Compositions for treating cftr-mediated diseases

Abstract

This invention relates to pharmaceutical compositions formulated into multiple granules, said granules containing bis((14) S )-8-[3-(2-{two screws[2.0.2 4 .1 3 [[Heptane-7-yl]ethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ#-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.1] 11 , 14 .0#, 1 #] 24-carbon-1(23),5,7,9,19,21-hexane-3-oxide) calcium, ( R )-1-(2,2-difluorobenzo[d][1,3]dioxane-5-yl)- N Solid dispersions of 1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indol-5-yl)cyclopropaneformamide and N A solid dispersion of -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, a method for manufacturing and processing the particles, and a method for treating cystic fibrosis with the pharmaceutical composition.

Description

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 550,817, filed February 7, 2024, the contents of which are incorporated herein by reference in their entirety.

[0002] This invention relates to pharmaceutical compositions in multiple granular forms suitable for administration to children, said granules containing bis((14) S )-8-[3-(2-{two screws[2.0.2 4 .1 3 [[Heptane-7-yl]ethoxypyrazole-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ] 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11 , 14 .0 5 , 10 ]C24-C-1(23),5,7,9,19,21-hexane-3-oxide)calcium, ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H -indol-5-yl)cyclopropaneformamide and N -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, including methods for formulating granules, manufacturing and processing granules, and methods for treating cystic fibrosis using said pharmaceutical composition.

[0003] One aspect of the invention provides granules suitable for pediatric administration, comprising a modulator of the cystic fibrosis transmembrane conduction regulator (CFTR). Cystic fibrosis (CF) is a recessive genetic disorder that affects approximately 70,000 children and adults worldwide. Despite advances in CF treatment, there remains no cure.

[0004] In patients with cystic fibrosis (CF), mutations in CFTR, endogenously expressed in the respiratory epithelium, reduce apical anion secretion, leading to an imbalance in ion and fluid transport. This reduced anion transport results in increased mucus accumulation in the lungs and associated microbial infections, ultimately causing death in CF patients. In addition to respiratory problems, CF patients often suffer from gastrointestinal issues and pancreatic insufficiency, which, if left untreated, can also lead to death. Furthermore, most men with cystic fibrosis are infertile, and women with cystic fibrosis experience reduced fertility.

[0005] Sequence analysis of the CFTR gene 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. USA87:8447-8451). To date, more than 2,000 CF gene mutations have been identified; currently, the CFTR2 database contains information on only 485 of these identified mutations, with sufficient evidence to define 401 mutations as pathogenic. The most common pathogenic mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the mutant protein being unable to leave the endoplasmic reticulum (ER) and be transported to the plasma membrane. Consequently, the number of CFTR channels in the membrane for anion transport is far less than that observed in cells expressing wild-type CFTR (i.e., CFTR without the mutation). In addition to impaired transport, the mutation also results in defective channel gating. The reduced number of channels in the membrane, along with the gating defect, leads to reduced anion and fluid transport across the epithelium (Quinton, PM (1990), FASEB J. 4: 2709-2727). Channels defective due to the F508del mutation still function, although less than those of wild-type CFTR channels (Dalemans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). Besides F508del, other disease-causing CFTR mutations that lead to defects in transport, synthesis, and / or channel gating can be upregulated or downregulated to alter anion secretion and change disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where it regulates transmembrane anion flux and the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is essential for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of approximately 1480 amino acids encoding a protein composed of tandem repeat sequences of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. Two transmembrane domains are linked by a large polar regulatory (R) domain, which contains multiple phosphorylation sites that regulate channel activity and cellular transport.

[0008] Chloride ion transport occurs via ENaC and CFTR present on the apical membrane and Na+ expressed on the outer surface of the cell basolateral surface. + -K + This occurs through the synergistic action of the ATPase pump and Cl- channels. Secondary active transport of chloride ions from the luminal side leads to intracellular chloride ion accumulation, which can then be passively transported via Cl- channels. - Channels exit the cell, leading to vector transport. Na+ on the outer surface of the basal layer... + / 2Cl - / K + Cotransporter, Na + -K + -ATPase pump and basolateral membrane K + The arrangement of the channels and the arrangement of the CFTRs on the luminal side coordinate the secretion of chloride ions via the CFTRs on the luminal side. Because water itself may never be actively transported, its flow across the epithelium depends on the small transepithelial osmotic gradient generated by the overall flow of sodium and chloride ions.

[0009] (14 S )-8-[3-(2-{dispiro[2.0.2.1]heptane-7-yl}ethoxy)-1 H [-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14 .0 5,10 ] 24-C-1(22), 5, 7, 9, 19(23), 20-Hexaeno-2, 2, 4-Trione (Vanzacaftor), Bis((14) S )-8-[3-(2-{two screws[2.0.2 4 .1 3 [[Heptane-7-yl]ethoxypyrazole-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ]6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11 , 14 .0 5 , 10 ]C24-C-1(23),5,7,9,19,21-hexane-3-oxide) calcium (Vanzacator calcium salt) and ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H 5-Indol-5-yl)cyclopropaneformamide (tezacaftor) is a potent and selective CFTR corrector used to treat mutated forms of human CFTR-mediated diseases, such as cystic fibrosis. N -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deutivacaftor)) is a potent and selective CFTR enhancer that can enhance the activity of wild-type and mutant human CFTR and can be used to treat cystic fibrosis.

[0010] Children with CF may require medication compositions in formulations that are easy to swallow or mix with easily digestible foods. When administering medication compositions to children, the use of powders and crushed tablets often presents problems with administration and dosage. The following summarizes some of the challenges associated with developing pediatric formulations containing CFTR modulators.

[0011] Easy to apply Tablets and capsules are often difficult for young children to swallow. Therefore, easier-to-swallow alternatives, such as liquid formulations or suspensions, can be conveniently administered. However, the feasibility of liquid formulations and suspensions is limited when the water solubility of the active pharmaceutical ingredient is low.

[0012] Dosage accuracy Administering crushed tablets to children can lead to absorption problems; the fragments may be too difficult to swallow or fail to dissolve and remain undigested, resulting in treatment failure or dosage inaccuracy. Furthermore, dosage calculations for crushed tablets can be inaccurate due to the difficulty in handling them. The use of powder blends can also cause dosage inaccuracies. In other cases, the active powder may still adhere to the inner wall of the capsule, sachet, or packet upon application, resulting in a lower than required therapeutic dose. Such dosage inaccuracies are particularly common when the person administering the dose is inexperienced and when the dose is small, such as for treating pediatric patients. Therefore, dosage errors involving CF (creep-forming agent) active pharmaceutical ingredients become critical in the pediatric population, especially given that pharmaceutical CF active ingredients are administered at lower doses (e.g., less than 100 mg or less than 50 mg per unit). These dosage inaccuracies become particularly critical for pediatric patients with low dose deviation thresholds. The dosage of the pharmaceutical compound of the present invention administered each time is very low (the total unit dose of venzaccato is about 12 mg or less, for example, a total unit dose of about 1 mg, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, or about 12 mg). Administering low doses of one or more active pharmaceutical ingredients in the form of multiple particles increases the possibility of dosage inaccuracies because each individual particle must contain a specific portion of the total unit dose. Therefore, there is a need to develop pharmaceutical compositions that can provide a very small amount of the drug with minimal deviation.

[0013] Manufacturing reproducibility In the manufacturing of compressed solid dosage forms such as granules, physical force is used to eject the dosage form from a mold. The composition must be formulated to make the granules sufficiently rigid to withstand the ejection force without breaking. High ejection forces are generated when there is significant friction between the compressed dosage form and the mold wall. These are undesirable because high ejection forces can damage the dosage form during ejection and can also cause premature wear of the pressing equipment (which in itself can lead to reproducibility issues).

[0014] Dispersion A potential method for administering CFTR-modifying compounds to pediatric patients is to mix the dosage form with liquids or soft foods. To achieve this, the dosage form must be soft enough to disintegrate and disperse rapidly in the mouth or application medium.

[0015] Palatability Palatability (e.g., aroma, taste, texture, and mouthfeel) is an extremely important factor in achieving acceptable medication adherence in pediatric formulations. CFTR modifiers may present an unpleasant taste or bitterness. For example, the CFTR modifier ivacato has a strong bitter taste. Therefore, to achieve satisfactory patient adherence, formulations containing specific amounts of sweeteners and / or flavoring agents are often required to mask this unpleasant taste or bitterness. Simultaneously, sweeteners or blends of sweeteners can contribute to an unpleasant mouthfeel. For example, blends of mannitol and sucrose with aspartame have been found to have a “gritty” texture, which, despite their good flavor profile, makes them unsuitable for use in pediatric formulations containing ivacato.

[0016] Physical and chemical stability The physical and chemical stability of a pharmaceutical particle composition depends largely on the specific formulation used. If the composition is not properly formulated, this can lead to undesirable chemical or physical changes, such as the active pharmaceutical ingredient being converted into a solid form with lower bioavailability.

[0017] Bioavailability All of the above factors must be optimized without affecting bioavailability. Bioavailability is highly unpredictable, and any changes to the formulation may unexpectedly lead to a decrease in bioavailability.

[0018] Therefore, there is a need to develop drug particle compositions of venzaccato, tezaccato, and deuterated ivacato suitable for treating pediatric patients with CF, wherein the compositions possess physical and chemical stability, bioavailability, the ability to deliver sustained small doses of a specific amount, are sufficiently rigid for continuous manufacturing, and can be rapidly dispersed to provide acceptable solubility and bioavailability after administration. The compositions of the present invention have been developed to balance all these factors and meet all these requirements.

[0019] There is a need for stable, bioavailable drug particle compositions of venzaccato, tezaccato, and deuterated ivacato to treat unmet medical needs in specific populations, such as children aged 12 to 24 months and 2 to 5 years who are unable to swallow adult tablets.

[0020] There is a need for stable, bioavailable drug particle compositions of venzaccato, tezaccato, and deuterated ivacato to enable accurate and flexible dosing to pediatric patients aged 12 to 24 months and 2 to 5 years by varying the unit dose, the number of particles in the sachet, packet, or capsule. Summary of the Invention

[0021] This invention relates to pharmaceutical particle compositions comprising venzacator, tezacator, and deuterated ivacato, and methods for manufacturing and administering such pharmaceutical compositions. The pharmaceutical particle compositions comprising venzacator, tezacator, and deuterated ivacato may further comprise one or more excipients, including one or more fillers, sweeteners, disintegrants, wetting agents, flow aids, and lubricants.

[0022] The pharmaceutical particle compositions disclosed herein can be reproducibly manufactured and have been found to be able to accurately administer venzaccato to pediatric patients at unit doses of about 12 mg or less (e.g., about 1 mg, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, or about 12 mg unit doses) while maintaining ideal palatability and ease of administration. The pharmaceutical particle compositions disclosed herein have also been found to possess beneficial properties such as improved dispersibility, physical and chemical stability, and high bioavailability.

[0023] The pharmaceutical compositions of the present invention are formulated into various granules. The granules can be packaged in capsules, sachets, pouches, capsules, bottles, or blister packs to provide a unit dosage form. The granules can also be compressed into other solid forms, such as pills, beads, granules, microparticles, tablets, or other comparable dosage forms. In one embodiment, the pharmaceutical particle composition described herein comprises: (a) crystalline venzacator calcium hydrate form D, a solid dispersion containing tezacator, and a solid dispersion containing deuterated ivacato; and (b) one or more pharmaceutically acceptable excipients (e.g., one or more fillers, sweeteners, disintegrants, optional wetting agents, flow aids, and lubricants), wherein a plurality of particles are contained in a unit dosage form, and further wherein the unit dosage form comprises a unit dose (i.e., an specified amount) of venzacator calcium hydrate form D (ranging from at least about 1 mg to at least about 12.7 mg per unit dosage form), amorphous tezacator (ranging from about 10 mg to about 50 mg per unit dosage form), and amorphous deuterated ivacato (ranging from about 15 mg to about 150 mg per unit dosage form).

[0024] In one embodiment, the present invention provides a unit dosage form of a pharmaceutical composition comprising a plurality of particles, each particle being formulated for delivering about 0.1 mg to about 12.7 mg (e.g., about 1 mg, about 2.1 mg, about 3 mg, about 4.2 mg, about 6 mg, about 6.4 mg, about 8 mg, about 8.5 mg, about 10 mg, about 10.6 mg, or about 12.7 mg) of crystalline tezacotto calcium salt hydrate form D, a solid dispersion comprising about 10 mg to about 50 mg (e.g., about 10 mg, about 16 mg, about 24 mg, about 32 mg, or about 48 mg) of amorphous tezacotto, and a solid dispersion comprising about 40 mg to about 150 mg (e.g., about 50 mg, about 75 mg, about 100 mg, or about 150 mg) of amorphous deuterated ivacathoto. In some embodiments, the present invention provides a pharmaceutical composition formulated into a delivery unit dosage form comprising about 4.2 mg of crystalline venzacator calcium hydrate form D, about 16 mg of amorphous tizacator, and about 50 mg of amorphous deuterated ivacathort. In some embodiments, the present invention provides a pharmaceutical composition formulated into a delivery unit dosage form comprising about 6.4 mg of crystalline venzacator calcium hydrate form D, about 24 mg of amorphous tizacator, and about 75 mg of amorphous deuterated ivacathort. In some embodiments, the present invention provides a pharmaceutical composition formulated into a delivery unit dosage form comprising about 8.5 mg of crystalline venzacator calcium hydrate form D, about 32 mg of amorphous tizacator, and about 100 mg of amorphous deuterated ivacathort. In some embodiments, the present invention provides pharmaceutical compositions formulated into delivery unit dosage forms comprising about 12.7 mg of crystalline venzacator calcium hydrate form D, about 48 mg of amorphous tezacator, and about 150 mg of amorphous deuterated evacato.

[0025] In some embodiments, the pharmaceutical particle compositions disclosed herein comprise a first solid dispersion comprising tezacotto and a second solid dispersion comprising deuterated ivacalto. In some embodiments, one or both solid dispersions are spray-dried dispersions. In some embodiments, the solid dispersions and spray-dried dispersions disclosed herein may comprise excipients, such as polymers and / or surfactants.

[0026] In some embodiments, sodium dodecyl sulfate (SLS) is used as a surfactant in the deuterated ivacato solid dispersion. The content of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion can be between 0.1% and 15% w / w. For example, the range is from 0.5% w / w to 10% w / w, such as from 0.5% w / w to 5% w / w, for example 0.5% w / w to 4% w / w, 0.5% w / w to 3% w / w, 0.5% w / w to 2% w / w, 0.5% w / w to 1% w / w, or 0.5% w / w. In some embodiments, the content of the surfactant is at least 0.1% w / w or at least 0.5% w / w relative to the total weight of the solid dispersion. The content of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion can also be between about 0.1% w / w and about 15% w / w. For example, the content ranges from about 0.5% w / w to about 10% w / w, such as from about 0.5% w / w to about 5% w / w, for example, about 0.5% w / w to about 4% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 0.5% w / w. In some embodiments, the surfactant content is at least about 0.1% w / w or at least about 0.5% w / w relative to the total weight of the solid dispersion. In some embodiments, the surfactant is SLS. In some embodiments, the solid dispersion of deuterated ivacato contains about 0.5% SLS by weight of the deuterated solid dispersion.

[0027] In some embodiments, tizacato or deuterated ivacato is present in an amount exceeding half the weight percentage of the dispersion. In some embodiments, the first solid dispersion comprises from about 70 wt% to about 90 wt% (e.g., from about 75 wt% to about 85 wt%) of tizacato. In some embodiments, the second solid dispersion comprises from 70 wt% to 90 wt% (e.g., from about 75 wt% to about 85 wt%) of deuterated ivacato. For example, in some embodiments, in a solid dispersion containing tizacato, the polymer is present at about 20 wt% of the solid dispersion weight, and amorphous tizacato is present at about 80 wt% of the solid dispersion weight.

[0028] In one embodiment, the solid dispersion of tizacalt comprises about 80% by weight of amorphous tizacalt (by weight of solid dispersion) and about 20% by weight of HPMC (by weight of solid dispersion).

[0029] In one embodiment, the solid dispersion of deuterated ivacarto comprises about 80% by weight of amorphous deuterated ivacarto (by weight of the solid dispersion), about 19.5% by weight of HPMCAS (by weight of the solid dispersion), and about 0.5% by weight of SLS (by weight of the dispersion).

[0030] In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of 5 to 100 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of 15 to 40 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of 15 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of about 5 to about 100 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of about 15 to about 40 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of about 15 micrometers.

[0031] In further embodiments, in addition to the active pharmaceutical ingredient (API), the pharmaceutical composition disclosed herein also comprises one or more fillers (e.g., mannitol, cellulose, calcium carbonate, starch, sugars (e.g., dextrose, lactose, etc.)) at a concentration of at least about 10% by weight of the composition (e.g., about 10% to about 50% by weight, about 20% to about 60% by weight, about 30% to about 70% by weight); a sweetener (e.g., sucralose, sorbitol, saccharin, fructose, aspartame, or combinations thereof) at a concentration of at least about 10% by weight or less (e.g., about 0% to about 10% by weight, about 0% to about 5% by weight, about 0% to about 3% by weight); and a disintegrant (e.g., croscarmellose sodium, starch glycolate sodium, or combinations thereof) at a concentration of at least about 10% by weight or less. (e.g., about 0% to about 10% by weight, about 0% to about 8% by weight, about 0% to about 6% by weight); optionally, a wetting agent (e.g., sodium dodecyl sulfate, SLS) having a concentration of at least about 10% by weight or less (e.g., about 0% to about 10% by weight, about 0% to about 5% by weight, about 0% to about 2% by weight); a flow aid (e.g., colloidal silica, talc or a combination thereof) having a concentration of at least about 3% by weight or less (e.g., about 0% to about 3% by weight, about 0% to about 2% by weight, about 0% to about 1% by weight); and a lubricant (e.g., magnesium stearate, stearic acid, hydrogenated oil, sodium fumarate stearate or any combination thereof) having a concentration of at least about 3% by weight or less (e.g., about 0% to about 3% by weight, about 0% to about 2% by weight, about 0% to about 1% by weight).

[0032] Such pharmaceutical compositions may optionally contain one or more colorants, flavorings and / or tasters to enhance their visual appeal, taste and aroma.

[0033] In one aspect, the present invention comprises a pharmaceutical composition comprising crystalline tezacator calcium salt hydrate form D, a first solid dispersion comprising amorphous tezacator, a second solid dispersion comprising amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, gliding agents and lubricants, and optionally wetting agents.

[0034] In some embodiments, the filler comprises mannitol, which is present in an amount from about 10% to about 45% by weight of the composition. In some embodiments, the filler comprises lactose, which is present in an amount from about 25% to about 45% by weight of the composition. In some embodiments, the filler is binary, comprising both mannitol and lactose. In some embodiments, the binary filler comprises mannitol, which is present in an amount from about 10% to about 45% by weight of the composition (e.g., about 10% to about 15%, about 11% to about 13%, about 12%, about 12.5%), and lactose, which is present in an amount from about 25% to about 45% by weight of the composition (e.g., about 30% to about 40%, about 34% to about 38%, about 35%, about 35.5%, about 36%). In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of about 1:5. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:4. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:3. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:2. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:1.5. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:approximately 5. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:approximately 4. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:approximately 3. In some embodiments, the binary filler comprises mannitol and lactose in a weight ratio of approximately 1:approximately 2. In some implementations, the binary filler comprises mannitol and lactose in a weight ratio of about 1:about 1.5.

[0035] In one embodiment, the sweetener comprises sucralose, which is present in an amount from about 0.1% to about 5% (e.g., about 1% to about 4%, about 2% to about 3%, about 2%, about 2.2%, about 2.3%, about 2.4%) based on the weight of the composition.

[0036] In one embodiment, the disintegrant comprises croscarmellose sodium, which is present in an amount from about 1% to about 8% (e.g., about 2% to about 7.5%, about 3.5% to about 7%, about 5% to about 6.5%) based on the weight of the composition.

[0037] In one embodiment, the wetting agent comprises sodium dodecyl sulfate, which is present in an amount of about 2% or less (e.g., about 0% to about 2%, about 0% to about 1%) based on the weight of the composition.

[0038] In one embodiment, the flow aid comprises: talc, colloidal silica (i.e., colloidal silica), precipitated silica, magnesium oxide, magnesium silicate, leucine, and starch. In a further embodiment, the flow aid comprises colloidal silica present in an amount from about 0.1% to about 5% (e.g., about 0.1% to about 4%, about 0.5% to about 3%, about 0.5%, about 1%, about 1.5%) based on the weight of the composition.

[0039] In one embodiment, the lubricant comprises magnesium stearate, which is present in an amount from about 0.5% to about 2.0% (e.g., about 0.75% to about 1.25%, about 0.5% to about 1.5%, about 0.5%, about 1%, about 1.5%, about 2%) based on the weight of the composition.

[0040] This invention addresses stable solid dosage forms, such as granules, that overcome the aforementioned problem of dosage inaccuracy, particularly for pediatric patients. These stable solid unit dosage forms can have any shape, including oval, spherical, cylindrical, elliptical, cubic, square, or rectangular. Granules can have a flat surface, a shallow surface, a standard surface, a deeply convex surface, or a bi-convex surface, or a combination of these surfaces.

[0041] In one aspect, the pharmaceutical particle composition is formulated into unit dosage forms, such as capsules, sachets, etc., containing at least one or more particles to simplify the administration of the pharmaceutical composition. In some embodiments, the unit dosage form may include a capsule or sachet containing at least one or more particles. In another embodiment, the unit dose may include a sachet, pouch, or capsule containing a specific dose of crystalline tezacotto calcium hydrate form D, a solid dispersion containing amorphous tezacotto, and a solid dispersion containing deuterated ivacathotoxin, all in particle form.

[0042] Such pharmaceutical compositions as described herein can be in the form of a plurality of particles comprising any number (e.g., at least 10, at least 20, at least 40, at least 60, at least 80, at least 90, at least 100, or more than 100, at least about 10, at least about 20, at least about 40, at least about 60, at least about 80, at least about 90, at least about 100, or more than about 100, including all ranges in between). In one embodiment, the plurality of particles comprises about 20 to about 40 particles (e.g., about 25, about 30, about 35). In one embodiment, the plurality of particles comprises 30 particles. In one embodiment, the plurality of particles comprises about 30 particles. Therefore, the pharmaceutical compositions as described herein can be in the form of a single particle or in the form of a plurality of particles.

[0043] In one embodiment, the plurality of particles comprises 30 particles, wherein the plurality of particles contains a unit dose of 4 mg vazacalorie. In one embodiment, the plurality of particles comprises 45 particles, wherein the plurality of particles contains a unit dose of 6 mg vazacalorie. In one embodiment, the plurality of particles comprises 60 particles, wherein the plurality of particles contains a unit dose of 8 mg vazacalorie. In one embodiment, the plurality of particles comprises 90 particles, wherein the plurality of particles contains a unit dose of 12 mg vazacalorie. In one embodiment, the plurality of particles comprises about 30 particles, wherein the plurality of particles contains a unit dose of about 4 mg vazacalorie. In one embodiment, the plurality of particles comprises about 45 particles, wherein the plurality of particles contains a unit dose of about 6 mg vazacalorie. In one embodiment, the plurality of particles comprises about 60 particles, wherein the plurality of particles contains a unit dose of about 8 mg vazacalorie. In one embodiment, the plurality of particles comprises about 90 particles, wherein the plurality of particles contains a unit dose of about 12 mg vazacalorie.

[0044] In another respect, the particles described herein are colored, such as by adding coloring agents to the particle formulation or by coloring the particle surface.

[0045] In other embodiments, the pharmaceutical composition comprising multiple particles may be packaged in a sachet, capsule, bag, bottle, or blister pack, or optionally further compressed into different solid unit dose forms, which can be conveniently administered to patients who have difficulty swallowing adult-sized tablet formulations. Therefore, these novel pharmaceutical compositions and single-dose formulations containing said pharmaceutical compositions are sensorily acceptable to the patient, can be sprinkled into liquids or soft foods, and disintegrate or disperse in a variety of liquid, soft food, or food compositions (such as milk (including breast milk), infant formula or toddler formula, applesauce, water, plain yogurt, ice cream, or baby food), thereby ensuring that the entire prescribed dose has disintegrated or dispersed and can be administered to patients who have difficulty swallowing adult tablets. Baby foods include, but are not limited to, carrots or carrot puree. The pharmaceutical composition may also be administered in strawberry jam, rice pudding, chocolate pudding, etc. In one embodiment, the unit dose form is sprinkled into a soft food and administered. In another embodiment, the unit dose form is sprinkled into a liquid and administered. In one embodiment, the unit dose form is sprinkled into a soft food, mixed, and administered. In another embodiment, the unit dose is sprinkled into a liquid, mixed, and administered. The liquid may include, but is not limited to, infant formula, milk, or breast milk. In some cases, for smaller particles, the contents of a sachet, packet, capsule, bottle, or pouch may be administered directly into the mouth before breastfeeding or formula feeding. The administration method of the present invention may also optionally include, for smaller particles, administering the contents of a sachet, packet, capsule, bottle, or pouch into the mouth before administering a liquid or beverage. In some embodiments, any administration method of the present invention may optionally include oral administration with a fatty food, such as a standard CF high-calorie, high-fat meal, or snack. In other embodiments, any administration method of the present invention may optionally include oral administration with, before, or after a fatty food such as a standard CF high-calorie, high-fat meal, or snack. In one embodiment, the pharmaceutical compositions of the present invention and their solid single-dose forms have particular use in treating CFTR-mediated diseases in a pediatric patient population.

[0046] In one embodiment, the pharmaceutical composition is a unit dose form comprising a plurality of particles, wherein said unit dose form comprises from about 1 mg to about 12.7 mg of crystalline venzacator calcium hydrate form D. In some embodiments, the pharmaceutical composition is a unit dose form comprising a plurality of particles, wherein said unit dose form comprises about 4.2 mg of crystalline venzacator calcium hydrate form D. In some embodiments, the pharmaceutical composition is a unit dose form comprising a plurality of particles, wherein said unit dose form comprises about 6.4 mg of crystalline venzacator calcium hydrate form D. In some embodiments, the pharmaceutical composition is a unit dose form comprising a plurality of particles, wherein said unit dose form comprises about 8.5 mg of crystalline venzacator calcium hydrate form D. In some embodiments, the pharmaceutical composition is a unit dose form comprising a plurality of particles, wherein said unit dose form comprises about 12.7 mg of crystalline venzacator calcium hydrate form D.

[0047] In one embodiment, the pharmaceutical composition is a unit-dose form comprising multiple particles, wherein said unit-dose form comprises from about 10 mg to about 50 mg of amorphous or substantially amorphous tezacotto. In some embodiments, the pharmaceutical composition is a unit-dose form comprising multiple particles, wherein said unit-dose form comprises about 16 mg of amorphous or substantially amorphous tezacotto. In some embodiments, the pharmaceutical composition is a unit-dose form comprising multiple particles, wherein said unit-dose form comprises about 24 mg of amorphous or substantially amorphous tezacotto. In some embodiments, the pharmaceutical composition is a unit-dose form comprising multiple particles, wherein said unit-dose form comprises about 32 mg of amorphous or substantially amorphous tezacotto. In some embodiments, the pharmaceutical composition is a unit-dose form comprising multiple particles, wherein said unit-dose form comprises about 48 mg of amorphous or substantially amorphous tezacotto.

[0048] In one embodiment, the pharmaceutical composition is a unit dose form comprising multiple particles, wherein said unit dose form comprises from about 15 mg to about 150 mg of amorphous or substantially amorphous deuterated ivacartoel. In some embodiments, the pharmaceutical composition is a unit dose form comprising multiple particles, wherein said unit dose form comprises about 50 mg of amorphous or substantially amorphous deuterated ivacartoel. In some embodiments, the pharmaceutical composition is a unit dose form comprising multiple particles, wherein said unit dose form comprises about 75 mg of amorphous or substantially amorphous deuterated ivacartoel. In some embodiments, the pharmaceutical composition is a unit dose form comprising multiple particles, wherein said unit dose form comprises about 100 mg of amorphous or substantially amorphous deuterated ivacartoel. In some embodiments, the pharmaceutical composition is a unit dose form comprising multiple particles, wherein said unit dose form comprises about 150 mg of amorphous or substantially amorphous deuterated ivacartoel.

[0049] In another embodiment, the one or more solid dispersions comprising tezacotto and deuterated ivacalto are present in the pharmaceutical composition of the present invention, in a total content of about 20% to about 50% by weight of the pharmaceutical composition, and the unit dose is in the form of particles, the shape of which is cylindrical, oval, conical, spherical, elliptical, polygonal or a combination thereof, wherein the longest dimension or diameter of the particles is about 1.5 mm to about 4.0 mm.

[0050] In a further embodiment, the combined solid dispersion is present in an amount of about 20% to about 50% by weight of the pharmaceutical composition, and the unit dose is in the form of particles, which are cylindrical, oval, conical, spherical, elliptical, polygonal or a combination thereof, wherein the longest dimension or diameter of the particles is about 2.0 mm.

[0051] In some embodiments, the weight of a single particle is from about 5.0 mg to about 10 mg. In some embodiments, the weight of a single particle is from about 6.0 mg to about 9.0 mg. In some embodiments, the weight of a single particle is from about 6.5 mg to about 8.0 mg. In some embodiments, each particle weighs about 7.0 mg. In some embodiments, each particle has a diameter of about 2.0 mm and a weight of about 7.0 mg.

[0052] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising amorphous tezacator, a solid dispersion comprising amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 4.2 mg crystalline venzacator calcium hydrate form D, about 16 mg substantially amorphous or amorphous tezacator, and about 50 mg amorphous or substantially amorphous deuterated ivacato.

[0053] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising amorphous tezacator, a solid dispersion comprising amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 6.4 mg crystalline venzacator calcium hydrate form D, about 24 mg substantially amorphous or amorphous tezacator, and about 75 mg amorphous or substantially amorphous deuterated ivacato.

[0054] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising amorphous tezacator, a solid dispersion comprising amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 8.5 mg crystalline venzacator calcium hydrate form D, about 32 mg substantially amorphous or amorphous tezacator, and about 100 mg amorphous or substantially amorphous deuterated ivacato.

[0055] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising amorphous tezacator, a solid dispersion comprising amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 12.7 mg crystalline venzacator calcium hydrate form D, about 48 mg substantially amorphous or amorphous tezacator, and about 150 mg amorphous or substantially amorphous deuterated ivacato.

[0056] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising substantially amorphous or amorphous tezacator, a solid dispersion comprising substantially amorphous or amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 4.2 mg crystalline venzacator calcium hydrate form D, about 16 mg substantially amorphous or amorphous tezacator, and about 50 mg amorphous or substantially amorphous deuterated ivacato.

[0057] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising substantially amorphous or amorphous tezacator, a solid dispersion comprising substantially amorphous or amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 6.4 mg crystalline venzacator calcium hydrate form D, about 24 mg substantially amorphous or amorphous tezacator, and about 75 mg amorphous or substantially amorphous deuterated ivacato.

[0058] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising substantially amorphous or amorphous tezacator, a solid dispersion comprising substantially amorphous or amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 8.5 mg crystalline venzacator calcium hydrate form D, about 32 mg substantially amorphous or amorphous tezacator, and about 100 mg amorphous or substantially amorphous deuterated ivacato.

[0059] Another aspect of the invention provides a method of administering a pharmaceutical composition by orally administering a plurality of granules once daily to a patient, such as a human pediatric patient, the granules comprising crystalline venzacator calcium hydrate form D, a solid dispersion comprising substantially amorphous or amorphous tezacator, a solid dispersion comprising substantially amorphous or amorphous deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, wherein the unit dose comprises about 12.7 mg crystalline venzacator calcium hydrate form D, about 48 mg substantially amorphous or amorphous tezacator, and about 150 mg amorphous or substantially amorphous deuterated ivacato.

[0060] definition As used herein, the terms "active pharmaceutical ingredient" or "API" refer to a bioactive compound. The APIs used in the pharmaceutical compositions of this invention comprise two CF-corrected compounds, bis((14) S )-8-[3-(2-{two screws[2.0.2 4 .1 3 [[Heptane-7-yl]ethoxypyrazole-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ] 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11 , 14 .0 5 , 10 ]C24-C-1(23),5,7,9,19,21-hexane-3-oxide) calcium (Vanzacator calcium salt) and ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H -Indole-5-yl)cyclopropaneformamide (tizacalo) and CF enhancer N -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deuterated evacarto).

[0061] Wanzakato As used in this article, the term "Vanzakato" is related to (14) S )-8-[3-(2-{dispiro[2.0.2.1]heptane-7-yl}ethoxy)-1 H [-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11, 14 .0 5,10 The tetracoc-1(22), 5,7,9,19(23), and 20-hexaeno-2,2,4-trione are interchangeable and have the following structures: (I).

[0062] As used in this article, "Vanzacator calcium salt" refers to bi((14) S )-8-[3-(2-{two screws[2.0.24 .1 3 [[Heptane-7-yl]ethoxypyrazole-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ] 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11 , 14 .0 5 , 10 ]Calcium 23,5,7,9,19,21-hexane-3-oxide, i.e., the calcium salt of Vanzacator.

[0063] Venzacator is described in International Patent Publications WO 2019 / 161078, WO 2020 / 102346, WO 2021 / 030554, WO 2021 / 030552, WO 2022 / 036060, and WO 2022 / 125826, all of which are incorporated herein by reference. These publications also describe methods for manufacturing venzacator and demonstrate that venzacator is a CFTR corrective therapeutic agent. WO 2021 / 030552 further describes a method for manufacturing venzacator calcium salt hydrate form D.

[0064] In some embodiments, the Vanzacator calcium salt hydrate form D is characterized by its X-ray powder diffraction pattern having signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ. In some embodiments, the Vanzacator calcium salt hydrate form D is characterized by its X-ray powder diffraction pattern having: (a) signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ; and (b) one or more signals selected from 5.5 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, 22.1 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ.

[0065] In some embodiments, the vanzacator calcium salt hydrate form D is characterized by its X-ray powder diffraction pattern having: (a) signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ; and (b) two or more signals selected from 5.5 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, 22.1 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ. In some embodiments, the Vanzacator calcium salt hydrate form D is characterized by its X-ray powder diffraction pattern having: (a) signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ; and (b) three or more signals selected from 5.5 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, 22.1 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ. In some embodiments, the vanzacator calcium salt hydrate form D is characterized by its X-ray powder diffraction pattern having: (a) signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ; and (b) four or more signals selected from 5.5 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, 22.1 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ.

[0066] In some embodiments, the Vanzacator calcium hydrate form D is characterized by its X-ray powder diffraction pattern having signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, 22.8 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ. In some embodiments, the Vanzacator calcium hydrate form D is characterized by its X-ray powder diffraction pattern having signals at 6.1 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 22.8 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ.

[0067] In some implementations, the venzacator calcium salt hydrate form D is characterized by... Figure 1 Essentially similar X-ray powder diffraction patterns.

[0068] Tizacato As used in this article, the term "tizacator" can be distinguished from ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H (-indol-5-yl)cyclopropaneformamide is used interchangeably. Tizacatol can be described as having the following structure: .

[0069] Tizacato has been previously described in U.S. Patent Publication US 2009 / 0131492 and International Patent Publications WO 2011 / 119984 and WO 2015 / 160787, all of which are incorporated herein by reference.

[0070] Deuterium Ivacardo As used in this article, the term "deuterated ivakato" can be used in conjunction with... N -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide is used interchangeably. Deuterated ivacarto has the following structure: .

[0071] Deuterated ivacatto has been previously described in international patent publications WO 2012 / 158885, WO 2017 / 053455, WO2017 / 053711, WO 2018 / 080591 and WO 2019 / 109021, all of which are incorporated herein by reference.

[0072] The terms “about” and “approximately”, when used in conjunction with a dose, amount, or weight percentage of an ingredient in a composition or dosage form, include a specified dose, amount, or weight percentage, or a range of doses, amounts, or weight percentages, recognized by those skilled in the art, as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. The terms “about” and “approximately” may refer to an acceptable error in a particular numerical value (e.g., weight, size, amount, weight percentage, or duration) as determined by those skilled in the art, depending in part on how the value is measured or determined. In some embodiments, the terms “about” and “approximately” mean within 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the terms “about” and “approximately” mean within 10% of a given value or range. In some embodiments, the terms “about” and “approximately” mean within 15% of a given value or range. In some implementations, the terms "about" and "approximately" mean within 20% of a given value or range. In some implementations, the terms "about" and "approximately" mean within 25% of a given value or range. As used herein, the symbol "~" preceding a numerical value has the same meaning as "about" and "approximately".

[0073] As used in this article, "CFTR" or "CFTR protein" refers to the transmembrane conduction regulation protein in cystic fibrosis.

[0074] As used herein, the term "regulator" refers to a compound that increases the activity of biological compounds such as proteins. For example, a CFTR regulator is a compound that increases the activity of CFTR. The activity increase caused by CFTR regulators includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0075] As used herein, a "CF enhancer" refers to a compound that exhibits biological activity, characterized by enhancing the gating function of mutant CFTR proteins present on the cell surface to approximately the level of the wild type (i.e., a compound that enhances or induces the activity of CFTR protein channels located on the cell surface, thereby resulting in increased functional activity). Deuterated ivacatol disclosed herein is a CFTR enhancer.

[0076] As used herein, the term "CFTR corrector" refers to a compound that can enhance or induce the amount of functional CFTR proteins on the cell surface, thereby resulting in increased functional activity. Venzacator and tezacator disclosed herein are CFTR correctors.

[0077] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0078] As used herein, the terms “treatment”, “treating,” etc., generally refer to the improvement of CF or its symptoms in a subject, or the reduction of the severity of CF or one or more symptoms of CF. As used herein, “treatment” includes, but is not limited to, the following: increased growth in the subject, weight gain, reduced mucus in the lungs, improved pancreatic and / or liver function, reduced chest infection, and / or reduced cough or shortness of breath. Any improvement or reduction of these symptoms can be readily assessed using standard methods and techniques known in the art.

[0079] As used herein, the term “in combination with” when referring to two or more compounds, reagents or other active pharmaceutical ingredients means that the two or more compounds, reagents or active pharmaceutical ingredients are administered to the patient before, simultaneously or after each other.

[0080] As used herein, the term "amorphous" refers to a solid material that lacks long-range order at its molecular positions. Amorphous solids are typically supercooled liquids in which molecules are arranged randomly, thus lacking a defined arrangement, such as molecular packing, and without long-range order. Amorphous solids are typically isotropic, meaning they exhibit similar properties in all directions and do not have a defined melting point. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, it exhibits one or more broad peaks (e.g., halos) in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, see US 2004 / 0006237. In some embodiments, the solid material may comprise an amorphous compound, and the material is characterized, for example, by the lack of one or more sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the material is not crystalline but amorphous as determined by XRPD). Alternatively, one or more broad peaks (e.g., halos) may appear in the XRPD spectrum of the material. See US 2004 / 0006237, which compares the XRPDs of amorphous materials and solution materials. Solid materials containing amorphous compounds are characterized, for example, by a wider melting temperature range compared to the melting temperature range of pure crystalline solids. Other techniques, such as Raman spectroscopy, infrared spectroscopy, and solid-state NMR, can be used to characterize crystalline or amorphous forms.

[0081] In some embodiments, the solid material may comprise a mixture of crystalline solids and amorphous solids. Solid materials prepared to contain amorphous compounds may also, for example, contain up to about 30% crystalline solids. Solid materials prepared to contain amorphous compounds may also, for example, contain up to 30% crystalline solids. In some embodiments, solid materials prepared to contain amorphous compounds may also, for example, contain up to 25%, 20%, 15%, 10%, 5%, 2%, about 25%, about 20%, about 15%, about 10%, about 5%, or about 2% crystalline solids. In embodiments where the solid material comprises a mixture of crystalline solids and amorphous solids, characterization data such as XRPD may include indicators of both crystalline and amorphous solids.

[0082] As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order at its molecular positions. For example, a substantially amorphous material has less than about 15% crystallinity (e.g., less than about 10% or less than about 5%). It should also be noted that the term "substantially amorphous" includes the descriptive term "amorphous," which refers to a material that does not have (0%) crystallinity.

[0083] As used herein, the term "dispersion" refers to a dispersion system in which one substance (dispersed phase) is distributed in discrete units throughout a second substance (continuous phase or medium). The size of the dispersed phase can vary considerably (e.g., from single molecules, nanometers to colloidal particles a few micrometers in size). Generally, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. In this invention, the solid dispersion may include an amorphous drug in an amorphous polymer or an amorphous drug in a crystalline polymer. In some embodiments, the solid dispersion comprises a drug constituting the dispersed phase and a polymer constituting the continuous phase.

[0084] As used herein, the term "solid dispersion" generally refers to a solid dispersion of two or more components. In some embodiments, the solid dispersion comprises a single API (e.g., tizacaloto or deuterated ivacaloto). In some embodiments, the solid dispersion comprises two APIs (e.g., tizacaloto and deuterated ivacaloto). In some embodiments, the solid dispersion comprises a polymer, but may also comprise other components, such as surfactants or other pharmaceutical excipients, wherein the one or more drugs (e.g., tizacaloto and / or deuterated ivacaloto) are substantially amorphous (e.g., containing about 15% or less (e.g., about 10% or less, or about 5% or less)) crystalline drugs or amorphous (i.e., free of crystalline drugs), and the physical stability and / or dissolution and / or solubility of the substantially amorphous or amorphous drugs are enhanced by the other components. Solid dispersions typically comprise compounds dispersed in a suitable carrier medium (e.g., a solid carrier). For example, the carrier comprises a polymer (e.g., a water-soluble polymer or a partially water-soluble polymer) and may contain optional excipients, such as functional excipients (e.g., one or more surfactants) or non-functional excipients (e.g., one or more fillers). Another exemplary solid dispersion is a coprecipitate or eutectic of tezacator and / or deuterated ivacator, optionally comprising at least one polymer.

[0085] As used herein, “crystallinity” refers to the degree of structural order in a solid. For example, a substantially amorphous material has a crystallinity of less than about 15%, or the crystallinity of its solid structure is less than about 15%. In another instance, a completely amorphous material has a crystallinity of zero (0%).

[0086] As used herein, the terms “X-ray powder diffraction pattern,” “X-ray powder diffraction pattern,” “XRPD pattern,” and “XRPD spectrum” interchangeably refer to an experimentally obtained pattern plotting signal location (x-axis) and signal intensity (y-axis). For amorphous materials, an X-ray powder diffraction pattern may contain one or more broad signals; and for crystalline materials, an X-ray powder diffraction pattern may contain one or more signals, each identified by an angular value measured in degrees 2θ (°2θ) on the x-axis of the X-ray powder diffraction pattern, which may be expressed as “signal at ... degrees 2θ,” “signal at ... 2θ values,” and / or “signal at at least ... 2θ values ​​selected from ....”

[0087] As used herein, a “signal” or “peak” refers to a point in an XRPD pattern where the intensity, measured in counts, is localized. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Indeed, those skilled in the art will recognize that several well-established methods are capable of and suitable for determining the presence of signals in a pattern, such as Rietveld refinement.

[0088] As used in this article, “signal at ... degrees 2θ” refers to the X-ray reflection position (° 2θ) measured and observed in an X-ray powder diffraction experiment.

[0089] The repeatability of the angle value is within ±0.2°2θ, that is, the angle value can be any value between the angle value +0.2°2θ, the angle value -0.2°2θ, or both of these endpoints (angle value +0.2°2θ and angle value -0.2°2θ).

[0090] As used herein, the term "granule" refers to a solid granular pharmaceutical composition suitable for administration to patients (e.g., pediatric patients) who have difficulty swallowing large tablets or capsules. As used herein, "granule" is equivalent to similar terms such as tablets, sprinkles, pills, beads, granules, particles, and lozenges, wherein multiple granules may be contained in capsules, packets, bags, sachets, bottles, or blister packs to provide a unit dosage form.

[0091] As used herein, “unit dose form” and “unit dosage form” are used interchangeably to refer to a package (e.g., capsule, sachet, pouch, or pouch) containing multiple particles, wherein the solid dosage form uses an API (e.g., vena cavato, tezacator, and / or deuterated evacato) containing a specified amount (i.e., unit dose) each time.

[0092] As used herein, "excipient" is an inactive ingredient in a pharmaceutical composition. Examples of excipients include fillers, sweeteners, disintegrants, glidants, lubricants, etc.

[0093] As used herein, a “diluent” or “filler” is an excipient that increases the volume of a pharmaceutical composition. Examples of fillers include mannitol, lactose, cellulose (such as microcrystalline cellulose and ethyl cellulose, cellulose acetate), calcium carbonate, potato starch, sorbitol, polyols, dextrose, or combinations thereof.

[0094] As used herein, a "disintegrant" is an excipient that enables a pharmaceutical composition to hydrate and facilitate tablet dispersion. Examples of disintegrants include croscarmellose sodium and / or carboxymethyl starch sodium.

[0095] As used herein, a "sweetener" is an excipient that imparts a sweet taste to a pharmaceutical composition and / or masks other unpleasant tastes. Examples of sweeteners include sucralose, sorbitol, xylitol, and combinations thereof.

[0096] As used herein, a "flow aid" is an excipient that imparts enhanced flow properties to a pharmaceutical composition. Examples of flow aids include colloidal silica, precipitated silica, and / or talc.

[0097] As used herein, “colorant” is an excipient that imparts a desired color to a pharmaceutical composition. Examples of colorants include commercially available pigments such as FD&C Blue 1 aluminum lake, FD&C Blue 2, other FD&C blue pigments, titanium dioxide, iron oxide, and / or combinations thereof.

[0098] As used herein, a "lubricant" is added to a pharmaceutical composition to minimize adhesion to surfaces, particularly for pharmaceutical compositions compressed into granules. Lubricants facilitate the ejection of pharmaceutical composition granules from the mold. Examples of lubricants include magnesium stearate, stearic acid (stear), hydrogenated oil, sodium fumarate stearate, or any combination thereof.

[0099] As used in this article, “average particle size” is the average particle size measured using various techniques such as laser scattering, image analysis, or sieving analysis.

[0100] As used in this article, "bulk density" is the mass of a material particle divided by the total volume occupied by the particle. The total volume includes the particle volume, the volume of the voids between particles, and the volume of internal pores. Bulk density is not an inherent property of a material; it changes depending on how the material is processed.

[0101] As used herein, a “wetting agent” or “surfactant” is a wetting agent that imparts enhanced solubility and / or wettability to a pharmaceutical composition. Examples of wetting agents include sodium dodecyl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitol monooleate (e.g., Tween™), or any combination thereof.

[0102] Deuterium-ivakato is deuterium ( 2 It is labeled with H). In chemical structure, deuterium is represented by "D".

[0103] The concentration of one or more isotopes (e.g., deuterium) incorporated into ivacato can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance. In some embodiments, if the substituents in the compounds of this disclosure represent deuterium, then such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). Detailed Implementation

[0104] This invention relates to pharmaceutical compositions containing bis((14) S )-8-[3-(2-{two screws[2.0.2 4 .1 3 [[Heptane-7-yl]ethoxypyrazole-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ] 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11 , 14 .0 5 , 10 ]C24-C-1(23),5,7,9,19,21-hexane-3-oxide) calcium (Vanzacator calcium salt), ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H -Indole-5-yl)cyclopropaneformamide (tizacalo) and N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deuterated ivacarto), comprising methods of formulating a solid composition into granules, manufacturing and processing the granules, and methods of treating cystic fibrosis with said pharmaceutical composition. In some embodiments, the venzacarto calcium salt is crystalline venzacarto calcium salt hydrate form D. In some embodiments, tizacarto is amorphous tizacarto in a solid dispersion. In some embodiments, deuterated ivacarto is amorphous tizacarto in a solid dispersion.

[0105] solid dispersions In some embodiments, the pharmaceutical compositions disclosed herein comprise a first solid dispersion comprising amorphous tezacotto and a second solid dispersion comprising amorphous deuterated ivacathotoxin. In some embodiments, one or both solid dispersions are spray-dried dispersions.

[0106] In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of 5 to 100 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of 15 to 40 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of 15 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of about 5 to about 100 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of about 15 to about 40 micrometers. In some embodiments, the first solid dispersion and the second solid dispersion each independently comprise a plurality of particles with an average particle size of about 15 micrometers.

[0107] In some embodiments, the solid dispersions and spray-dried dispersions of this disclosure may contain other excipients, such as polymers and / or surfactants. Any suitable polymers and surfactants known in the art may be used. Some exemplary polymers and surfactants are described below.

[0108] Solid dispersions of amorphous tezacotto and / or amorphous deuterated ivacato can be prepared by any suitable method known in the art, such as spray drying, lyophilization, hot melting, or freeze-milling / freeze-pulverization. Typically, such spray drying, lyophilization, hot melting, or freeze-milling / freeze-pulverization techniques yield amorphous forms of APIs (e.g., tezacotto and deuterated ivacato).

[0109] Spray drying is a process of converting a liquid feed into dry particulate form. Optionally, a second drying process, such as fluidized bed drying or vacuum drying, may be used to reduce residual solvent to pharmaceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot gas to evaporate and dry the droplets. The formulation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be atomized using the selected spray drying equipment. In one procedure, the formulation is sprayed into a warm, filtered gas stream that evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone separator). The exhaust gas is then discharged along with the solvent, or alternatively, the exhaust gas is sent to a condenser to capture and potentially recover the solvent. Spray drying can be performed using commercially available types of equipment. For example, commercial spray dryers manufactured by Buchi Ltd. and Niro (e.g., the PSD series of spray dryers manufactured by Niro) (see US 2004 / 0105820; US 2003 / 0144257).

[0110] Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th edition, edited by RH Perry, DW Green and JO Maloney, McGraw-Hill book co. (1984); and Marshall, “Atomization and Spray-Drying,” 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0111] Solvent removal may require subsequent drying steps, such as tray drying, fluidized bed drying, vacuum drying, microwave drying, drum drying, or double-cone vacuum drying. In one embodiment, the solid dispersion and spray-dried dispersion of this disclosure are fluidized bed dried. In one method, the solvent includes a volatile solvent, such as a solvent with a boiling point less than 100°C. In some embodiments, the solvent includes a mixture of solvents, such as a mixture of volatile solvents or a mixture of volatile and non-volatile solvents. When using a mixture of solvents, the mixture may contain one or more non-volatile solvents, for example, wherein the amount of non-volatile solvents in the mixture is less than 15%, for example, less than 12%, less than 10%, less than 8%, less than 5%, less than 3%, or less than 2%. When using a mixture of solvents, the mixture may also contain one or more non-volatile solvents, for example, wherein the amount of non-volatile solvents in the mixture is less than about 15%, for example, less than about 12%, less than about 10%, less than about 8%, less than about 5%, less than about 3%, or less than about 2%.

[0112] The particle size and temperature drying range can be varied to prepare optimal solid dispersions. As those skilled in the art will understand, smaller particle sizes will improve solvent removal. However, studies have found that smaller particles can lead to lower bulk density, which in some cases may not provide optimal solid dispersions for downstream processing.

[0113] The solid dispersions disclosed herein (e.g., spray-dried dispersions) may optionally include surfactants. Surfactants or surfactant mixtures typically reduce the interfacial tension between the solid dispersion and the aqueous medium. Suitable surfactants or surfactant mixtures can also enhance the water solubility and bioavailability of APIs derived from the solid dispersion (e.g., amorphous tezacator and / or amorphous deuterated ivacathoter). Surfactants used in conjunction with this disclosure include, but are not limited to, sorbitol fatty acid esters (e.g., Spans®), polyoxyethylene sorbitol fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS), sodium sulfosuccinate (docusate sodium), sodium deoxycholate (DOSS), sorbitol monostearate, tristearate sorbitan, hexadecyltrimethylammonium bromide (HTAB), sodium N-lauroyl sarcosinate, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, Gelucire 44 / 14, ethylenediaminetetraacetic acid (EDTA), vitamin E d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), lecithin, monosodium glutamate monohydrate, Labrasol, PEG 8 caprylic / capric glyceride, Transcutol, diethylene glycol monoethyl ether, and Solutol. HS-15, polyethylene glycol / hydroxystearate, taurine, Pluronic F68, Pluronic F108, and Pluronic F127 (or any other polyoxyethylene-polyoxypropylene copolymer (Pluronics®) or saturated polyethylene glycol-modified glycerol ester (Gelucirs®)). Specific examples of such surfactants that may be used in conjunction with this disclosure include, but are not limited to, Span 65, Span 25, Tween 20, Capryol 90, Pluronic F108, sodium lauryl sulfate (SLS), vitamin E TPGS, pluronic, and copolymers.

[0114] In some embodiments, SLS is used as a surfactant in amorphous deuterated ivacato solid dispersions. The content of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion can be between 0.1% and 15% w / w. For example, the range is from 0.5% w / w to 10% w / w, such as from 0.5% w / w to 5% w / w, for example 0.5% w / w to 4% w / w, 0.5% w / w to 3% w / w, 0.5% w / w to 2% w / w, 0.5% w / w to 1% w / w, or 0.5% w / w. In some embodiments, the content of the surfactant is at least 0.1% w / w or at least 0.5% w / w relative to the total weight of the solid dispersion. In some embodiments, the amount of surfactant is SLS, which is 0.5% by weight. The content of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion can also be between about 0.1% w / w and about 15% w / w. For example, the content ranges from about 0.5% w / w to about 10% w / w, such as from about 0.5% w / w to about 5% w / w, for example, about 0.5% w / w to about 4% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 0.5% w / w. In some embodiments, the surfactant content is at least about 0.1% w / w or at least about 0.5% w / w relative to the total weight of the solid dispersion. In some embodiments, the amount of surfactant is SLS, which is about 0.5% by weight.

[0115] Another aspect of this disclosure provides a single spray-dried dispersion comprising amorphous tezacotto and amorphous deuterated ivacalto, wherein the dispersion is prepared without the use of a polymer, and wherein the spray-dried dispersion is produced by: (i) providing a mixture substantially consisting of amorphous tezacotto and amorphous deuterated ivacalto and a solvent; and (ii) forcing the mixture through a nozzle under spray-drying conditions to produce the spray-dried dispersion.

[0116] In some embodiments, the solid dispersions contained in the pharmaceutically acceptable compositions of this disclosure can be prepared by non-spray drying techniques (such as, for example, cryo-milling / cryo-pulverizing techniques). Solid dispersions containing amorphous tezacotto or amorphous deuterated ivacalotto can also be prepared by hot melt extrusion techniques.

[0117] In some embodiments, the solid dispersions of this disclosure (e.g., spray-dried dispersions) comprise one or more polymers. Any suitable polymer known in the art may be used in this disclosure. Exemplary suitable polymers include those selected from cellulose-based polymers, polyoxyethylene polymers, polyethylene-propylene glycol copolymers, vinyl-based polymers, PEO-polyvinylcaprolactam-based polymers, and polymethacrylate-based polymers.

[0118] Cellulose-based polymers include methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate succinate, and copolymers thereof. Polyoxyethylene polymers include polyethylene glycol, polyethylene glycol, poloxamer, and copolymers thereof. Vinyl-based polymers include polyvinylpyrrolidone (PVP) and PVP / VA. PEO-polyvinylcaprolactam-based polymers include polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-based graft copolymers (e.g., Soluplus®). Polymethacrylate-based polymers are cationic and anionic polymers synthesized from dimethylaminoethyl methacrylate, methacrylic acid, and methacrylate in varying ratios. Several types are commercially available and can be obtained as dry powders, aqueous dispersions, or organic solutions. Examples of such polymethacrylate-based polymers include poly(methacrylic acid, ethyl acrylate) (1:1), dimethylaminoethyl methacrylate-methyl methacrylate copolymer, and Eudragit®.

[0119] In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HMPCAS) and hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose or HPMC), or a combination of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose. Based on the content (wt%) of acetyl and succinyl groups and particle size in the HPMC molecule, various grades of HPMC can be obtained. For example, HPMC grades L, M, and H can be obtained. HPMC-H is a grade containing approximately 10 wt%–14 wt% acetyl groups and approximately 4 wt%–8 wt% succinyl groups. Each HPMC grade can be obtained with two particle sizes: F (fine powder) and G (granular). HPMC comes in various types (e.g., HPMC type E, F, J, and K). HPMC type E indicates approximately 28%–30% methoxy groups and approximately 7%–12% hydroxypropoxy groups. Various E grades are available, ranging from low to high viscosity. For example, E3 indicates that the viscosity of HPMC measured in a 2% aqueous solution at 20°C is approximately 2.4–3.6 mPa·s; E15 indicates that the viscosity of HPMC measured in a 2% aqueous solution at 20°C is approximately 12–18 mPa·s; and E50 indicates that the viscosity of HPMC measured in a 2% aqueous solution at 20°C is approximately 40–60 mPa·s.

[0120] In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, or a combination of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose. In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose acetate succinate L, or hydroxypropyl methylcellulose acetate succinate H. In some embodiments, the polyoxyethylene polymer or polypropylene glycol copolymer is polyethylene glycol or pluronic. In some embodiments, the polyoxyethylene polymer or polyethylene glycol-propylene glycol copolymer is polyethylene glycol 3350 or poloxamer 407. In some embodiments, the vinyl-based polymer is a vinyl polyvinylpyrrolidone polymer, such as polyvinylpyrrolidine K30 or polyvinylpyrrolidine VA 64. In some embodiments, the polymethacrylate polymer is Eudragit® L100-55 or Eudragit® E PO. In some embodiments, the polymer is selected from cellulose polymers, such as HPMC and / or HPMCAs.

[0121] In one embodiment, the polymer is soluble in an aqueous medium. The solubility of the polymer can be pH-independent or pH-dependent. The latter includes one or more enteric polymers. The term "enteric polymer" refers to a polymer that preferentially dissolves in the weaker acidic environment of the intestine relative 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. Suitable polymers are chemically and biologically inert. To improve the physical stability of the solid dispersion, the polymer has a glass transition temperature (Tg) as high as possible. For example, polymers with a glass transition temperature at least equal to or greater than the glass transition temperature of the API. Other polymers have glass transition temperatures within about 10 to about 15°C of the API.

[0122] Additionally, the polymer exhibits low hygroscopicity, for example, less than about 10%. For comparison purposes in this application, the hygroscopicity of the polymer or composition was characterized at about 60% relative humidity. In some preferred embodiments, the polymer has a water absorption rate of less than 10%, for example, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, or less than 2%. Hygroscopicity also affects the physical stability of the solid dispersion. Typically, moisture adsorbed in the polymer can significantly reduce the Tt of the polymer and the resulting solid dispersion. g This will further reduce the physical stability of the solid dispersion as described above.

[0123] In one embodiment, the polymer is one or more water-soluble or partially water-soluble polymers. Water-soluble or partially water-soluble polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)) or ethyl cellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); acrylates, such as polymethacrylates (e.g., Eudragit® E); cyclodextrins (e.g., β-cyclodextrin) and their copolymers and derivatives, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate).

[0124] In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC), such as HPMC E50, HPMC CE15, or HPMC E3.

[0125] As described herein, the polymer can be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate hydroxypropyl methylcellulose acetate (CAP)), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl cellulose (CMC) or salts thereof (e.g., sodium salts, such as (CMC-Na)); cellulose 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 hydroxypropyl methylcellulose acetate succinate HG grade (HPMCAS-HG).

[0126] In yet another embodiment, the polymer is a polyvinylpyrrolidone copolymer, such as a vinylpyrrolidone / vinyl acetate copolymer (PVP / VA).

[0127] In embodiments where tizacato or deuterated ivacato forms a solid dispersion with a polymer (e.g., with HPMC, HPMCAS, or PVP / VA polymers), the amount of polymer ranges from 0.1% by weight to 99% by weight relative to the total weight of the solid dispersion. Unless otherwise stated, the percentages of the drug, polymer, and other excipients as described in the dispersion are given as weight percentages. The amount of polymer is typically at least 20%, and preferably at least 30%, for example, at least 35%, at least 40%, at least 45%, or 50% (e.g., 49.5%). This amount is typically 99% or less, and preferably 80% or less, for example, 75% or less, 70% or less, 65% or less, 60% or less, or 55% or less. In one embodiment, the amount of polymer is at most 50% of the total weight of the dispersion (and even more specifically, between 40% and 50%, such as 49%, 49.5%, or 50%). In one embodiment, the amount of polymer is up to about 50% of the total weight of the dispersion (and even more specifically, between about 40% and about 50%, such as about 49%, about 49.5% or about 50%).

[0128] In some embodiments, the API (e.g., tizacalo or deuterated evacalo) and the polymer are present in substantially equal amounts by weight, for example, each of the polymer and the drug constitutes half the weight percentage of the dispersion. For example, the polymer is present at 49.5% by weight, and amorphous tizacalo (or amorphous deuterated evacalo) is present at 50% by weight. In another embodiment, amorphous tizacalo (or amorphous deuterated evacalo) is present in an amount greater than half the weight percentage of the dispersion. In some embodiments, the first solid dispersion comprises from 70% to 90% by weight (e.g., from 75% to 85% by weight) of amorphous tizacalo. In some embodiments, the second solid dispersion comprises from 70% to 90% by weight (e.g., from 75% to 85% by weight) of amorphous deuterated evacalo. For example, in some embodiments, the polymer is present in a solid dispersion containing tizacaloto at 20% by weight, and amorphous tizacaloto is present at 80% by weight. In other embodiments, the solid dispersion containing amorphous deuterated ivacaloto comprises 19.5% by weight of polymer, 80% by weight of amorphous deuterated ivacaloto, and 0.5% by weight of SLS. In some embodiments, the first solid dispersion comprises from about 70% by weight to about 90% by weight (e.g., from about 75% by weight to about 85% by weight) of amorphous tizacaloto. In some embodiments, the second solid dispersion comprises from 70% by weight to 90% by weight (e.g., from about 75% by weight to about 85% by weight) of amorphous deuterated ivacaloto. For example, in some embodiments, the polymer is present in a solid dispersion containing tizacaloto at about 20% by weight, and amorphous tizacaloto is present at about 80% by weight. In other embodiments, the solid dispersion of amorphous deuterated ivacalo comprises about 19.5% by weight of polymer, about 80% by weight of amorphous deuterated ivacalo and about 0.5% by weight of SLS.

[0129] In one embodiment, the solid dispersion of amorphous tezacotto comprises about 80% amorphous tezacotto (by weight of solid dispersion) and about 20% HPMC (by weight of solid dispersion).

[0130] In one embodiment, the solid dispersion of amorphous deuterated ivacarto contains about 80% amorphous deuterated ivacarto (by weight of the solid dispersion), about 19.5% HPMCAS (by weight of the solid dispersion), and about 0.5% SLS (by weight of the dispersion).

[0131] Any one or more spray-dried dispersions of amorphous tezacotto and amorphous deuterated ivacarto may be used in the pharmaceutical compositions disclosed herein. Examples of amorphous tezacotto and its pharmaceutically acceptable salts can be found in WO2015 / 160787 and WO 2011 / 119984, all of which are incorporated herein by reference. Solid dispersions of non-deuterated analogues of deuterated ivacarto and methods for preparing such dispersions are disclosed in PCT Publication No. WO 2007 / 079139, which is also incorporated herein by reference.

[0132] Pharmaceutical Composition In one aspect, the present invention provides a pharmaceutical particle composition comprising a mixture of two CF corrector APIs (e.g., crystalline venzacator calcium hydrate form D and amorphous tezacator) and a CF enhancer API (e.g., amorphous deuterated ivacalorium). As illustrated herein, the pharmaceutical particle composition of the present invention may be a mixture of venzacator, tezacator, and deuterated ivacalorium, as well as one or more excipients described herein. This pharmaceutical composition can be packaged into unit dosage forms, such as tablets, capsules, sachets, lozenges, blister packs, etc., containing a specified dose of the particles of the present invention.

[0133] In some embodiments, the present invention provides a pharmaceutical particle composition, each particle comprising from about 0.05 to about 0.2 mg of crystalline vazacator calcium hydrate form D. For example, each particle may comprise about 0.05 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, or about 0.2 mg of crystalline vazacator calcium hydrate form D. Each unit dosage form (e.g., a particle package) provides about 1 mg to about 12.7 mg of crystalline vazacator calcium hydrate form D. In some embodiments, the unit dose form comprises about 4.2 mg of crystalline vazacator calcium hydrate form D. In some embodiments, the unit dose form comprises about 6.4 mg of crystalline vazacator calcium hydrate form D. In some embodiments, the unit dose form comprises about 8.5 mg of crystalline vazacator calcium hydrate form D. In some embodiments, the unit dose form comprises about 12.7 mg of crystalline vazacator calcium hydrate form D.

[0134] In some embodiments, the present invention provides a pharmaceutical particle composition, each particle comprising from about 0.25 to about 0.75 mg of amorphous tizacalotor, or about 0.25 to about 0.75 mg of a solid dispersion containing amorphous tizacalotor. For example, each particle may comprise about 0.25 mg, about 0.5 mg, or about 0.75 mg of amorphous tizacalotor, or about 0.3 mg, about 0.5 mg, or about 0.7 mg of a solid dispersion containing amorphous tizacalotor. In some embodiments, a unit dose contains about 16 mg of amorphous tizacalotor. In some embodiments, a unit dose contains about 24 mg of amorphous tizacalotor. In some embodiments, a unit dose contains about 32 mg of amorphous tizacalotor. In some embodiments, a unit dose contains about 48 mg of amorphous tizacalotor. In some embodiments, a unit dose contains about 20 mg of a solid dispersion containing amorphous tizacalotor. In some embodiments, the unit dose comprises about 30 mg of a solid dispersion containing amorphous tezacotto. In some embodiments, the unit dose comprises about 40 mg of a solid dispersion containing amorphous tezacotto. In some embodiments, the unit dose comprises about 60 mg of a solid dispersion containing amorphous tezacotto.

[0135] In some embodiments, the present invention provides a pharmaceutical particle composition, each particle comprising from about 1.0 to about 3.0 mg of amorphous deuterated ivacartoel, and / or about 1.0 to about 3.0 mg of a solid dispersion containing amorphous deuterated ivacartoel. For example, each particle may comprise about 1.0 mg, about 1.5 mg, or about 2.0 mg of amorphous deuterated ivacartoel, or about 1.0 mg, about 2.0 mg, or about 3.0 mg of a solid dispersion containing amorphous deuterated ivacartoel. In some embodiments, a unit dose contains about 50 mg of amorphous deuterated ivacartoel. In some embodiments, a unit dose contains about 75 mg of amorphous deuterated ivacartoel. In some embodiments, a unit dose contains about 100 mg of amorphous deuterated ivacartoel. In some embodiments, a unit dose contains about 150 mg of amorphous deuterated ivacartoel. In some embodiments, the unit dose comprises about 62.5 mg of a solid dispersion containing amorphous deuterated ivacartole. In some embodiments, the unit dose comprises about 94 mg of a solid dispersion containing amorphous deuterated ivacartole. In some embodiments, the unit dose comprises about 125 mg of a solid dispersion containing amorphous deuterated ivacartole. In some embodiments, the unit dose comprises about 188 mg of a solid dispersion containing amorphous deuterated ivacartole.

[0136] In some embodiments, the present invention provides a pharmaceutical particle composition, each particle comprising from about 0.05 to about 0.5 mg of crystalline venzacator calcium hydrate form D, from about 0.25 to about 0.75 mg of amorphous tizacator, and from about 0.5 to about 1.0 mg of amorphous deuterated ivacato. In some embodiments, each particle comprises about 0.14 mg of crystalline venzacator calcium hydrate form D, about 0.5 mg of amorphous tizacator, and about 1.7 mg of amorphous deuterated ivacato. In some embodiments, a unit dose comprises about 4.2 mg of crystalline venzacator calcium hydrate form D, about 16 mg of amorphous tizacator, and about 50 mg of amorphous deuterated ivacato. In some embodiments, a unit dose comprises about 6.4 mg of crystalline venzacator calcium hydrate form D, about 24 mg of amorphous tizacator, and about 75 mg of amorphous deuterated ivacato. In some embodiments, the unit dose comprises about 8.5 mg of crystalline venzacator calcium hydrate form D, about 36 mg of amorphous tezacator, and about 100 mg of amorphous deuterated ivacalator. In some embodiments, the unit dose comprises about 12.7 mg of crystalline venzacator calcium hydrate form D, about 48 mg of amorphous tezacator, and about 150 mg of amorphous deuterated ivacalator.

[0137] In some embodiments, the present invention provides a pharmaceutical particle composition, each particle comprising from about 0.05 to about 0.2 mg of crystalline venzacator calcium hydrate form D, from about 0.25 to about 0.75 mg of amorphous tizacator solid dispersion, and from about 0.5 to about 1.0 mg of amorphous deuterated ivacato solid dispersion. In some embodiments, each particle comprises about 0.1 mg of crystalline venzacator calcium hydrate form D, about 0.7 mg of amorphous tizacator solid dispersion, and about 2.0 mg of deuterated ivacato solid dispersion. In some embodiments, a unit dose comprises about 4.2 mg of crystalline venzacator calcium hydrate form D, about 20 mg of amorphous tizacator, and about 60 mg of amorphous deuterated ivacato. In some embodiments, the unit dose comprises about 6.4 mg of crystalline venzacator calcium hydrate form D, about 30 mg of amorphous tizacator solid dispersion, and about 94 mg of amorphous deuterated ivacato solid dispersion. In some embodiments, the unit dose comprises about 8.5 mg of crystalline venzacator calcium hydrate form D, about 40 mg of amorphous tizacator solid dispersion, and about 125 mg of amorphous deuterated ivacato solid dispersion. In some embodiments, the unit dose comprises about 12.7 mg of crystalline venzacator calcium hydrate form D, about 60 mg of amorphous tizacator solid dispersion, and about 188 mg of amorphous deuterated ivacato solid dispersion.

[0138] In addition to the solid dispersions of tezacotto and deuterated ivacato, the pharmaceutical particle compositions of the present invention also contain one or more excipients, such as fillers, sweeteners, disintegrants, wetting agents, flow aids, lubricants, colorants, flavoring agents, or combinations thereof. It is noteworthy that some excipients may have multiple functions; for example, some fillers may also be sweeteners, and some disintegrants may also be wetting agents (e.g., mannitol can be used as both a filler and a sweetener).

[0139] The fillers suitable for use in this invention are compatible with the components of the pharmaceutical particle composition, i.e., they substantially do not reduce the solubility, chemical stability, physical stability, or biological activity of the pharmaceutical composition. Examples of one or more fillers include, but are not limited to, mannitol, lactose, sucrose, dextrose, maltodextrin, sorbitol, xylitol, powdered cellulose, polyols, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, talc, starch (i.e., potato starch), pregelatinized starch, calcium hydrogen phosphate, calcium sulfate, and calcium carbonate, or combinations thereof.

[0140] In one embodiment, the filler comprises microcrystalline cellulose.

[0141] In a further embodiment, one or more fillers in the pharmaceutical particle composition of the present invention are binary fillers comprising a mixture of two fillers. In another further embodiment, the binary filler is a mixture of mannitol and another filler. In yet another embodiment, the binary filler is a mixture of lactose (e.g., lactose monohydrate) and another filler. In some embodiments, the binary filler is a mixture of mannitol and lactose (e.g., lactose monohydrate).

[0142] In some embodiments, the pharmaceutical particle composition comprises a binary filler comprising mannitol and lactose in a ratio of approximately 3:1. In some embodiments of this disclosure, a mannitol to lactose binary filler ratio of 1:approximately 3 can improve the properties of the pharmaceutical particle composition, such as palatability and processability, without negatively impacting, for example, dissolution, dispersibility, and / or bioavailability. For example, in some embodiments, pharmaceutical particle compositions comprising 1 to approximately 3 parts mannitol to lactose binary filler have been observed to require lower extrusion forces during manufacturing, even at higher compression pressures, compared to pharmaceutical compositions comprising mannitol as the sole filler. Since the composition is less likely to be damaged upon ejection from the mold after compression, the ability to use lower extrusion forces allows for more reliable manufacturing of the composition.

[0143] The pharmaceutical particle composition also contains a sweetener to mask and enhance the flavor of the composition. In some embodiments, one or more sweeteners include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Examples of suitable sweeteners include natural and artificial sweeteners. Examples may include, but are not limited to, glucose, sucrose, maltose, mannose, dextrose, fructose, lactose, trehalose, maltitol, lactitol, xylitol, sorbitol, mannitol, tagatose, glycerol, erythritol, isomaltitol, maltose, sucralose, aspartame, neotame, alitame, neohesperidin dihydrochalcone, cyclohexylsulfamate (i.e., sodium cyclohexylsulfamate), thaumatin, acetaminophen, saccharin, and sodium saccharin. In some embodiments, the sweetener contains sucralose at a concentration of about 1% to 2% by weight.

[0144] The disintegrants suitable for use in this invention can enhance the dispersion of pharmaceutical particle compositions and are compatible with the components of the pharmaceutical composition, i.e., they substantially do not reduce the chemical stability, physical stability, or biological activity of the pharmaceutical composition. Exemplary disintegrants include: croscarmellose sodium (e.g., AcDiSol), sodium alginate, calcium alginate, alginic acid, starch, pregelatinized starch, sodium carboxymethyl starch, polyvinylpyrrolidone, polyvinylpyrrolidone copolymer, croscarmellose, calcium carboxymethyl cellulose, cellulose and its derivatives, sodium carboxymethyl cellulose, soybean polysaccharides, clay, gum (i.e., guar gum), ion exchange resins, effervescent systems based on food acid and basic carbonate components, and sodium bicarbonate. In some embodiments, the pharmaceutical composition comprises about 4% to about 8% croscarmellose sodium by weight of the composition. In another example, the pharmaceutical composition comprises about 6% croscarmellose sodium by weight of the pharmaceutical composition.

[0145] The wetting agents and / or surfactants suitable for use in this invention can enhance the solubility or wettability of the pharmaceutical particle composition and are compatible with the components of the pharmaceutical composition, i.e., they substantially do not reduce the chemical stability, physical stability, or biological activity of the pharmaceutical composition. In some embodiments, the one or more wetting agents comprise one or more surfactants. Examples of wetting agents / surfactants include, but are not limited to, the following: sodium lauryl sulfate (also known as sodium dodecyl sulfate (SDS)), cetearyl alcohol, polycitrol emulsified wax, gelatin, casein, sodium docusate, benzalkonium chloride, calcium stearate, polyethylene glycol, phosphates, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 80, polysorbate 20), gum arabic, cholesterol, tragacanth gum, polyoxyethylene 20 stearate ether, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivatives, polyethylene glycol hydrogenated castor oil, fatty acid sorbitan esters, vitamin E or tocopherol derivatives, vitamin E TPGS, tocopherol esters, lecithin, phospholipids and their derivatives, poloxamer, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, monoglycerides and diglycerides, propylene glycol esters of fatty acids, glycerides of fatty acids (i.e., glyceryl monostearate), ethylene glycol palmitate, polyoxyglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkyl aryl polyether alcohol (Triton®), and polyoleic glycerides. The use of a wetting agent in the pharmaceutical composition of this invention is optional.

[0146] The flow aids suitable for use in this invention can enhance the flow properties of pharmaceutical compositions and are compatible with the components of the pharmaceutical composition, i.e., they substantially do not reduce the solubility, chemical stability, physical stability, or biological activity of the pharmaceutical composition. A "flow aid" is a substance that promotes powder flow by reducing interparticle friction and cohesive forces. In some embodiments, one or more excipients may include one or more flow aids. Examples of flow aids include, but are not limited to, talc, colloidal silica (e.g., Cabosil M-5P), precipitated silica, magnesium oxide, magnesium silicate, leucine, and starch. In some embodiments, the compositions of this invention contain colloidal silica as a flow aid. In some embodiments, the pharmaceutical particle composition contains about 0.5% to about 1.5% by weight of colloidal silica (by weight of the composition). In some embodiments, the pharmaceutical particle composition contains about 1.0% by weight of magnesium stearate by weight of the composition.

[0147] Lubricants suitable for use in this invention improve the compression and ejection of compressed pharmaceutical compositions from a mold. The lubricants may also have anti-stick or non-stick properties and minimize adhesion during various operations of this invention (including encapsulation, etc.), and are compatible with the components of the pharmaceutical composition, i.e., they do not substantially reduce the solubility or bioactivity of the pharmaceutical composition. Examples of lubricants include, but are not limited to, talc, fatty acids, stearic acid, magnesium stearate, calcium stearate, sodium stearate, stearic acid, glyceryl monostearate, sodium lauryl sulfate, sodium stearate fumarate, hydrogenated oil (i.e., hydrogenated vegetable oil), polyethylene glycol, fatty alcohols, fatty acid esters, glyceryl behenate, mineral oil, vegetable oil, leucine, sodium benzoate, or combinations thereof. In some embodiments, the pharmaceutical particle composition of this invention comprises magnesium stearate as a flow aid. In some embodiments, the pharmaceutical particle composition comprises about 0.5% by weight to about 2.0% by weight of magnesium stearate based on the weight of the composition. In some embodiments, the pharmaceutical particle composition of the present invention comprises about 1.0% by weight of magnesium stearate based on the weight of the composition.

[0148] The pharmaceutical particle compositions of the present invention may optionally contain one or more colorants, flavoring agents, and / or flavorings to enhance the visual appeal, taste, and / or odor of the composition. Suitable colorants, flavoring agents, or flavorings are compatible with the components of the pharmaceutical composition, i.e., they substantially do not reduce the solubility, chemical stability, physical stability, or biological activity of the pharmaceutical composition. In one embodiment, the pharmaceutical particle composition comprises colorants, flavoring agents, and / or flavorings.

[0149] Suitable flavoring agents may include, for example, various flavoring agents known to those skilled in the art, such as, for example, natural flavoring agents, artificial flavoring agents, and combinations thereof. The flavoring agents are compatible with the components of the pharmaceutical composition, i.e., they substantially do not reduce the chemical stability, physical stability, or biological activity of the pharmaceutical composition. Flavoring agents may be selected, for example, from synthetic flavoring oils and flavoring aromatics and / or oils, oleoresins, extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof. Non-limiting examples of flavoring oils include spearmint oil, cinnamon oil, wintergreen oil (methyl salicylate), peppermint oil, clove oil, laurel oil, fennel oil, eucalyptus oil, thyme oil, cedarwood leaf oil, nutmeg oil, allspice oil, sage oil, nutmeg bark oil, bitter almond oil, and cinnamon oil. Suitable flavorings also include, for example, artificial, natural, and synthetic floral or fruit flavorings such as vanilla, ethyl vanillin, citrus oils (e.g., lemon, orange, tangerine, lime, and grapefruit) and fruit flavorings (e.g., natural and / or artificial flavorings of apple, pear, peach, orange, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot), as well as combinations thereof. Flavorings may be used in liquid or solid form and, as described above, may be used alone or in mixtures. Other flavorings may include, for example, certain aldehydes and esters such as cinnamyl acetate, cinnamaldehyde, citral diethyl acetal, dihydrocarvyl acetate, eugenol formate, 4-methyl anisole, etc., as well as combinations thereof.

[0150] In some embodiments, the present invention provides a pharmaceutical particle composition that can be used to treat patients with human CFTR mutations.

[0151] In other embodiments, the present invention provides unit dose forms comprising a plurality of particles. The unit dose form comprises a compressed powdered pharmaceutical particle composition as described above, with one or more functional excipients added, such as disintegrants, flow aids, lubricants, fillers, and / or wetting agents, to facilitate the compression of the powdered pharmaceutical composition into a compressed pharmaceutical composition and to facilitate the disintegration and dissolution of the compressed powder. The compressed pharmaceutical particle composition can be formulated into unit dose forms, such as tablets, capsules, pouches, sachets, bottles, and blister packs containing a plurality of such particles. The number of particles required per unit dose form will depend on the concentrations of venzacator, tezacator, and deuterated ivacator in each particle, and the final amount of venzacator required for the unit dose form. For illustrative purposes only, the unit dose form contains 30 particles, each containing 0.14 mg crystalline venzacator calcium hydrate form D, 0.54 mg amorphous tezacator, and 1.66 mg amorphous deuterated cafurotor, providing a unit dose of 4.2 mg crystalline venzacator calcium hydrate form D, 16.1 mg amorphous tezacator, and 49.9 mg amorphous deuterated ivacarotor.

[0152] In some embodiments, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit dosage form comprises crystalline venzacator calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacator in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivacathoator in amounts ranging from about 15 mg to about 150 mg.

[0153] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising tezacator and a first polymer; c. A solid dispersion comprising deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit dosage form comprises crystalline venzacator calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacator in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivacathoator in amounts ranging from about 15 mg to about 150 mg; and Tizacator and / or deuterated ivacator are essentially amorphous forms; In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and The characteristic of the Wanzacator calcium salt hydrate form D is that its X-ray powder diffraction pattern has signals at 6.1±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, and 22.8±0.2 degrees 2θ.

[0154] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and The vanzacator calcium salt hydrate form D is characterized by its X-ray powder diffraction pattern having: (a) signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ; and (b) one or more signals selected from 5.5 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, 22.1 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ.

[0155] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and The characteristic of the Wanzacator calcium salt hydrate form D is that its X-ray powder diffraction pattern has: (a) signals at 6.1 ± 0.2 degrees 2θ, 16.2 ± 0.2 degrees 2θ, and 22.8 ± 0.2 degrees 2θ; and (b) two or more signals selected from 5.5 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, 22.1 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 27.6 ± 0.2 degrees 2θ.

[0156] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and The characteristic of Vonzacator calcium salt hydrate form D is that it is similar to... Figure 1 Essentially similar X-ray powder diffraction patterns.

[0157] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit doses consist of approximately 4.2 mg of crystalline venzacator calcium salt hydrate form D, approximately 16 mg of amorphous tezacator, and approximately 50 mg of amorphous deuterated ivacathoter.

[0158] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit doses include approximately 6.4 mg of crystalline venzacator calcium salt hydrate form D, approximately 24 mg of amorphous tezacator, and approximately 75 mg of amorphous deuterated ivacathoter.

[0159] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit doses include approximately 8.5 mg of crystalline venzacator calcium salt hydrate form D, approximately 32 mg of amorphous tezacator, and approximately 100 mg of amorphous deuterated ivacathoter.

[0160] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; The unit doses include approximately 12.7 mg of crystalline venzacator calcium salt hydrate form D, approximately 48 mg of amorphous tezacator, and approximately 150 mg of amorphous deuterated ivacathoter.

[0161] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight of amorphous tezacator and approximately 20% by weight of HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacato, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit dose forms comprise crystalline venzacator calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacator in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivacathoator in amounts ranging from about 15 mg to about 150 mg.

[0162] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit doses consist of approximately 4.2 mg of crystalline venzacator calcium salt hydrate form D, approximately 16 mg of amorphous tezacator, and approximately 50 mg of amorphous deuterated ivacathoter.

[0163] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit doses include approximately 6.4 mg of crystalline venzacator calcium salt hydrate form D, approximately 24 mg of amorphous tezacator, and approximately 75 mg of amorphous deuterated ivacathoter.

[0164] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit doses include approximately 8.5 mg of crystalline venzacator calcium salt hydrate form D, approximately 32 mg of amorphous tezacator, and approximately 100 mg of amorphous deuterated ivacathoter.

[0165] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit doses include approximately 12.7 mg of crystalline venzacator calcium salt hydrate form D, approximately 48 mg of amorphous tezacator, and approximately 150 mg of amorphous deuterated ivacathoter.

[0166] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Approximately 2% by weight of crystalline Vanzacator calcium salt in hydrate form D, based on the weight of the composition; b. About 10% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous tizacalo and about 20% by weight of HPMC. c. About 30% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous deuterated ivacarto, about 19.5% by weight of HPMCAS and about 0.5% by weight of SLS, based on the weight of the dispersion. d. About 48% by weight of one or more fillers based on the weight of the composition; e. Approximately 6% by weight of the disintegrant based on the weight of the composition; f. About 2% by weight of sweetener based on the weight of the composition; g. About 1% by weight of a gliding agent based on the weight of the composition; and h. About 1% by weight of lubricant based on the weight of the composition; The unit doses consist of approximately 4.2 mg of crystalline venzacator calcium salt hydrate form D, approximately 16 mg of amorphous tezacator, and approximately 50 mg of amorphous deuterated ivacathoter.

[0167] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Approximately 2% by weight of crystalline Vanzacator calcium salt in hydrate form D, based on the weight of the composition; b. About 10% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous tizacalo and about 20% by weight of HPMC. c. About 30% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous deuterated ivacarto, about 19.5% by weight of HPMCAS and about 0.5% by weight of SLS, based on the weight of the dispersion. d. About 48% by weight of one or more fillers based on the weight of the composition; e. Approximately 6% by weight of the disintegrant based on the weight of the composition; f. About 2% by weight of sweetener based on the weight of the composition; g. About 1% by weight of a gliding agent based on the weight of the composition; and h. About 1% by weight of lubricant based on the weight of the composition; The unit doses include approximately 6.4 mg of crystalline venzacator calcium salt hydrate form D, approximately 24 mg of amorphous tezacator, and approximately 75 mg of amorphous deuterated ivacathoter.

[0168] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Approximately 2% by weight of crystalline Vanzacator calcium salt in hydrate form D, based on the weight of the composition; b. About 10% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous tizacalo and about 20% by weight of HPMC. c. About 30% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous deuterated ivacarto, about 19.5% by weight of HPMCAS and about 0.5% by weight of SLS, based on the weight of the dispersion. d. About 48% by weight of one or more fillers based on the weight of the composition; e. Approximately 6% by weight of the disintegrant based on the weight of the composition; f. About 2% by weight of sweetener based on the weight of the composition; g. About 1% by weight of a gliding agent based on the weight of the composition; and h. About 1% by weight of lubricant based on the weight of the composition; The unit doses include approximately 8.5 mg of crystalline venzacator calcium salt hydrate form D, approximately 32 mg of amorphous tezacator, and approximately 100 mg of amorphous deuterated ivacathoter.

[0169] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Approximately 2% by weight of crystalline Vanzacator calcium salt in hydrate form D, based on the weight of the composition; b. About 10% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous tizacalo and about 20% by weight of HPMC. c. About 30% by weight of the composition of a solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous deuterated ivacarto, about 19.5% by weight of HPMCAS and about 0.5% by weight of SLS, based on the weight of the dispersion. d. About 48% by weight of one or more fillers based on the weight of the composition; e. Approximately 6% by weight of the disintegrant based on the weight of the composition; f. About 2% by weight of sweetener based on the weight of the composition; g. About 1% by weight of a gliding agent based on the weight of the composition; and h. About 1% by weight of lubricant based on the weight of the composition; The unit doses include approximately 12.7 mg of crystalline venzacator calcium salt hydrate form D, approximately 48 mg of amorphous tezacator, and approximately 150 mg of amorphous deuterated ivacathoter.

[0170] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and Mannitol was present in approximately 12.1% by weight.

[0171] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. A solid dispersion comprising amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Lubricating agents; and h. Lubricant; Each particle contains approximately 0.14 mg of crystalline venzacator calcium salt hydrate form D, approximately 0.54 mg of amorphous tezacator, and approximately 1.66 mg of amorphous deuterated ivacathoter.

[0172] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising approximately 80% by weight amorphous tezacator and approximately 20% by weight HPMC; c. A solid dispersion comprising approximately 80% by weight of amorphous deuterated ivacarto, approximately 19.5% by weight of HPMCAS and approximately 0.5% by weight of SLS; d. A binary filler composed of mannitol and lactose; e. Crosslinked sodium carboxymethyl cellulose; f. Sucralose; g. Colloidal silica; and h. Magnesium stearate; The unit dose formulation comprises crystalline venacitabine calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacotto in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivaccato in amounts ranging from about 15 mg to about 150 mg; and Each unit dosage form contains approximately 30 particles.

[0173] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline venzacator calcium salt hydrate form D, in an amount of about 1% to about 5% by weight of the pharmaceutical composition. b. An amorphous solid dispersion of tezacotto, in an amount of about 8% to about 12% by weight of the pharmaceutical composition; c. An amorphous solid dispersion of deuterated ivacato, comprising about 25% to about 35% by weight of the pharmaceutical composition; d. Sucralose, in an amount of about 1% to about 3% by weight of the pharmaceutical composition; e. Croscarmellose sodium, in an amount of about 1% to about 10% by weight of the pharmaceutical composition; f. Colloidal silica, in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition; g. Magnesium stearate, in an amount of about 0.5% to about 2.0% by weight of the pharmaceutical composition; h. Mannitol, in an amount of about 10% to about 15% by weight of the pharmaceutical composition; and i. Lactose monohydrate, in an amount of about 30% to 40% by weight of the pharmaceutical composition; Furthermore, the unit dosage form comprises approximately 0.1 to approximately 12.7 mg of crystalline venzacator calcium salt hydrate form D, approximately 10 to approximately 50 mg of amorphous tezacator, and approximately 15 to approximately 150 mg of amorphous deuterated ivacathoter.

[0174] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline venzacator calcium salt hydrate form D, in an amount of about 2% by weight of the pharmaceutical composition. b. An amorphous solid dispersion of tezacotto, comprising about 10% by weight of the pharmaceutical composition; c. An amorphous solid dispersion of deuterated ivacato, comprising approximately 30% by weight of the pharmaceutical composition; d. Sucralose, in an amount of about 2.3% by weight of the pharmaceutical composition; e. Croscarmellose sodium, in an amount of about 6% by weight of the pharmaceutical composition; f. Colloidal silica, in an amount of about 1% by weight of the pharmaceutical composition; g. Magnesium stearate, in an amount of about 1% by weight of the pharmaceutical composition; h. Mannitol, in an amount of about 12% by weight of the pharmaceutical composition; and i. Lactose monohydrate, in an amount of about 36% by weight of the pharmaceutical composition; Furthermore, each unit dosage form contains approximately 4.2 mg of crystalline venzacator calcium salt hydrate form D, approximately 16 mg of amorphous tezacator, and approximately 50 mg of amorphous deuterated ivacathoter.

[0175] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline venzacator calcium salt hydrate form D, in an amount of about 2% by weight of the pharmaceutical composition. b. An amorphous solid dispersion of tezacotto, comprising about 10% by weight of the pharmaceutical composition; c. An amorphous solid dispersion of deuterated ivacato, comprising approximately 30% by weight of the pharmaceutical composition; d. Sucralose, in an amount of about 2.3% by weight of the pharmaceutical composition; e. Croscarmellose sodium, in an amount of about 6% by weight of the pharmaceutical composition; f. Colloidal silica, in an amount of about 1% by weight of the pharmaceutical composition; g. Magnesium stearate, in an amount of about 1% by weight of the pharmaceutical composition; h. Mannitol, in an amount of about 12% by weight of the pharmaceutical composition; and i. Lactose monohydrate, in an amount of about 36% by weight of the pharmaceutical composition; Furthermore, the unit dosage form contains approximately 6.4 mg of crystalline venzacotto calcium salt hydrate form D, approximately 24 mg of amorphous tezacotto, and approximately 75 mg of amorphous deuterated ivacathotoxin.

[0176] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline venzacator calcium salt hydrate form D, in an amount of about 2% by weight of the pharmaceutical composition. b. An amorphous solid dispersion of tezacotto, comprising about 10% by weight of the pharmaceutical composition; c. An amorphous solid dispersion of deuterated ivacato, comprising approximately 30% by weight of the pharmaceutical composition; d. Sucralose, in an amount of about 2.3% by weight of the pharmaceutical composition; e. Croscarmellose sodium, in an amount of about 6% by weight of the pharmaceutical composition; f. Colloidal silica, in an amount of about 1% by weight of the pharmaceutical composition; g. Magnesium stearate, in an amount of about 1% by weight of the pharmaceutical composition; h. Mannitol, in an amount of about 12% by weight of the pharmaceutical composition; and i. Lactose monohydrate, in an amount of about 36% by weight of the pharmaceutical composition; Furthermore, the unit dosage form contains approximately 8.5 mg of crystalline venzacotto calcium salt hydrate form D, approximately 32 mg of amorphous tezacotto, and approximately 100 mg of amorphous deuterated ivacathotoxin.

[0177] In another aspect, the present invention includes a pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each particle comprises: a. Crystalline venzacator calcium salt hydrate form D, in an amount of about 2% by weight of the pharmaceutical composition. b. An amorphous solid dispersion of tezacotto, comprising about 10% by weight of the pharmaceutical composition; c. An amorphous solid dispersion of deuterated ivacato, comprising approximately 30% by weight of the pharmaceutical composition; d. Sucralose, in an amount of about 2.3% by weight of the pharmaceutical composition; e. Croscarmellose sodium, in an amount of about 6% by weight of the pharmaceutical composition; f. Colloidal silica, in an amount of about 1% by weight of the pharmaceutical composition; g. Magnesium stearate, in an amount of about 1% by weight of the pharmaceutical composition; h. Mannitol, in an amount of about 12% by weight of the pharmaceutical composition; and i. Lactose monohydrate, in an amount of about 36% by weight of the pharmaceutical composition; Furthermore, the unit dosage form contains approximately 12.7 mg of crystalline venzacator calcium salt hydrate form D, approximately 48 mg of amorphous tezacator, and approximately 150 mg of amorphous deuterated ivacathoter.

[0178] Administration of the pharmaceutical composition In another aspect, the present invention also provides a method for treating or reducing the severity of a patient's disease, the method comprising administering to the patient one of a pharmaceutical composition as defined herein. In some embodiments, the disease is cystic fibrosis.

[0179] In some embodiments, the method of administration of the present invention comprises orally administering a liquid or beverage (including but not limited to milk (including breast milk), infant formula, or toddler formula) or soft food (including but not limited to applesauce, plain yogurt, ice cream, baby food (including carrots and carrot puree)) into a unit dose form sprinkled into the pharmaceutical composition of the present invention. It is noteworthy that any method of administration of the present invention may optionally comprise orally administering it with a fatty food such as a standard CF high-calorie, high-fat meal, or snack. In some embodiments, any method of administration of the present invention may optionally comprise orally administering it with, before, or after a fatty food such as a standard CF high-calorie, high-fat meal, or snack.

[0180] It is also worth noting that the method of administration of the present invention includes administering the composition of the present invention to a patient based on age or weight. In some embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient is 12 to 24 months or 2 to 5 years old. In yet other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes, but is not limited to, patients weighing greater than or equal to about 14 kg. In yet other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes, but is not limited to, patients weighing less than 14 kg. In yet other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing from about 7.5 kg to less than 14 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing multiple particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 5 kg to less than 7.5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing multiple particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 2.5 kg to less than 5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing multiple particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing less than 7.5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing multiple particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 5 kg to more than 5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing less than 5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient every 24 hours, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 2.5 kg to more than 2.5 kg.

[0181] It is also worth noting that the method of administration of the present invention includes administering the composition of the present invention to a patient based on age or weight. In some embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient once daily, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient is 12 to 24 months or 2 to 5 years old. In yet other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient once daily, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes, but is not limited to, patients weighing greater than or equal to about 14 kg. In yet other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient once daily, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes, but is not limited to, patients weighing less than 14 kg. In yet other embodiments, the method of administering the pharmaceutical composition includes orally administering at least one capsule or sachet containing a plurality of particles to a patient once daily, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing from about 7.5 kg to less than 14 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering, once daily, to a patient at least one capsule or sachet containing a plurality of particles, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 5 kg to less than 7.5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering, once daily, to a patient at least one capsule or sachet containing a plurality of particles, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 2.5 kg to less than 5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering, once daily, to a patient at least one capsule or sachet containing a plurality of particles, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing less than 7.5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering, once daily, to a patient at least one capsule or sachet containing a plurality of particles, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing about 5 kg to more than 5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering, once daily, to a patient at least one capsule or sachet containing a plurality of particles, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes, but is not limited to, patients weighing less than 5 kg. In other embodiments, the method of administering the pharmaceutical composition includes orally administering, once daily, to a patient at least one capsule or sachet containing a plurality of particles, wherein each particle contains the pharmaceutical composition as described herein, wherein the patient includes those weighing from about 2.5 kg to more than 2.5 kg.

[0182] In some embodiments, the patient has at least one F508del mutation in the CFTR gene. In some embodiments, the patient has a CFTR gene mutation that, based on in vitro data, responds to the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present invention. In some embodiments, the patient has a CFTR gene mutation that, based on clinical data, responds to the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present invention. In some embodiments, the patient is heterozygous and has an F508del mutation in one allele and a mutation selected from Table 1 in the other allele. Table 1: CFTR mutations

[0183] In some embodiments, the method includes treating or reducing the severity of cystic fibrosis in a patient, including administering to the patient a pharmaceutical composition comprising a compressed pharmaceutical composition. In one embodiment, a capsule pharmaceutical composition comprising about 1 mg to about 12.7 mg of vena cavato calcium hydrate form D, about 10 mg to about 50 mg of amorphous tezacotto, and about 15 mg to about 150 mg of amorphous deuterated ivacathoto is administered to the patient in a unit dosage form.

[0184] In some embodiments, the method includes treating or reducing the severity of cystic fibrosis in a patient by administering to the patient the compressed pharmaceutical composition of the present invention, i.e., a capsule or sachet containing multiple particles, comprising a unit dosage form of about 4.2 mg venzacator calcium hydrate form D, about 20 mg tezacator, and about 60 mg deuterated ivacalorie. In some embodiments, the method includes treating or reducing the severity of cystic fibrosis in a patient by administering to the patient the compressed pharmaceutical composition of the present invention, i.e., a capsule or sachet containing multiple particles, comprising a unit dosage form of about 6.4 mg venzacator calcium hydrate form D, about 24 mg tezacator, and about 75 mg deuterated ivacalorie. In some embodiments, the method includes treating or reducing the severity of cystic fibrosis in a patient by administering to the patient the compressed pharmaceutical composition of the present invention, i.e., a capsule or sachet containing multiple particles, comprising a unit dosage form of about 8.5 mg venzacator calcium hydrate form D, about 32 mg tezacator, and about 100 mg deuterated ivacalorie. In some embodiments, the method includes treating or reducing the severity of cystic fibrosis in a patient by administering to the patient the compressed pharmaceutical composition of the present invention, i.e., a capsule or sachet containing multiple particles, comprising a unit dosage form of about 12.7 mg venzacator calcium hydrate form D, about 48 mg tezacator, and about 150 mg deuterated ivacalorie.

[0185] It is also worth noting that the method of administration of the present invention may optionally include oral administration of the pharmaceutical composition as described herein without food or beverage. In one embodiment of the invention, oral administration is performed immediately after the patient has eaten or drunk water, or shortly thereafter (e.g., within about 30 minutes). In another embodiment, oral administration is performed at least 1 hour after eating or drinking water (e.g., at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 8 hours, at least 12 hours, or at least 24 hours). For example, in one instance, the method of administering the pharmaceutical composition includes orally administering to a patient once daily the contents of at least one capsule or a sachet or packet containing multiple granules, each granule containing venzaccato, tezaccato, and deuterated ivacato, one or more fillers, sweeteners, disintegrants, optionally wetting agents, flow aids, and lubricants, and another treatment or medical procedure. Specific combinations of therapies (therapeutic agents or procedures) employed in combination will take into account the compatibility of the desired therapeutic agents and / or procedures with the desired therapeutic effect to be achieved. It should also be understood that the treatments employed may achieve the desired effect on the same condition (e.g., the compounds of the present invention may be administered in parallel with another agent used to treat the same condition), or they may achieve different effects (e.g., controlling any side effects). As used herein, an adjunct therapeutic agent typically administered to treat or prevent a particular disease or symptom is referred to as “the disease or symptom appropriate for treatment”.

[0186] In one implementation, the additional therapeutic agent is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, or nutritional agents.

[0187] In one embodiment, the adjuvant is an antibiotic. Exemplary antibiotics commonly used herein include tobramycin (including tobramycin inhalation powder (TIP)), azithromycin, aztreonam (including aztreonam aerosol form), amikacin (including its liposomal formulation), ciprofloxacin (including its formulation suitable for inhalation), levofloxacin (including its aerosol formulation), and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0188] In another embodiment, the adjuvant is a mucin-dissolving agent. Exemplary mucin-dissolving agents applicable herein include Pulmozyme®.

[0189] In another embodiment, the adjuvant is a bronchodilator. Exemplary bronchodilators include salbutamol, orosinaline sulfate, pirboterol acetate, salmeterol, or terbutaline sulfate.

[0190] In another embodiment, the adjuvant effectively restores fluid to the surface of the lung airways. Such adjuvants improve the movement of salts in and out of cells, making mucus in the lung airways more moist and thus easier to clear. Exemplary such adjuvants include hypertonic saline, denofosole tetrasodium ([[(3) S 5 R )-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxacyclopentan-2-yl]methoxy-hydroxyphosphoryl][[[(2 R ,3 S 4 R 5 R )-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxacyclopentan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]hydrogen phosphate) or bronchitol (mannitol inhalation formulation).

[0191] In another embodiment, the adjuvant is an anti-inflammatory agent, i.e., an agent capable of reducing inflammation in the lungs. Exemplary such agents available herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simvastatin.

[0192] In another embodiment, the adjuvant is a CFTR modulator other than venzacator, i.e., an agent that modulates CFTR activity. Exemplary 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-{(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid). R ,4a R 5 R 7a R )-2-[(3 S )-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxooctahydrocyclopentano[ b ]pyran-5-yl}heptanoic acid) or (3-(6-(1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)cyclopropanecarbamate-3-methylpyridin-2-yl)benzoic acid. In another embodiment, the additive is (3-(6-(1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)cyclopropanecarbamate-3-methylpyridin-2-yl)benzoic acid.

[0193] In another embodiment, the adjuvant is a nutritional supplement. Exemplary such supplements include pancreatic lipases (pancreatic enzyme replacement therapy), including Pancrease®, Pancreascarb®, Ultrase® or Creon®, Liprotamase® (formerly known as Trizytek®), Aquadeks® or glutathione inhalers. In one embodiment, the nutritional supplement is pancreatic lipase.

[0194] Example To provide a fuller understanding of the invention described herein, the following embodiments are presented. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0195] abbreviation ACN = Acetonitrile AUC = Area under the curve Boc = tert-Butoxycarbonyl DCM = dichloromethane DMF = dimethylformamide DMSO = dimethyl sulfoxide ESI = Electrospray Ionization FTNMR = Fourier Transform Nuclear Magnetic Resonance HPLC = High Performance Liquid Chromatography HPMC = Hydroxypropyl Methylcellulose HPMCAS = Hydroxypropyl methylcellulose acetate succinate IPA = Isopropyl alcohol IPAc = Isopropyl acetate KF = Karl Fischer titration LC = Liquid Chromatography LCMS = Liquid Chromatography-Mass Spectrometry MeTHF = 2-Methyltetrahydrofuran MS = Mass Spectrometry MTBE = Methyl tert-butyl ether NMR = Nuclear Magnetic Resonance pn = Material Number SDD = Spray-dried dispersion SFC = Supercritical Fluid Chromatography SLS = Sodium lauryl sulfate THF = Tetrahydrofuran TLC = Thin-layer chromatography UPLC = Ultra-high performance liquid chromatography UV = ultraviolet light wt% = weight percentage General UPLC / HPLC analytical methods Unless otherwise stated, the yield of enantiomers separated by chiral SFC is expressed as a percentage of the theoretical yield of the racemic single enantiomer.

[0196] LC Method A: Analytical-grade reversed-phase UPLC, using an Acquity UPLC BEH C manufactured by Waters. 18 The column (30 × 2.1 mm, 1.7 μm particles) (pn: 186002349) was run with a dual gradient of 1-99% mobile phase B over 1.2 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0197] LC Method B: Analytical-grade reversed-phase UPLC, using an Acquity UPLC BEH C manufactured by Waters. 18 The column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) was run with a dual gradient of 1-99% mobile phase B over 3.0 min. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0198] LC Method D: Analytical-grade reversed-phase UPLC, using an Acquity UPLC BEH C manufactured by Waters. 18 The column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) was run with a dual gradient of 1-99% mobile phase B for 5.0 min. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0199] LC Method F: Analytical-grade reversed-phase UPLC, using an Acquity UPLC BEH C manufactured by Waters. 18The column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) was run with a dual gradient of 1-99% mobile phase B for 15.0 min. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0200] LC Method Q: Merck Millipore Chromolith SpeedROD C 18 The column (50 × 4.6 mm) was run in a dual gradient from 5% to 100% mobile phase B over 12 minutes. Mobile phase A = water (0.1% trifluoroacetic acid). Mobile phase B = acetonitrile (0.1% trifluoroacetic acid).

[0201] Example 1: Synthetic Venzacator calcium salt hydrate form D Part A. (14) S 8-Bromo-12,12-Dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14.05,10 Synthesis of tetracoc-1(23),5,7,9,19,21-hexane-2,2,4-trione Step 1: ( E )-(2-oxotetrahydropyran-3-yl)methoxide (sodium salt) A 5 L three-necked round-bottom flask was equipped with a mechanical stirrer, heating mantle, feeding funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. Under a nitrogen atmosphere, sodium hydride (59.91 g, 60% w / w, 1.498 mol) was added to the flask, followed by heptane (1.5 L), resulting in a gray suspension. Stirring was initiated, and the temperature inside the flask was recorded as 19 °C. Ethanol (3.451 g, 74.91 mmol) was then added to the flask via a syringe, causing gas to escape. A clear, pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol) was added to the feeding funnel. This solution was added dropwise over 1 hour, causing gas to escape and gradually exothermic to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 hours and then cooled to room temperature. The mixture was stirred overnight at room temperature (approximately 10 hours). The reaction mixture was then vacuum filtered through a glass frit-core Buchner funnel (medium porosity) under a nitrogen stream. The filter cake was washed with heptane (2 × 250 mL) and filtered for several minutes. The slightly heptane-containing filter cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 hours to give a white solid (205 g, 1.36 mol, 91% yield) as the desired product. E )-(2-oxotetrahydropyran-3-yl)methoxide (sodium salt).

[0202] Step 2: 3-Methylenetetrahydropyran-2-one Equip a 5 L three-necked round-bottom flask with a mechanical stirrer, heating mantle, feeding funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. Under a nitrogen atmosphere, add (…) to the container. E(2-oxotetrahydropyran-3-yl)methoxide (sodium salt) (205 g, 1.366 mol) and tetrahydrofuran (1640 mL) were added to give a white suspension. Stirring was started, and the temperature in the container was recorded as 19 °C. Then, paraformaldehyde (136.6 g, 4.549 mol) was added to the container in a single, solid-state addition. The resulting suspension was heated to 63 °C and maintained at this condition for 15 hours. After heating, the reaction mixture became slightly gelatinous. The white gelatinous mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining residue was partitioned in a separatory funnel using ethyl acetate (1000 mL), saturated sodium chloride solution (500 mL), and saturated sodium bicarbonate solution (500 mL). Organic matter was removed, and the remaining aqueous phase was extracted with ethyl acetate (5 × 300 mL). The combined organic matter was dried over sodium sulfate (500 g) and then vacuum filtered through a Buchner funnel with a glass frit core lined with 20 mm diatomaceous earth. The filter cake was washed with ethyl acetate (250 mL). The clarified filtrate was concentrated under reduced pressure to obtain a clear, pale yellow oil (135 g) as the desired crude product. This material was purified by rapid silica gel column chromatography (liquid loading), eluting with 100% hexane to 60% ethyl acetate in hexane over 1 hour, collecting 450 mL fractions. The product was detected by TLC on silica gel (eluting with 3:1 hexane / ethyl acetate and visualized under UV). The product fractions were combined and concentrated under reduced pressure to obtain a clear, colorless oil (132 g, 1.18 mol, 72% yield, containing 16 wt% residual ethyl acetate as determined by NMR) as the desired product, 3-methylenetetrahydropyran-2-one. ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ 6.18 (q, J = 1.9 Hz, 1H), 5.60 (q, J = 1.9 Hz, 1H), 4.40 - 4.26 (m, 2H), 2.61 (ddt, J = 7.0, 6.3, 2.0Hz, 2H), 1.90 - 1.75 (m, 2H).

[0203] Step 3: 3-(2-methyl-2-nitropropyl)tetrahydropyran-2-one A 5000 mL three-necked round-bottom flask was equipped with a mechanical stirrer, a cooling bath (used as an auxiliary container), a J-Kem temperature probe, a feeding funnel, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, 2-nitropropane (104.9 g, 1.177 mol) was added to the flask. Stirring was initiated, and the temperature inside the flask was recorded as 19 °C. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (22.41 g, 147.2 mmol) was added to the flask as a single, pure addition, yielding a clear, pale yellow solution. No exothermic reaction was observed. A solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 mL) was added dropwise to the feeding funnel over 1 hour, yielding a clear, pale yellow solution that gradually exothermed to 24 °C. The reaction mixture was continued to be stirred at room temperature for 3.5 hours, and then concentrated under reduced pressure. The remaining residue was dissolved in dichloromethane (1000 mL) and partitioned with 500 mL of a 3:2 mixture of 1 molar citric acid solution and saturated sodium chloride solution. The resulting organic phase was a clear, pale blue solution, and the aqueous phase was a slightly turbid, very pale blue solution. The organic matter was removed, and the remaining aqueous phase was extracted with dichloromethane (300 mL). The combined organic matter was washed with saturated sodium chloride solution (300 mL), dried over sodium sulfate (250 g), and filtered through a glass frit-core Buchner funnel. The filtrate was concentrated to approximately 200 mL under reduced pressure. The clear, pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 mL), and the turbid solution was concentrated to approximately 200 mL under reduced pressure to obtain a suspension. The mixture was diluted again with methyl tert-butyl ether (1500 mL) and concentrated to approximately 250 mL under reduced pressure. The resulting suspension was allowed to stand overnight (approximately 12 hours) at room temperature. The solid was collected by vacuum filtration in a glass frit Buchner funnel, and the filter cake was washed with cold methyl tert-butyl ether (2 × 150 mL), followed by filtration for 30 minutes. The substance was further dried in a vacuum oven at 45 °C for 5 hours to give a white solid (160 g, 0.795 mol, 81% yield) as the desired product 3-(2-methyl-2-nitropropyl)tetrahydropyran-2-one. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ 4.34 (ddd, J = 11.1, 9.3, 4.3 Hz, 1H), 4.20 (dt, J = 11.1, 5.1 Hz, 1H),2.75 - 2.62 (m, 1H), 2.56 (dd, J= 14.9, 5.2 Hz, 1H), 2.01 - 1.89 (m, 2H), 1.89- 1.67 (m, 2H), 1.55 (d, J = 6.0 Hz, 6H), 1.44 (dddd, J = 12.8, 11.5, 8.1, 6.6Hz, 1H).

[0204] Step 4: ( S )-3-(2-methyl-2-nitropropyl)tetrahydro-2 H Preparation of 2-pyran-2-one racemic 3-(2-methyl-2-nitropropyl)tetrahydro-2 H -Pyran-2-one was dissolved in MeOH / ACN 70 / 30 v / v at 80 g / L ± 8 g / L (target value 80 ± 2 g / L), and separated on Chiralpak AD 20 μm as the stationary phase using MeOH / ACN 70 / 30 v / v as the mobile phase. S )-3-(2-methyl-2-nitropropyl)tetrahydro-2 H -Pyran-2-one is the peak 2.

[0205] (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one optional recrystallization :Will( S )-3-(2-methyl-2-nitropropyl)tetrahydro-2 H 9.5 kg of pyran-2-one (1.0 equivalent) was stirred in isopropanol (76 L, 8 volumes) and then heated to >70°C to dissolve the solid. The mixture was then cooled to 20°C over 4–5 hours, the solid was separated by filtration, and the filter cake was washed with isopropanol (4.75 L, 0.5 volumes) and dried under vacuum. The substance was then dried under vacuum to obtain ( S )-3-(2-methyl-2-nitropropyl)tetrahydro-2 H -Pyran-2-one, with a recovery rate of approximately 90%.

[0206] Step 5: ( S Synthesis of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidone-2-one The Raney Nickel 2400 (77 wt%, 2.8 kg) suspension was allowed to stand for 2 days. The settled liquid was decanted into waste liquid, and the remaining catalyst was added to the reactor with the assistance of water (2.6 kg), followed by degassing with N2. In the second reactor, ( S)-3-(2-methyl-2-nitropropyl)tetrahydro-2 H A mixture of pyran-2-one (13.9 kg) and EtOH (170.8 kg) was heated to 30 °C, degassed with N2, and then transferred to a reactor containing Raney nickel. The transfer was assisted by rinsing with EtOH (29.8 kg). The mixture was purged three times with nitrogen and three times with hydrogen. The contents of the reactor were heated to 60–65 °C and stirred with H2 (4–8 psi) until the reaction was complete (18 hours). The mixture was cooled to 15–20 °C, purged three times with nitrogen, and then filtered through a diatomaceous earth cake (3.0 kg) moistened with ethanol (3.2 kg). The reactor and the diatomaceous earth cake were washed with ethanol (2 × 14.0 kg). The filtrate was distilled to a final volume of approximately 25 L and then heated to 45 °C. Then add MTBE (269.4 kg), maintain the temperature at 48-50°C, and distill at 48-55°C under ambient pressure to a final volume of approximately 30 L. Subsequently, add two more portions of MTBE (269.4 kg and 187.4 kg) in sequence, and then concentrate to a volume of approximately 30 L.

[0207] The contents of the reactor were inoculated at 40°C. S )-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidone-2-one (70.1 g). The inoculated crystallization slurry was cooled to 15°C for 3.5 hours, then stirred at 12-15°C for 16.5 hours, and then filtered. The reactor and filter cake were then washed with cold (-2 to -10°C) MTBE (2 × 10 kg). The filter cake was dried to constant weight to obtain ( S 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidone-2-one (10.4 kg; 88%) is a white crystalline solid.

[0208] ( S Recrystallization of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidone-2-one: SA mixture of 10.3 kg of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidone-2-one and 28.2 kg of DCM was stirred and heated to 25 °C for 2 hours, then transferred to another reactor through an in-line filter (45 μm). The initial reactor was flushed with 6.8 kg of DCM at 21 °C for 10 minutes, then transferred to another reactor through an in-line filter. 38.1 kg of MTBE was added to the solution at 25–30 °C, and the mixture was distilled at 35–52 °C and atmospheric pressure for 2.5 hours to a final volume of approximately 30 L. 38.2 kg of MTBE was added to the reactor at 45–50 °C. The resulting suspension was distilled at 49–55 °C and atmospheric pressure for 3.25 hours to a final volume of approximately 30 L. The contents of the reactor were cooled to 21 °C for 2.5 hours and stirred at 20 °C for 16 hours. The suspension was then filtered. The reactor and filter cake were washed with MTBE (7.7 kg, 0.0 °C). The filter cake was filtered over a period of 2 days. Yield: 9.1 kg (88.3%) of off-white solids. 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (s,1H), 4.38 (s, 1H), 3.38 (t, J = 6.5 Hz, 2H), 2.37 (qd, J = 9.5, 4.4 Hz, 1H), 2.02(dd, J = 12.4, 8.6 Hz, 1H), 1.78 - 1.63 (m, 1H), 1.50 - 1.33 (m, 3H), 1.16 (d, J = 17.9 Hz, 7H). ESI-MS m / z calculated value: 171.12593, measured value: 172.0 [M+1] + GCMS: 100% (AUC). Chiral HPLC: 100% (AUC).

[0209] Step 6: ( S Synthesis of 3-(5,5-dimethylpyrrolid-3-yl)propane-1-ol At 30-40°C, LiAlH4 particles (332.5 g, 8.760 mol, 1.50 equivalents) were slowly added to a reactor containing 10.00 L of 2-MeTHF (10 volumes). The mixture was then heated to 75°C. SA mixture of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidone-2-one (1,000 g, 5.840 mol, 1.00 equivalent) and 2-methyltetrahydrofuran (10.00 L, 10 volumes) was prepared in a separate reactor and heated to 65 °C, then carefully transferred to a reactor containing a LiAlH4 mixture after 2 hours. The mixture was stirred at 70 °C until the reaction was complete (18–24 hours), then cooled to 0–10 °C. Water (400.0 mL, 1 × LiAlH4 wt) was then carefully added while keeping the mixture temperature below 30 °C. A 15% NaOH aqueous solution (400.0 mL, 1 × LiAlH4 wt) was then added, followed by water (400.0 mL, 1 × LiAlH4 wt), while keeping the mixture temperature below 30 °C. The resulting mixture was heated to 60 °C and maintained at that temperature for at least 30 minutes. The mixture was cooled to 20-30°C, and then diatomaceous earth (200 g, 20 wt%) was added. The mixture was then filtered through a diatomaceous earth pad. The reactor and filter cake were washed with 2-MeTHF (4.0 L, 4.0 volume). The filtrate was concentrated under vacuum to give a pyrrolidine compound (…). S 3-(5,5-dimethylpyrrolidone-3-yl)propane-1-ol (872 g; 94.95% yield) was a transparent oil.

[0210] 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ 3.36 (t, J = 6.3 Hz, 3H), 2.95 (dd, J =10.6, 7.6 Hz, 1H), 2.40 (dd, J = 10.6, 7.7 Hz, 1H), 2.12 - 1.97 (m, 1H), 1.69(dd, J = 12.1, 8.2 Hz, 1H), 1.47 - 1.25 (m, 5H), 1.08 (s, 3H), 1.02 (s, 3H).

[0211] Step 7: ( S Synthesis of 6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidone-1-yl)nicotinamide Stirring SA mixture of 3-(5,5-dimethylpyrrolidin-3-yl)propane-1-ol (2325 g, 14.8 mol) and 6-bromo-2-fluoropyridine-3-carboxamide (3400 g, 15.5 mol) in 2-methyltetrahydrofuran (23 L) was then added, followed by the addition of potassium carbonate (2650 g, 19.2 mol) and deionized water (7 L). The mixture was stirred at <25 °C until the reaction was complete (≥16 hours).

[0212] The aqueous phase was removed, and the upper organic phase was washed with water (7 L) and a 2% sodium chloride aqueous solution (7 L). The organic layer was concentrated to approximately 19 L under reduced pressure. 2-Methyltetrahydrofuran was expelled from the mixture by two consecutive additions and concentrations of acetonitrile (2 × 20 L), followed by distillation. Acetonitrile (20 L) was added to the remaining solution, and the reaction was heated to 85 °C for 2 hours, then cooled to 25 °C at a rate of 10 °C / h. The slurry was cooled to 10 °C and stirred for 4 hours, then filtered. The filter cake was washed twice with acetonitrile (2 × 3 L), and the solid was dried under vacuum to obtain ( S 6-Bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidone-1-yl)nicotinamide, a white crystalline solid (3850 g, 73% yield).

[0213] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.34 (dd, J =7.7, 1.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 4.42 (t, J = 5.1 Hz, 1H), 3.39 (q, J =5.7 Hz, 2H), 3.29 - 3.12 (m, 2H), 2.19 (dt, J = 10.9, 5.8 Hz, 1H), 1.92 (dd, J =11.9, 5.7 Hz, 1H), 1.53 (s, 3H), 1.50 (s, 3H), 1.48 – 1.29 (m, 5H).

[0214] Step 8: ( S Synthesis of 6-bromo-2-(4-(3-(1,3-dioxoisoindoline-2-yl)propyl)-2,2-dimethylpyrrolidine-1-yl)nicotinamide Will( S A mixture of 2.65 kg (7.4 mol) of 6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidone-1-yl)nicotinamide, 2-methyltetrahydrofuran (16 L), and triethylamine (900 g, 8.88 mol) was stirred at 20 °C, followed by the addition of methanesulfonyl chloride (933 g, 8.14 mol) over 2 hours. The mixture was stirred at 20 °C until the reaction was complete (usually 16 hours). The resulting mixture was filtered, and the filter cake was washed with tert-butyl methyl ether (2 × 4 L). The combined filtrate (containing the methanesulfonate intermediate) was transferred to a reactor and diluted with dimethyl sulfoxide (16 L). Phthalimide (1198 g, 8.14 mol) was added to the mixture. The mixture was stirred until a solution was obtained, then potassium carbonate (1023 g, 7.4 mol) was added. The mixture was stirred and heated to 70 °C until the reaction was complete (2 hours). The mixture was cooled to 20 °C and diluted with 2-methyltetrahydrofuran (16 L), then deionized water (21 L) was added. The phases were separated, and the upper organic phase was washed with deionized water (10 L) and a saturated sodium chloride aqueous solution (2 × 1 L). The organic phase was diluted with toluene (16 L) and concentrated to approximately 10 L under reduced pressure. The solid was separated by filtration, and the filter cake was washed with toluene (2 × 2 L). The resulting solid was dried to give the compound ( S Nicotinamide, 6-bromo-2-(4-(3-(1,3-dioxoisoindoline-2-yl)propyl)-2,2-dimethylpyrrolidine-1-yl), is a grayish-white solid (3393 g, 6.99 mol, 94% yield).

[0215] 1 H NMR (400 MHz, DMSO- d 6) δ 7.91 – 7.80 (m, 4H), 7.80 – 7.71 (m, 1H), 7.42 – 7.36 (m, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.29 – 7.09 (m, 3H), 6.67 (d, J =7.7 Hz, 1H), 3.59 (t, J = 6.9 Hz, 2H), 3.23 (t, J = 10.4 Hz, 1H), 3.16 (dd, J =10.2, 7.4 Hz, 1H), 2.30 (s, 2H), 2.28 – 2.13 (m, 1H), 1.90 (dd,J = 12.0, 5.6Hz, 1H), 1.71 – 1.53 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H), 1.47 – 1.23 (m, 3H).

[0216] Step 9: Synthesis of perfluorophenyl 6-fluoropyridine-2-sulfonate Add an aqueous solution of KHCO3 (approximately 90.30 mL, 20% w / v, 180.4 mmol) to a solution of 2,3,4,5,6-pentafluorophenol (33.21 g, 180.4 mmol) in iPrOAc (175 mL). Stir the mixture at room temperature for 10 minutes. Then add a solution of 6-fluoropyridine-2-sulfonyl chloride (35.29 g, 180.4 mmol) in iPrOAc (25 mL) while maintaining the temperature below 20 °C. Stir the reaction mixture at ambient temperature for 1 hour to complete the reaction. Remove the aqueous layer and wash the organic layer with water (50 mL), dry it with Na2SO4, and then concentrate it by rotary evaporation to remove most of the solvent and precipitate a white solid. Add heptane (70 mL) and stir the slurry at ambient temperature. The solid was collected by filtration, washed with heptane (30 mL), and dried under vacuum to give 58.76 g of perfluorophenyl 6-fluoropyridine-2-sulfonic acid as a white solid. The mother liquor was concentrated by rotary evaporation, and then 1 mL of (iPrOAc) / 20 mL of (heptane) was added, and the mixture was stirred overnight at ambient temperature. The resulting solid was collected and dried overnight in a vacuum oven at ambient temperature under N2 purging to give 0.87 g of the second batch of product. A total of 59.63 g (96% yield) of perfluorophenyl 6-fluoropyridine-2-sulfonic acid was obtained. 1 H NMR (400 MHz, DMSO- d 6) δ8.46 (q, J = 7.7 Hz, 1H), 8.20 (dd, J = 7.5, 2.0 Hz, 1H), 7.84 (dd, J = 8.3, 2.2Hz, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -64.25 (s, 1F), -152.20 – -152.69 (m,2F), -154.84 (t, J = 23.3 Hz, 2F), -161.00 – -161.74 (m, 1F).

[0217] Step 10: ( S )-6-bromo-2-(4-(3-(1,3-dioxoisoindoline-2-yl)propyl)-2,2-dimethylpyrrolidine-1-yl)- N Synthesis of -((6-fluoropyridin-2-yl)sulfonyl)nicotinamide A lithium tert-butoxide solution (1,905.13 g, 2.20 equivalents, 20% w / w, in THF) was added to ( S A mixture of 6-bromo-2-(4-(3-(1,3-dioxoisoindoline-2-yl)propyl)-2,2-dimethylpyrrolidone-1-yl)nicotinamide (1,050 g, 1.00 equivalent) and perfluorophenyl 6-fluoropyridine-2-sulfonic acid (890.93 g, 1.20 equivalent) in 2-MeTHF (10.5 L, 10.0 volume) was added, maintaining an internal temperature below -2°C. The mixture was stirred at -10°C until the reaction was complete (typically 0.5 h). An aqueous solution of HCl (5.25 L, 5 volumes, 1 N) was added, while maintaining an internal temperature <20°C. Then, 2-MeTHF (5.0 L, 5 volumes) was added to the reactor at ambient temperature, and the phases were separated. The lower aqueous phase was discarded. The organic phase was washed with water (5 volumes) and then concentrated to 5 volumes under vacuum, maintaining a temperature below 50°C. Add 2-MeTHF (10.0 L, 10 volumes) and concentrate the mixture again to 5 volumes. Add 2-MeTHF (5 volumes) and heat the heterogeneous mixture to 70°C and stir until completely dissolved. Then, linearly cool the mixture to 45°C over 6 hours and maintain it at 45°C for 6 hours. Then, cool the mixture to 25°C over 2 hours, and then add heptane (10.0 L, 10 volumes) to the mixture over 3 hours. Discharge the mixture from the reactor and separate the solids. Then, wash the reactor and filter cake twice with a mixture of 2-MeTHF (2.0 L, 2 volumes) and heptane (2.0 L, 2 volumes). Dry the solids under vacuum at 45°C to obtain ( S )-6-bromo-2-(4-(3-(1,3-dioxoisoindoline-2-yl)propyl)-2,2-dimethylpyrrolidine-1-yl)- N -((6-Fluoropyridin-2-yl)sulfonyl)nicotinamide. 1 H NMR (400 MHz, DMSO-) d 6) δ 13.05 (s, 1H), 8.37 (q, J = 7.8 Hz, 1H), 8.11 (dd, J= 7.4, 1.9 Hz, 1H), 7.95 – 7.88 (m, 2H), 7.88 –7.81 (m, 2H), 7.59 (dd, J = 8.1, 2.4 Hz, 2H), 6.78 (d, J = 7.9 Hz, 1H), 3.59 (t, J = 6.8 Hz, 2H), 2.45 (dd, J = 8.8, 3.9 Hz, 2H), 2.17 (s, 1H), 1.87 (dd, J = 11.9,5.5 Hz, 1H), 1.56 (dddd, J = 22.3, 16.7, 8.9, 4.1 Hz, 2H), 1.47 (s, 3H), 1.44(s, 3H), 1.35 (t, J = 12.1 Hz, 1H), 1.21 (ddd, J = 13.3, 10.5, 5.4 Hz, 1H), 1.00(dtd, J = 14.1, 9.4, 5.7 Hz, 1H).

[0218] Step 11: ( S Synthesis of 6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidine-3-yl)propyl)carbamoyl)benzoic acid The previous step yielded (containing) S The reaction solution of 6-bromo-2-(4-(3-(1,3-dioxoisoindoline-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide was cooled and a solution of LiOH•H₂O (284 g, 6.77 mol; 3 equivalents) in water (2.19 L; 2 volume equivalents) was added while maintaining the temperature below 10°C. The biphase mixture was stirred at 5–15°C until the reaction was complete (approximately 2 hours). 2 M HCl (5.64 L, 11.3 mol; 5 equivalents) was added dropwise over approximately 1 hour while maintaining the reaction temperature below 10°C. The pH of the aqueous phase was approximately 2. The phases were separated, and the organic phase was then concentrated to a minimum volume to remove most of the 2-MeTHF (40°C / 150–70 Torr). The reaction mixture was ready for the next step without further treatment.

[0219] Step 12: ( S )-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidone-1-yl)-6-bromo -N Synthesis of -((6-fluoropyridin-2-yl)sulfonyl)nicotinamide The previous step yielded (containing) S A concentrate of benzoic acid was diluted with CH3CN (6.56 L; 6 volume equivalents) and water (3.83 L; 2 volume equivalents), and then oxalic acid (508 g, 5.64 mol; 2.5 volume equivalents) was added. The resulting solution was heated at 60 °C until the reaction was complete (at least about 4 hours). The solution was cooled to 0–10 °C, and then a solution of K2CO3 (2.18 kg, 15.8 mol; 7 volume equivalents) in water (3.83 L; 3.5 volume equivalents) was added dropwise while keeping the reaction temperature below 10 °C. The solid was collected by filtration. The moistened filter cake was washed sequentially with water (2 × 2.2 L; 2 volume equivalents) and i-PrOH (2 × 600 mL; 0.5 volume equivalents), air-dried by suction, and then vacuum-dried (50℃ / 30 Torr) to obtain ( S )-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidone-1-yl)-6-bromo- N -((6-Fluoropyridin-2-yl)sulfonyl)nicotinamide (959 g; total yield of three steps: 83%; >98% AUC) is a white fine powder. 1 H NMR (400 MHz, DMSO-d6) δ8.09 (q, J = 7.9 Hz, 1H), 7.83 (dd, J = 7.5, 2.2 Hz, 1H), 7.67 (s, 3H), 7.39 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 8.2, 2.4 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 3.20 -2.99 (m, 2H), 2.81 (td, J = 7.2, 4.7 Hz, 2H), 2.08 (dh, J = 15.3, 7.0 Hz, 1H), 1.84 (dd, J= 11.8, 5.7 Hz, 1H), 1.54 (q, J = 7.6 Hz, 2H), 1.48 (s, 3H), 1.47 (s,3H), 1.37 (t, J = 11.9 Hz, 1H), 1.26 (ddd, J = 29.1, 13.8, 7.4 Hz, 2H).

[0220] Step 13: (14) S 8-Bromo-12,12-Dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14 .0 5,10 Synthesis of tetracoc-1(23),5,7,9,19,21-hexane-2,2,4-trione Will( S )-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidone-1-yl)-6-bromo- N A mixture of 1,850 g (950 g, 1.85 mol) and Na₂CO₃ (392 g, 3.69 mol; 2 equivalences) in DMSO (7.60 L; 8 volume equivalents) was heated at 85 °C until the reaction was complete (approximately 6 hours). The suspension was cooled to <15 °C and diluted with MeTHF (19.0 L; 20 volume equivalents). Water (13.3 L) was added slowly while maintaining the reaction temperature <15 °C. 2 M HCl (4.62 L, 9.24 mol; 5 equivalences) (pH ~2) was added while maintaining the reaction temperature <15 °C. The phases were separated, and the organic phase was washed twice with water (9.50 L; 10 volume equivalents) containing NaCl (190 g; 2 wt%). The organic phase was concentrated to the minimum volume (45°C / 180 Torr), and then washed with i-PrOAc (2-3 × 500 mL) to remove MeTHF. The concentrate was backfilled with i-PrOAc (3.800 L; 4 volume equivalents) and stirred at 45°C until crystallization occurred. (If necessary, the mixture can be inoculated (14) S 8-Bromo-12,12-Dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14 .0 5,10[14-C-1(23),5,7,9,19,21-hexane-2,2,4-trione]. The suspension was aged by stirring for at least 30 minutes, and then cooled to 20°C. After aging at 20°C for at least 2 hours, the solid was collected by filtration. The filter cake was washed with 1:1 i-PrOAc / MTBE (500 mL), air-dried by suction, and then vacuum dried (40-55°C / <100 Torr / N2 purging) to obtain (14 S 8-Bromo-12,12-Dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14 .0 5,10 ] Twenty-tetracarbon-1(23),5,7,9,19,21-hexane-2,2,4-trione• 0.8 i-PrOAc (830 g; yield 78% after correction for i-PrOAc solvates) is a slightly yellowish white powder.

[0221] The filtrate was concentrated to approximately 400 mL to obtain a second batch of product. The mixture was then inoculated and aged at 15–20 °C. The solid was collected by filtration. The filter cake was washed sequentially with 1:1 i-PrOAc / MTBE (200 mL) and MTBE (100 mL), air-dried by suction, and then vacuum-dried (55 °C / <100 Torr / N2 purging) to give (14S)-8-bromo-12,12-dimethyl-2λ. 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14 .0 5,10 ] Ticos(23),5,7,9,19,21-hexane-2,2,4-trione • 0.67 i- PrOAc (113 g; corrected yield 11%) is a pale yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 9.13 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.4, 7.3 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.99(hept, J = 6.3 Hz, 1H), 4.57 (d, J= 8.8 Hz, 1H), 4.02 - 3.85 (m, 1H), 3.27 -3.09 (m, 2H), 2.96 (t, J = 10.2 Hz, 1H), 2.35 (p, J = 9.5 Hz, 1H), 2.02 (s, 3H), 1.95 (dd, J = 12.1, 6.7 Hz, 1H), 1.72 - 1.59 (m, 6H), 1.58 (s, 3H), 1.55 (s,3H), 1.43 (d, J = 40.1 Hz, 1H), 1.23 (d, J = 6.3 Hz, 5H).

[0222] Part B. Synthesis of the free form of Venzacatol A The reactor is equipped with a top stirrer, a reflux condenser, an N2 bubbling line and outlet, and a temperature probe. (14) S )-8-bromo-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.1] 11,14 .0 5,10 ] Ticoscar-1(23),5,7,9,19,21-hexane-2,2,4-trione (120 g 86% w / w IPAc [103.2 g (14 S 8-Bromo-12,12-Dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclic [17.3.1.1] 11,14 .0 5,10 [23),5,7,9,19,21-hexane-2,2,4-trione], 0.21 mol, 1 equivalent), 3-(2-(dispiro[2.0.2] 4 .1 3 [Heptane-7-yl)ethoxy)-1 H A mixture of pyrazole (42.6 g, 0.21 mol, 1 equivalent), 325 mesh K₂CO₃ (63.4 g, 0.46 mol, 2.2 equivalents), CuI (3.3 g, 17.2 mmol, 0.083 equivalents), and BuOAc (740 mL) was added to the reactor. The mixture was stirred at ambient temperature. Then, DMF (300 mL, 2.9 volume) and... N , N′-Dimethylcyclohexane-1,2-diamine (14.6 g or 16.2 ml, 0.1 mol, 0.49 equivalents) was added, and the mixture was purged with three N2 / vacuum / N2 cycles. The mixture was then heated to 120 °C and held for 4 hours, followed by cooling to ambient temperature. 10% w / v oxalic acid aqueous solution (860 mL, 0.96 mol, 4.6 equivalents) was added dropwise, and the mixture was stirred for at least 1 hour. The mixture was then filtered to remove the suspended solids. The removed solids were washed with (2 × 120 mL). The filtrate was separated into layers. The organic layer was washed with 8% w / v trisodium citrate aqueous solution (600 mL). If necessary, brine was added to promote phase separation. The organic layer was washed with 1:1 v / v water / brine (400 mL). The organic layer was filtered through a diatomaceous earth filter. The filter pad was washed with IPAc (150 mL). The filtrate was concentrated, and then 800 mL of 1-PrOH (7.8 v / v) was added, and the mixture was concentrated. This step was repeated once more. Toluene (800 mL) was added, and the mixture was concentrated. This step was repeated once more to obtain a thick slurry. The crude mixture was concentrated to 300 mL of toluene (2.9 v / v). The slurry was stirred overnight, and the solid was collected by filtration and washed with toluene (2 × 100 mL, 0.97 v / v). The solid was purged with nitrogen and dried under vacuum at 50 °C until the loss on drying did not exceed 1.0%, to give Venzacatol as a white / off-white solid (107.0 g, 83%, 94.5% (AUC) HPLC purity).

[0223] Recrystallization: Venzacator form A [22.2 g, 94.6% (AUC)] was suspended in toluene (440 mL, 20 volumes, based on Venzacator form A) and the mixture was heated to reflux. After maintaining reflux for 2 hours, the mixture was cooled to ambient temperature for 8 hours. After stirring overnight at ambient temperature, the solid was collected by filtration and washed with toluene (40 mL, 1.8 volumes). The solid was purged with nitrogen and dried under vacuum at 50 °C until the loss on drying did not exceed 1.0%, yielding Venzacator form A as a white / off-white solid (18.8 g, 84%, 96.8% (AUC) HPLC purity).

[0224] Second recrystallization: Venzacator form A [17.5 g, 97.0% (AUC) Venzacator form A] was suspended in toluene (350 mL, 20 volumes, based on Venzacator form A), and the mixture was heated to reflux. After maintaining reflux for at least 2 hours, the mixture was cooled to ambient temperature for 8 hours. After stirring overnight at ambient temperature, the solid was collected by filtration and washed with toluene (40 mL, 1.8 volumes). The solid was purged with nitrogen and dried under vacuum at 50 °C until the loss on drying did not exceed 1.0%, yielding Venzacator form A (free form) as a white / off-white solid (15.7 g, 89%, 98.4% (AUC) HPLC purity).

[0225] Part C. Venzacator calcium salt hydrate form A 0.2 mmol of free venzacator A and 0.1 mmol of dry Ca(OMe)₂ powder were added to IPA at approximately 45 mg / mL, followed by the addition of approximately 10% spiked water. The mixture was heated to 70 °C to prepare venzacator calcium hydrate form A. Initially, all solids dissolved. After 5 minutes, a white solid precipitated. The resulting slurry was stirred at room temperature for 4 days. The solid, venzacator calcium hydrate form A, was separated by vacuum filtration and vacuum dried overnight at 40 °C (approximately 78% separation yield).

[0226] An alternative method for preparing vanzacator calcium hydrate form A uses 10 g of free vanzacator A, 63 mL of IPA, and 7 mL of water. The slurry is heated to 55–65 °C. 1.1 equivalents of NaOH are added to the mixture. The mixture is stirred until homogeneous. The solution is then cooled to 25 °C, and 0.1 g of vanzacator sodium hydrate form A is added. The slurry is stirred for 18 hours. The solution is then heated to 45 °C. 0.1 g of vanzacator calcium hydrate form A is inoculated into the slurry. After 5 hours, a solution of 0.55 equivalents of CaCl2, 9 mL of IPA, and 1 mL of water is added. The resulting slurry is stirred for 2 hours. The slurry is cooled to 20 °C after 5 hours. The resulting solid is collected by vacuum filtration, and the resulting wet cake is washed with 50 mL of water. The washed wet cake is air-dried for 1 hour. The air-dried wet cake was transferred to a vacuum oven and dried at 45°C under slight nitrogen purging for 20 hours to obtain crystalline vanzacator calcium salt hydrate form A (8.5 g, 82% separation yield).

[0227] Part D. Synthesis of Venzacatol calcium salt hydrate form D Add 0.5 mL of EtOH:water 67:33 w / w to approximately 25 mg of vanzacator calcium hydrate form A. Heat the slurry to 65°C for 8 days. Collect the solid obtained by vacuum filtration as vanzacator calcium hydrate form D.

[0228] Alternatively, 89 g of vanzacator sodium hydrate form A was mixed with 1080 mL of IPA and 120 mL of water to prepare vanzacator calcium hydrate form D. The slurry was heated to 55-65°C. 18 g of vanzacator calcium hydrate form D seed crystals were added to the slurry. The slurry was wet-milled, and a solution of 0.55 equivalents of CaCl2, 81 mL of IPA, and 9 mL of water was added over 5 hours. Wet milling was continued until X-ray powder diffraction confirmed that the slurry was entirely composed of vanzacator calcium hydrate form D. The obtained solid was collected by vacuum filtration and the wet cake was washed with 350 mL of water. The washed wet cake was air-dried for 1 hour. The air-dried wet cake was transferred to a vacuum oven and dried at 45°C under slight nitrogen purging for 20 hours to obtain crystalline vanzacator calcium hydrate form D (83.15 g, 90.6% separation yield).

[0229] Example 2: ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H (-indole-5-yl)cyclopropaneformamide (tizacator) The synthesis of tizacalo is described in U.S. Patent Publication US 2009 / 0131492, which is incorporated herein by reference. The production of tizacalo solid dispersions is described in International Patent Publications WO 2011 / 119984 and WO2015 / 160787, the entire contents of which are incorporated herein by reference.

[0230] Step 1: ( R )-2-(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H -Indole-2-yl)-2-methylpropionate benzyl ester and (( S )-2-(1-((( R )-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H 2,2-Dimethyl-1,3-dioxacyclopentan-4-yl)methyl 2-indol-2-methylpropionic acid Cesium carbonate (8.23 g, 25.3 mmol) was added to 2-(6-fluoro-5-nitro-1- H(-indol-2-yl)-2-methylpropionate benzyl ester (3.0 g, 8.4 mmol) and (S)-4-methylbenzenesulfonic acid (2,2-dimethyl-1,3-dioxacyclopentan-4-yl) methyl ester (7.23 g, 25.3 mmol) in DMF ( N , N The mixture was added to a solution of 17 mL of dimethylformamide (-dimethylformamide). The reaction was stirred at 80 °C under a nitrogen atmosphere for 46 hours. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was a viscous brown oil containing both of the above products, which could be directly proceeded to the next step without further purification. R )-2-(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H Benzyl (-indol-2-yl)-2-methylpropionate, ESI-MS m / z Calculated value: 470.2; Measured value: 471.5 (M+1) + Retention time: 2.20 minutes. S )-2-(1-((( R )-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H 2,2-Dimethyl-1,3-dioxacyclopentan-4-yl)methyl 2-indol-2-methylpropionic acid, ESI-MS m / z Calculated value: 494.5; Measured value: 495.7 (M+1) + Retention time: 2.01 minutes.

[0231] Step 2: ( R )-2-(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H -indol-2-yl)-2-methylpropane-1-ol The crude reaction mixture obtained in step 1 was dissolved in THF (42 mL) and cooled in an ice-water bath. LiAlH4 (16.8 mL 1 M solution, 16.8 mmol) was added dropwise. After the addition was complete, the mixture was stirred for another 5 minutes. The reaction was quenched by adding water (1 mL), 15% NaOH solution (1 mL), and then water (3 mL). The mixture was filtered through diatomaceous earth, and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30%-60% ethyl acetate-hexane) to give a brown oily substance. R)-2-(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H (-Indol-2-yl)-2-methylpropane-1-ol (2.68 g, 2-step yield 87%). ESI-MS m / z Calculated value: 366.4; Measured value: 367.3 (M+1) + Retention time: 1.68 minutes. 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (d, J = 7.6Hz, 1H), 7.65 (d, J = 13.4 Hz, 1H), 6.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64-4.60 (m, 1H), 4.52-4.42 (m, 2H), 4.16-4.14 (m, 1H), 3.76-3.74 (m, 1H), 3.63-3.53 (m, 2H), 1.42 (s, 3H), 1.38-1.36 (m, 6H) and 1.19 (s, 3H) ppm. (DMSO is dimethyl sulfoxide).

[0232] Step 3: ( R )-2-(5-amino-1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-1 H -indol-2-yl)-2-methylpropane-1-ol Will( R )-2-(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-5-nitro-1 H (-Indol-2-yl)-2-methylpropane-1-ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL), and the reaction mixture was washed with N2. Pd-C (250 mg, 5% wt) was then added. The reaction mixture was washed again with nitrogen, and then stirred under H2 (atmosphere). After 2.5 hours, only partial conversion to the product was observed by LCMS. The reaction mixture was filtered through diatomaceous earth and concentrated. The residue was returned to the above conditions. After 2 hours, LCMS indicated complete conversion to the product. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated to yield the product (1.82 g, 79%). ESI-MS m / z Calculated value: 336.2; Measured value: 337.5 (M+1) +Retention time: 0.86 minutes. 1 H NMR (400 MHz, DMSO- d 6) δ 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J =9.0 Hz, 1H), 6.03 (s, 1H), 4.79 - 4.76 (m, 1H), 4.46 (s, 2H), 4.37 - 4.31 (m,3H), 4.06 (dd, J = 6.1, 8.3 Hz, 1H), 3.70 - 3.67 (m, 1H), 3.55 - 3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.

[0233] Step 4: ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1 H -indol-5-yl)cyclopropaneformamide Add 3 drops of DMF to 1-(2,2-difluorobenzo[] d [1,3]dioxacyclopenten-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol) were stirred together. After 1 hour, a clear solution was formed. The solution was concentrated under vacuum, and then toluene (3 mL) was added, and the mixture was concentrated again. The toluene step was repeated again, and the residue was placed under high vacuum for 10 minutes. The acyl chloride was then dissolved in dichloromethane (10 mL) and added to ( R )-2-(5-amino-1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-1 H (-indol-2-yl)-2-methylpropane-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in a mixture of dichloromethane (45 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 1N HCl solution, saturated NaHCO3 solution, and brine, dried over MgSO4, and concentrated to give the product (3 g, 100%). ESI-MS m / zCalculated value: 560.6; Measured value: 561.7 (M+1) + Retention time: 2.05 minutes. 1 H NMR (400 MHz, DMSO- d 6) δ 8.31 (s, 1H), 7.53 (s,1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m,1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz,1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m,6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm.

[0234] Step 5: ( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1 H (-indole-5-yl)cyclopropaneformamide (tizacator) Will( R )-1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)- N -(1-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1 H (-indol-5-yl)cyclopropaneformamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added, followed by p-TsOH·H2O (p-toluenesulfonic acid hydrate) (204 mg, 1.1 mmol). The reaction was heated at 80 °C for 45 min. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50%–100% ethyl acetate-hexane) to give the product (1.3 g, 47%, via SFC ee > 98%). ESI-MS m / zCalculated value: 520.5; Measured value: 521.7 (M+1) + Retention time: 1.69 minutes. 1 H NMR (400 MHz, DMSO- d 6) δ8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.38 (m, 2H), 7.33 - 7.30 (m, 2H), 6.22(s, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.40 (dd, J = 2.6, 15.1 Hz, 1H), 4.10 (dd, J = 8.7, 15.1 Hz, 1H), 3.90 (s,1H), 3.65 - 3.54 (m, 2H), 3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s,3H), 1.32 (s, 3H) and 1.14 - 1.11 (m, 2H) ppm.

[0235] Example 3: Preparation of amorphous tezaccato solid dispersions In a suitably sized container equipped with a magnetic stirrer and stirring plate, a solvent system of DCM and MeOH was prepared at a ratio of 80 wt% DCM / 20 wt% MeOH. Hydroxypropyl methylcellulose polymer (HPMC, E15 grade) and tizacatellol were added to this solvent system at a ratio of 20 wt% hydroxypropyl methylcellulose / 80 wt% tizacatellol. The resulting mixture contained 12.5 wt% solids. The table below lists the actual amounts of various components and solvents used to generate this mixture: Solid spray dispersion components for amorphous tezaccato:

[0236] Mix the mixture until it is substantially homogeneous and all components are substantially dissolved.

[0237] Anhydro MS-35 spray dryer equipped with two 0.8 mm fluid nozzles (Schlick series 970 / 0 S4) was used. Under normal spray drying mode, the drying spray process parameters were operated according to the table below.

[0238] Process parameters for generating amorphous tezacator solid spray dispersion:

[0239] A high-efficiency cyclone separator separates the wet product from the spray gas and solvent vapor. The wet product is then transferred to a tray and placed in a vacuum dryer for drying to reduce residual solvent to a MeOH content of less than approximately 3000 ppm and a DCM content of less than 600 ppm, thereby producing an amorphous tizacato dry dispersion with a MeOH content of <0.02% and a DCM content of <0.06%.

[0240] Example 4: N Synthesis of -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deuterated evacarto) The synthesis of deuterated ivacalto is described in PCT Publication No. WO 2019 / 109021 and U.S. Patent No. 9,512,079, each of which is incorporated herein by reference.

[0241] Synthesis of deuterated ivacato Synthetic procedure for 4-(tert-butyl)benzene-2,6-d2-phenol-d Add 4-tert-butylphenol (14,503.2 g), K₂CO₃ (46.3 g), D₂O (1949 g, 1761 mL, 3.5 v / v), and MeOD (409 g, 503 mL, 1.0 v / v) to a 5 L round-bottom flask equipped with a top stirrer. Heat the mixture to reflux under a nitrogen atmosphere. Age the reaction mixture under reflux for 16 h. Cool the reaction mixture to room temperature and take a sample for conversion determination (%D incorporation). Cool the reaction to 5 °C and add 35% DCl solution (90 g, 71.2 mL). Age the reaction mixture at 5 °C for 2 h. Filter the resulting slurry and wash the filter cake with D₂O (836 g, 755 mL, 1.5 v / v). Repeat this process until the target %D incorporation is achieved (usually requiring two exchanges). Dry the wet cake in a vacuum oven at 40 °C with nitrogen percolation until constant weight is obtained. 4-(tert-butyl)benzene-2,6-d2-phenol-d ( 19 The yield was 506 g of white solid (98%) with a purity of 99.6% and a D doping percentage of 99.3%.

[0242] Synthetic procedures for 4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenol-6-d-phenol-d and 4-(tert-butyl)-2,6-bis(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenol-d 4-(tert-butyl)benzene-2,6- d 2-Phenol-d (101.8 g, 0.66 mol, 1.0 equivalent) was dissolved in DCM (400 mL) in a 2 L reactor. Tert-butanol-d... 10 (43.0 g, 0.51 mol, 0.77 equivalent) DCM was dissolved in 100 mL of DCM in a 250 mL flask. The tert-butanol-d6 solution was added to a 2 L reactor at room temperature. The reaction mixture was cooled to -5 °C. D2SO4 (51.1 g, 0.51 mol, 0.77 equivalent) was added dropwise through a feeding funnel while maintaining a temperature range of -4 °C to -2 °C. The reaction mixture was stirred at -2 °C for 3–4 hours. After complete conversion, the reaction was quenched by adding water (28 mL) and warmed to 18 °C–20 °C. The bottom aqueous layer was drained and discarded. The DCM layer was treated with a saturated aqueous solution of NaHCO3 (approximately 200 mL) to adjust the pH to 6–8. A saturated NaCl solution (400 mL) was added to the mixture. The resulting solution was stirred for 5 min and allowed to stand for 5 min. The lower DCM layer was drained into a 1 L flask. The aqueous layer was discarded. Concentrate the DCM solution to the minimum volume and add n-heptane (200 mL). Concentrate the solution to the minimum volume and add n-heptane to a final volume of 800 mL. Add 600 mL (6 volumes) of 0.5 N NaOH solution to the reactor, stir the resulting mixture for 5 min, and let it stand for at least 5 min. Discard the aqueous layer. Add 300 mL (3 volumes) of 1.0 N NaOH solution to the reactor, stir the resulting mixture for 5 min, and let it stand for at least 5 min. Discard the aqueous layer. Add 300 mL (3 volumes) of 1.0 N NaOH solution to the reactor, stir the resulting mixture for 5 min, and let it stand for at least 5 min. Discard the aqueous layer. Concentrate the remaining n-heptane solution to dryness to give the desired product 4-(tert-butyl)-2-(2-(methyl- d 3) Propan-2-yl-1,1,1,3,3,3- d 6) Benzene-6-d-phenol-d (18), a clear oily substance, 104.5 g, which proceeds to the next step without further purification.

[0243] Synthetic procedure for 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenol 4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3- d 6) Benzene-6-d-phenol-d (100 g, 0.462 mol, 1.0 equivalent) was dissolved in DCM (800 mL, 7 volumes) in a 2 L reactor, and the solution was stirred. The batch was cooled to 0 ± 3 °C. After 30 minutes, the following were added in portions to the batch: N 1-Bromosuccinimide (84.4 g, 0.462 mol, 1.0 equivalent). Stir the batch at 0 ± 2 °C for at least 30 minutes. Then heat the batch to 20 ± 2 °C over 2 hours and stir at 20 ± 2 °C for at least 12 hours. After complete conversion, add saturated aqueous solution of NaHCO3 (500 mL, 5 volumes) and stir the batch for at least 10 minutes. Stop stirring to allow phase separation for at least 5 minutes, and remove the DCM layer, then remove the aqueous layer. Add the DCM layer back to the container. Add saturated aqueous solution of NaHCO3 (500 mL, 5 volumes) to the batch and stir the batch for at least 10 minutes. Stop stirring to allow phase separation for at least 5 minutes, and remove the DCM layer, then remove the aqueous layer. Add the DCM layer back to the container and dilute with additional DCM (300 mL, 3 volumes). Distill the batch (removing 300 mL) and check for dryness by KF test. The resulting clear yellow solution of 17 was proceeded to the next step without further purification.

[0244] Synthetic procedure for 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenylmethyl carbonate Add a solution of 4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)benzene-6-d-phenol-d (136 g, 0.462 mol, 1.0 equivalent) in DCM to a clean reactor, then add another 130 mL of DCM and stir the solution. Add 4-(dimethylamino)pyridine (2.8 g, 0.023 mol, 0.05 equivalent) and triethylamine (70.1 g, 0.693 mol, 1.5 equivalent) to the batch. Cool the batch to 0 ± 3 °C. Add methyl chloroformate (48.0 g, 0.508 mol, 1.1 equivalent) dropwise to the batch over 40 minutes, while maintaining the batch temperature < 5 °C. Stir the batch at 3±2°C for at least 30 minutes, and then warm it to 20±2°C for 1 hour. After complete conversion, load 1 N HCl (400 mL, 3 volumes). Stir the batch for at least 10 minutes, and then allow the layers to separate for at least 5 minutes. Discard the lower organic layer, and then discharge the aqueous layer (first aqueous layer). Add the organic layer back to the reactor with 1 N HCl solution (400 mL, 3 volumes). Stir the batch for at least 10 minutes, and then allow the layers to separate for at least 5 minutes. Discard the lower organic layer. Add the first aqueous layer back to the reactor with DCM (300 mL, 2.2 volumes). Stir the batch for at least 10 minutes, and then allow the layers to separate for at least 5 minutes. Discard the lower organic layer and combine it with the first organic layer, and then remove the aqueous layer. Add the contents of both organic layers to the container. Load water (500 mL, 3.7 volumes) into the reactor. Stir the batch for at least 10 minutes, and then allow the layers to separate for at least 5 minutes. The lower organic layer was drained, followed by the aqueous layer. The organic layer was added back into the reactor along with DCM (400 mL, 3 volumes). The batch was distilled to remove 800 mL and checked for dryness by KF. The resulting clear yellow solution of 16 was compressed to the next step without further purification.

[0245] Synthetic procedure for 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)-3-nitrophenylmethyl carbonate 2-Bromo-4-(tert-butyl)-6-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenylmethyl carbonate was added to the reactor, and the solution was then cooled to 0°C. Sulfuric acid (4.9 equivalents) and nitric acid (100%, 2.0 equivalents) were added, while maintaining the temperature above 5°C. The reactants were stirred at 0°C for 2 hours until complete conversion. The reaction was then quenched with water (8.8 v / v) and diluted with DCM (1.7 v / v). The layers were separated, and the upper aqueous layer was extracted with DCM (2.8 v / v). After separation, the organic layers were combined, returned to the reactor, and washed with sodium bicarbonate (7.4% w / w, 6.8 v / v). After separation, the organic layers were returned to the reactor and washed with sodium chloride (23% w / w, 3.8 v / v). After separation, the organic layers were returned to the reactor and concentrated to the minimum volume. Add methanol (1.2 volume) and then concentrate to the minimum volume. Add methanol (1.2 volume) and then concentrate to the minimum volume. Add methanol (1.7 volume) and heat the slurry to reflux for 30 minutes, and then slowly cool to 5°C over 4 hours. Filter the solid product (15) and wash the filter cake with cold methanol (1.0 volume). Dry the solid 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)-3-nitrophenylmethyl carbonate (15) under vacuum at 40-50°C to give a grayish-white solid with a purity of 99.9% and a D doping of 99%.

[0246] Synthetic procedure for 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenylmethyl carbonate Add 5 wt% (50-65 wt% wet, JM type 37) of 5% Pd / C to the reactor. Add (4.0 volume) methanol. Shut down the system. Add N at 2.0 bar. 2(g) Purge. Use H at 2.0 bar. 2(g) Activation. At 25℃ ± 5℃, fill the container with H₂. 2(g) To 2.0 bar. Stir for at least 2 hours while maintaining a temperature of 25°C ± 5°C. Charge with 2.0 bar of N2. (g) Then purge. Add compound 15 (1.0 equivalent) and Na2HPO4 (2.3 equivalent) to the reactor. Add (11.0 volume) methanol. Shut down the system. Add N2HPO4 at 2.0 bar. 2(g) Purge. Use H at 2.0 bar. 2(g) Activation. At 25℃ ± 5℃, H₂ is introduced into the container. 2(g)To 2.0 bar. Stir for approximately 24 hours while maintaining the reaction temperature at 25°C ± 5°C. After complete conversion, add 7.7 volumes of MeOH to dilute the reaction mixture. Heat the reaction mixture to 35.0°C ± 5°C. Filter out the catalyst and Na₂HPO₄. Wash the reactor and filter cake with methanol (4.0 volumes) and filter, combining with the initial filtrate. Check the Pd content and, if necessary, perform resin treatment (resin treatment is: add SPM-32 resin (5 wt%). Stir the resin-treated solution at 35.0°C ± 5°C for at least 3 hours. Filter off the resin.) Wash the reactor and filter cake with methanol (2.0 volume) and filter, combining the results with the initial filtrate. Add NoritCASP activated carbon (3 wt%). Stir at 35.0 °C ± 5 °C for at least 3 hours. Filter off the activated carbon. Wash the reactor and filter cake with methanol (2.0 volume) and filter, combining the results with the initial filtrate. Distill under vacuum at no more than 50 °C to 8.0 volume. Add water (2.0 volume) while maintaining the temperature at 45 °C ± 5 °C. Cool the resulting slurry to 0 °C ± 5 °C over 2 hours. Maintain the slurry at 0 °C ± 5 °C and stir for at least 1 hour. Filter and wash the filter cake with 2.0 volume of methanol / water (8:2) at 0 °C ± 5 °C. 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenylmethyl carbonate (7) was dried under vacuum at no more than 40 °C to give a white solid with a purity >99.5%.

[0247] Synthetic procedure for 4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-formylamino)phenylmethyl carbonate The method for converting compound 7 into compound 8 can be carried out in a similar manner to that for compound 5 in Example 1 of PCT Publication No. WO 2019 / 109021.

[0248] N Synthetic Procedure for -(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deuterated evacartole) The procedure for converting 4-(tert-butyl)-2-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carbamoyl)phenylmethyl carbonate to deuterated ivacato may be performed in a similar manner to the synthesis of compound 1 in Example 1 of PCT Publication No. WO2019 / 109021.

[0249] Example 5: Preparation of deuterated ivacartosol solid dispersions Solid dispersions of non-deuterated analogues of deuterated ivacarto (ivacarto) and methods for preparing such dispersions are disclosed in PCT Publication No. WO 2007 / 079139, which is incorporated herein by reference. These same solid dispersions are suitable for use with deuterated ivacarto. Alternatively, spray-dried dispersions of deuterated ivacarto can be prepared using the following methods.

[0250] A mixture of deuterated ivacartole, HPMCAS, and SLS (80 wt% deuterated ivacartole / 19.5 wt% HPMCAS / 0.5 wt% SLS) was dissolved in a methyl ethyl ketone / water mixture to obtain a total solids loading of 11%. The resulting solution was spray-dried using a Buchner spray dryer under the following conditions: Nozzle diameter: 1.52 mm Outlet temperature: NOR: 50 – 60℃ DSL: 40 – 70℃ Condenser temperature: NOR: -5.5 – 0℃ DSL: -5.5 – 5.5℃ The obtained wet spray-dried dispersion was further dried under the following conditions to obtain a deuterated ivacatol spray-dried dispersion.

[0251] Jacket inlet temperature: NOR: Hold at ≤ 80℃ for 2 hours, then at ≤ 110℃ for ≤ 4 days DSL: Keep at ≤ 80℃ for 2 hours, then at ≤ 110℃ for ≤ 11 days, or at ≤ 120℃ for ≤ 1 day. Nitrogen flow rate (NOR: 2.5 – 8.0 m) 3 / hr; Range: 2.5 – 8.0 m 3 / hr) Vacuum pressure (NOR: ≤ -0.90 gauge pressure; range: ≤ -0.80 gauge pressure) Example 6: Preparation of Exemplary Formulation 1 Formulation 1

[0252] a Tezactor SDD composition: 80 / 20 wt% tezactor / HPMC b Deuterated Ivacartole SDD composition: 80 / 19.5 / 0.5 wt% Deuterated Ivacartole / HPMCAS / SLS Venzacator calcium hydrate form D, tizacator SDD, deuterated ivacato SDD, colloidal silica, and sucralose were weighed, sieved, and blended. Lactose monohydrate, mannitol, and cross-linked carboxymethyl cellulose were weighed, sieved, and blended separately. The two mixtures were then blended together. Magnesium stearate was weighed, sieved, and then blended with the resulting mixture. The resulting blend was then compressed into granules, which were filled into HPMC capsules / capsules, and finally packaged. The target weight of each granule was 7.0 mg, and the average target weight of ten granules was 70.0 mg.

[0253] Example 7: Preparation of Exemplary Formulation 2

[0254] c Tezactor SDD composition: 80 / 20 wt% tezactor / HPMC d Deuterated Ivacartole SDD composition: 80 / 19.5 / 0.5 wt% Deuterated Ivacartole / HPMCAS / SLS Particles were prepared according to the procedure in Example 6.

[0255] Example 8: Preparation of Exemplary Formulation 3

[0256] e Tezactor SDD composition: 80 / 20 wt% tezactor / HPMC f Deuterated Ivacartole SDD composition: 80 / 19.5 / 0.5 wt% Deuterated Ivacartole / HPMCAS / SLS Particles were prepared according to the procedure in Example 6.

Claims

1. A pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each of the particles comprises: a. Crystalline Vanzacator calcium salt hydrate form D; b. A solid dispersion comprising amorphous tezacator and a first polymer; c. Solid dispersions containing amorphous deuterated ivacartoel and a second polymer; d. One or more fillers; e. Disintegrants; f. Sweeteners; g. Flow aids; and h. Lubricant; and The unit dosage form comprises crystalline venzacator calcium salt hydrate form D in amounts ranging from about 1 mg to about 12.7 mg, amorphous tezacator in amounts ranging from about 10 mg to about 50 mg, and amorphous deuterated ivacathoator in amounts ranging from about 15 mg to about 150 mg.

2. The pharmaceutical composition of claim 1, wherein the unit dosage form comprises about 4.2 mg of crystalline venzacator calcium hydrate form D, about 16 mg of amorphous tezacator, and about 50 mg of amorphous deuterated ivacathoter.

3. The pharmaceutical composition of claim 1, wherein the unit dosage form comprises about 6.4 mg of crystalline venzacator calcium hydrate form D, about 24 mg of amorphous tezacator, and about 75 mg of amorphous deuterated ivacathoter.

4. The pharmaceutical composition of claim 1, wherein the unit dosage form comprises about 8.5 mg of crystalline venzacator calcium hydrate form D, about 32 mg of amorphous tezacator, and about 100 mg of amorphous deuterated ivacathoter.

5. The pharmaceutical composition of claim 1, wherein the unit dosage form comprises about 12.7 mg of crystalline venzacator calcium hydrate form D, about 48 mg of amorphous tezacator, and about 150 mg of amorphous deuterated ivacathoter.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the first polymer in the solid dispersion containing tezacotto is HPMC.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the second polymer in the solid dispersion comprising deuterated ivacastor is HPMCAS.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the solid dispersion comprising tezacotto and the first polymer comprises about 80% amorphous tezacotto and about 20% HPMC by weight of the dispersion.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the solid dispersion comprising deuterated ivacarto and the second polymer comprises about 80% amorphous deuterated ivacarto by weight of the dispersion, about 19.5% HPMCAS by weight of the dispersion, and about 0.5% SLS by weight of the dispersion.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the one or more fillers comprise mannitol.

11. The pharmaceutical composition of claim 10, wherein the mannitol is present in an amount of about 10% to about 14% by weight of the composition.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the one or more fillers comprise lactose.

13. The pharmaceutical composition of claim 12, wherein the lactose is present in an amount of about 35% to about 40% by weight of the composition.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the filler is a binary filler comprising mannitol and lactose.

15. The pharmaceutical composition of claim 14, wherein the binary filler comprises mannitol and lactose in a weight ratio selected from: 1:about 5, 1:about 4, 1:about 3, 1:about 2, and 1:about 1.

5.

16. The pharmaceutical composition of claim 14, wherein the binary filler comprises mannitol and lactose in a weight ratio of 1:about 3.

17. The pharmaceutical composition of claim 14, wherein the binary filler comprises mannitol and lactose in a weight ratio selected from 1:5, 1:4, 1:3, 1:2, and 1:1.

5.

18. The pharmaceutical composition of claim 14, wherein the binary filler comprises mannitol and lactose in a weight ratio of 1:

3.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the disintegrant is croscarmellose sodium.

20. The pharmaceutical composition of claim 19, wherein the croscarmellose sodium is present in an amount of about 6% by weight of the pharmaceutical composition.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the sweetener is sucralose.

22. The pharmaceutical composition of claim 21, wherein the sucralose is present in an amount of about 1% to about 2% by weight of the pharmaceutical composition.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the lubricant is magnesium stearate.

24. The pharmaceutical composition of claim 23, wherein the magnesium stearate is present in an amount of about 0.5% to about 2.0% by weight of the composition.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the flow aid is colloidal silica.

26. The pharmaceutical composition of claim 25, wherein the colloidal silica is present in an amount of about 0.5% to about 1.5% by weight of the composition.

27. A pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each of the particles comprises: a. About 1% to about 3% by weight of the composition in the form of crystalline Vanzacator calcium salt hydrate D, b. A solid dispersion comprising about 8% to about 11% by weight of the composition, wherein the solid dispersion comprises about 80% amorphous tizacalo and about 20% HPMC by weight of the solid dispersion. c. A solid dispersion comprising about 25% to about 35% by weight of the composition, wherein the solid dispersion comprises about 80% amorphous deuterated ivacatol, about 19.5% HPMCAS, and about 0.5% SLS by weight of the solid dispersion. d. Mannitol, comprising about 10% to about 14% by weight of the composition. e. Lactose, comprising about 30% to about 40% by weight of the composition. f. Sucralose, at about 1.5% to about 2.5% by weight of the composition. g. About 5% to about 7% of croscarmellose sodium based on the weight of the composition. h. about 0.5% to about 1.5% of colloidal silica based on the weight of the composition, and i. Magnesium stearate, about 0.5% to about 2.0% by weight of the composition.

28. The pharmaceutical composition of claim 27, wherein the mannitol and lactose are present in a ratio of 1:about 3 by weight.

29. The pharmaceutical composition of claim 27, comprising: a. Approximately 2% by weight of the crystalline vanzacator calcium salt in the form of hydrate D, b. About 9.5% by weight of the composition, wherein the solid dispersion comprises about 80% amorphous tizacalo and about 20% HPMC by weight of the solid dispersion. c. About 29.8% by weight of the composition of the solid dispersion, wherein the solid dispersion comprises about 80% by weight of amorphous deuterated ivacatrol, about 19.5% by weight of HPMCAS, and about 0.5% by weight of SLS. d. About 12.1% mannitol based on the weight of the composition. e. Approximately 36.3% lactose by weight of the composition. f. Approximately 2.3% sucralose by weight of the composition. g. About 6% croscarmellose sodium based on the weight of the composition, h. About 1% colloidal silica by weight of the composition, and i. About 1% magnesium stearate by weight of the composition.

30. A pharmaceutical composition formulated into a unit dosage form comprising a plurality of particles, wherein each of the particles comprises: j. About 1% to about 3% by weight of the composition in the form of crystalline Vanzacator calcium salt hydrate D, k. A solid dispersion comprising about 8% to about 11% by weight of the composition, wherein the solid dispersion comprises 80% amorphous tizacalo and 20% HPMC by weight of the solid dispersion.

1. A solid dispersion comprising about 25% to about 35% by weight of the composition, wherein the solid dispersion comprises 80% amorphous deuterated ivacarbide, 19.5% HPMCAS, and 0.5% SLS by weight of the solid dispersion. m. Mannitol, comprising about 10% to about 14% by weight of the composition. n. about 30% to about 40% lactose by weight of the composition. o. Sucralose, comprising about 1.5% to about 2.5% by weight of the composition. p. About 5% to about 7% of croscarmellose sodium based on the weight of the composition. q. about 0.5% to about 1.5% of colloidal silica based on the weight of the composition, and r. about 0.5% to about 2.0% magnesium stearate based on the weight of the composition.

31. The pharmaceutical composition of claim 30, wherein the mannitol and lactose are present in a ratio of 1:3 by weight.

32. The pharmaceutical composition of claim 30, comprising: j. Approximately 2% by weight of the crystalline vanzacator calcium salt in the form of hydrate D, k. About 9.5% by weight of the composition of the solid dispersion, wherein the solid dispersion comprises 80% amorphous tizacatour and 20% HPMC by weight of the solid dispersion.

1. About 29.8% by weight of the composition of the solid dispersion, wherein the solid dispersion comprises 80% by weight of amorphous deuterated ivacarbide, 19.5% by weight of HPMCAS and 0.5% by weight of SLS. m. about 12.1% mannitol by weight of the composition. n. Approximately 36.3% lactose by weight of the composition. o. Approximately 2.3% sucralose by weight of the composition, p. About 6% croscarmellose sodium based on the weight of the composition, q. About 1% colloidal silica by weight of the composition, and r. About 1% magnesium stearate by weight of the composition.

33. The pharmaceutical composition of any one of claims 25 to 32, wherein the unit dosage form comprises about 0.1 to about 12.7 mg of crystalline venzacator calcium salt hydrate form D, about 10 to about 50 mg of amorphous tezacator, and about 15 to 150 mg of amorphous deuterated ivacathoter.

34. The pharmaceutical composition of any one of claims 27 to 33, wherein the unit dosage form comprises about 4.2 mg of crystalline venzacator calcium hydrate form D, about 16 mg of amorphous tezacator, and about 50 mg of amorphous deuterated ivacathoter.

35. The pharmaceutical composition of any one of claims 27 to 33, wherein the unit dosage form comprises about 6.4 mg of crystalline venzacator calcium hydrate form D, about 24 mg of amorphous tezacator, and about 75 mg of amorphous deuterated ivacathoter.

36. The pharmaceutical composition of any one of claims 27 to 33, wherein the unit dosage form comprises about 8.5 mg of crystalline venzacator calcium hydrate form D, about 32 mg of amorphous tezacator, and about 100 mg of amorphous deuterated ivacathoter.

37. The pharmaceutical composition of any one of claims 27 to 33, wherein the unit dosage form comprises about 12.7 mg of crystalline venzacator calcium hydrate form D, about 48 mg of amorphous tezacator, and about 150 mg of amorphous deuterated ivacathoter.

38. The pharmaceutical composition of any one of claims 1 to 37, wherein the unit dose form comprises from about 18 to about 60 particles.

39. The pharmaceutical composition of any one of claims 1 to 38, wherein the unit dose form comprises about 30 particles.

40. The pharmaceutical composition of any one of claims 1 to 39, wherein the shape of the particles is cylindrical, oval, conical, spherical, elliptical, polygonal, or a combination thereof, wherein the longest dimension or diameter of the particles is about 2 mm.

41. A method for treating or reducing the severity of a CFTR-mediated disease in a pediatric patient, the method comprising administering to the pediatric patient a pharmaceutical composition as described in any one of claims 1 to 40.

42. The method of claim 41, wherein the CFTR-mediated disease is cystic fibrosis.

43. The method of claim 41 or claim 42, wherein the pharmaceutical composition of any one of claims 1 to 40 is administered once daily.

44. The method of any one of claims 41 to 43, wherein the patient weighs about 14 kg or more.

45. The method of any one of claims 41 to 43, wherein the patient weighs less than about 14 kg.

46. ​​The method of any one of claims 41 to 45, wherein the patient has at least one mutation selected from Table 1.

47. The method of any one of claims 41 to 45, wherein the patient's CFTR The F508del mutation of the gene is homozygous.

48. The method of any one of claims 41 to 45, wherein the patient has a heterozygous CFTR genotype and has an F508del mutation.

49. The pharmaceutical composition of any one of claims 1 to 40, for use in treating CFTR-mediated diseases in pediatric patients or reducing their severity.

50. The pharmaceutical composition used in claim 49, wherein the CFTR-mediated disease is cystic fibrosis.

51. The pharmaceutical composition used as claimed in claim 49 or claim 50, wherein the pharmaceutical composition is administered once daily.

52. The pharmaceutical composition used in any one of claims 49 to 51, wherein the patient weighs about 14 kg or more.

53. The pharmaceutical composition used in any one of claims 49 to 51, wherein the patient weighs less than 14 kg.

54. The pharmaceutical composition used in any one of claims 49 to 53, wherein the patient has at least one mutation selected from Table 1.

55. The pharmaceutical composition used in any one of claims 49 to 53, wherein the patient's... CFTR The F508del mutation of the gene is homozygous.

56. The pharmaceutical composition used in any one of claims 49 to 53, wherein the patient has a heterozygous CFTR genotype and has an F508del mutation.

57. The pharmaceutical composition of any one of claims 1 to 40, used to manufacture a medicament for treating or reducing the severity of CFTR-mediated diseases in pediatric patients.

58. The pharmaceutical composition used in claim 57, wherein the CFTR-mediated disease is cystic fibrosis.

59. The pharmaceutical composition used as claimed in claim 57 or claim 58, wherein the pharmaceutical composition is administered once daily.

60. The pharmaceutical composition used in any one of claims 57 to 59, wherein the patient weighs about 14 kg or more.

61. The pharmaceutical composition used in any one of claims 57 to 59, wherein the patient weighs less than 14 kg.

62. The pharmaceutical composition used in any one of claims 57 to 61, wherein the patient has at least one mutation selected from Table 1.

63. The pharmaceutical composition used in any one of claims 57 to 61, wherein the patient's... CFTR The F508del mutation of the gene is homozygous.

64. The pharmaceutical composition used in any one of claims 57 to 61, wherein the patient has a heterozygous CFTR genotype and has an F508del mutation.

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