately 50% by weight of a filler of the pharmaceutical composition.

12. The pharmaceutical composition of claim 11, wherein the filler comprises microcrystalline cellulose. 13.The pharmaceutical composition of any of claims 1-12, comprising from approximately 1% by weight to approximately 10% by weight of a disintegrant by weight of the pharmaceutical composition.

14. The pharmaceutical composition of claim 13, wherein the disintegrant comprises croscarmellose sodium.

15. The pharmaceutical composition of any of claims 1-14, comprising approximately 1% by weight of a lubricant by weight of the pharmaceutical composition.

16. The pharmaceutical composition of claim 15, wherein the lubricant comprises magnesium stearate.

17. The pharmaceutical composition of any of claims 1-7, wherein the tablet comprises from approximately 30 mg to approximately 85 mg of the first spray-dried dispersion. 18.The pharmaceutical composition of any of claims 1 or 17, wherein the tablet comprises from approximately 150 mg to approximately 250 mg of the second spray-dried dispersion.

19. The pharmaceutical composition of any of claims 1-18, wherein the tablet comprises from approximately 100 mg to approximately 300 mg of a filler.

20. The pharmaceutical composition of any of claims 1-19, wherein the tablet comprises from approximately 12 mg to approximately 36 mg of a disintegrant.

21. The pharmaceutical composition of any of claims 1-20, wherein the tablet comprises from approximately 1 mg to approximately 5 mg of a lubricant.

22. The pharmaceutical composition of any of claims 1-21 further comprises an additional therapeutic agent. 23.The pharmaceutical composition of claim 22, wherein the additional therapeutic agent is a CFTR corrector other than Compound 1.

24. The pharmaceutical composition of claim 22, wherein the additional therapeutic agent is a CFTR enhancer other than Compound 2.

25. A pharmaceutical composition of any preceding claim for use in a method of treating cystic fibrosis in a patient.

26. The pharmaceutical composition for use as in claim 25, wherein the method comprises orally administering the pharmaceutical composition to the patient.

27. The pharmaceutical composition for use as in any of claims 25 or 26, further comprising administering an additional therapeutic agent to the patient.

28. The pharmaceutical composition for use as in claim 27, wherein the additional therapeutic agent is administered before, after, or simultaneously with the pharmaceutical composition. 29.The pharmaceutical composition for use as in any of claims 25-28, wherein the patient is homozygous for the AF508 CFTR mutation.

30. The pharmaceutical composition for use as in any of claims 25-28, wherein the patient is heterozygous for the AF508 CFTR mutation.

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