Formulations for use in modulating RNA splicing and methods of making and using the same

Abstract

Described herein is a pharmaceutical composition comprising a small molecule splicing modulator compound that modulates splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.

Description

WSGR Docket No. 51503-780.601FORMULATIONS FOR USE IN MODULATING RNA SPLICING AND METHODS OF MAKING AND USING THE SAMECROSS REFERENCE

[0001] This application claims the benefit of priority to U. S. Provisional Application No. 63 / 740,976, filed December 31, 2024, which is incorporated herein by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 5, 2025, is named 51503-780_601_SL.xml and is 1,796 bytes in size.BACKGROUND

[0003] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing.

[0004] Small molecule splicing modulators (SMSMs) overcome many of the problems associated with therapies such as oligonucleotide technologies (antisense, RNA interference, etc.), including lack of oral bioavailability, and lack of blood-brain-barrier penetration, with the latter precluding delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancers, etc.).

[0005] The stability of a drug is a crucial aspect of drug development, as it directly impacts the efficacy and safety of the drug. Therefore, there remains a need of solid form formulations that comprise SMSMs.SUMMARY

[0006] In one aspect, disclosed herein is a pharmaceutical composition comprising an SMSM or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises an ASD formulation. In some embodiments, the pharmaceutical composition comprises an SDI formulation.

[0007] Provided in some embodiments herein is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier, wherein the compound is 6-(6-((2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol, wherein the pharmaceutical composition is in a solid dosage form. In some embodiments, the compound has a structure of (Compound B). InWSGR Docket No. 51503-780.601some embodiments, the compound is 6-(6-(((lR,2R,3S,5S)-2-Fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5-ol.

[0008] Provided in some embodiments herein is a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, the pharmaceutically acceptable excipient or carrier comprising a polymer. In some embodiment, the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises the Compound B and a polymer. In some embodiments, the ASD is a Spray Dry Intermediate (SDI). In some embodiments, the pharmaceutical composition comprises a Spray Dry Intermediate (SDI), and wherein the SDI comprises the Compound B and a polymer. In some embodiments, the polymer is a copolymer. In some embodiments, the polymer is an anionic polymer. In some embodiments, the polymer is a cationic polymer. In some embodiments, the polymer is an acidic polymer. In some embodiments, the polymer is a neutral polymer.

[0009] In some embodiments, the polymer comprises polyvinylpyrrolidone (PVP K30), polyvinylpyrrolidone-co-vinyl acetate (PVP-VA64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam -polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), methacrylic acid-methyl methacrylate copolymer (Eudragit LI 00), methacrylic acid -ethyl acrylate copolymer (Eudragit L100-55), or a combination thereof. In some embodiments, the polymer is selected from the group consisting of PVP-VA64, HPMC, HPMCP, and methacrylic acid-ethyl acrylate copolymer. In some embodiments, the polymer is selected from the group consisting of PVP-VA64 and HPMC.

[0010] In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 1:99 to about 50:50. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 10:90 to about 30:70. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 20:80.

[0011] In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer in an amorphous state.

[0012] In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 5% to 50% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 10% to 30% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 15% to 25% by weight.

[0013] In some embodiments, the composition comprises a core-shell structure.

[0014] In some embodiments, the core comprises the ADS or SDI. In some embodiments, the ASD or SDI is present in the core in an amount of about 5% to 40% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 5% to 35% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 10% to 30% by weight. In some embodiments,WSGR Docket No. 51503-780.601the ASD or SDI is present in the core in an amount of about 15% to 25% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 20% by weight.

[0015] In some embodiments, the core further comprises a binder, a filler, a glidant, a lubricant, or a combination thereof.

[0016] In some embodiments, the binder comprises a polymer. In some embodiments, the binder comprises crospovidone (e.g., Kollidon CL). In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 1% to 15% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 2% to 10% by weight. In some embodiments, the binder is present in the core in an amount of about 1% to 15% by weight. In some embodiments, the binder is present in the core in an amount of about 2% to 8% by weight. In some embodiments, the filler comprises lactose, cellulose, sucrose, mannitol, starch, or a combination thereof.

[0017] In some embodiments, the filler comprises mannitol (e.g., mannitol M200 grade or mannitol Ml 00 grade). In some embodiments, the filler comprises calcium phosphate. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 30% to about 90%, about 40 wt% to about 90 wt%, about 50 wt% to about 80 wt%, or about 60 wt% to about 75 wt% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 40% to 70% by weight. In some embodiments, the filler is present in the core in an amount of about 30% to 90% by weight. In some embodiments, the filler is present in the core in an amount of about 40 wt% to about 90 wt%, about 50 wt% to about 80 wt%, or about 60 wt% to about 75 wt% by weight. In some embodiments, the filler is present in the core in an amount of about 50% to 75% by weight. In some embodiments, the filler is present in the core in an amount of about 65% to 75% by weight.

[0018] In some embodiments, the glidant comprises silicon dioxide (e.g., fumed silica). In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.1% to 5% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.5% to 2% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.1% to 5% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.5% to 1.5% by weight.

[0019] In some embodiments, the lubricant comprises talc, magnesium stearate, sodium stearyl fumarate, or a combination thereof. In some embodiments, the lubricant comprises sodium stearyl fumarate. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% to 2% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% to 1.5% by weight. In some embodiments, the lubricant is present in the core in an amount of about 0.1% to 2% by weight. In some embodiments, the lubricant is present in the core in an amount of about 0.5% to 1.5% by weight.

[0020] In some embodiments, the core comprises the ASD or SDI, mannitol, crospovidone, silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and sodium stearyl fumarate. In some embodiments, the core comprises about 20 wt% of the ASD or SDI, about 71 wt% mannitol (e.g., mannitol M200), about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidalWSGR Docket No. 51503-780.601silicon dioxide), and about 1 wt% sodium stearyl fumarate. In some embodiments, the core comprises about 20 wt% of the ASD or SDI, about 71 wt% mannitol, about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80. In some embodiments, the core comprises about 20 wt% of the ASD or SDI, about 71 wt% mannitol, about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer is selected from the group consisting of PVP-VA64 and HPMC (e.g., HPMC E3LV).

[0021] In some embodiments, the core comprises about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate. In some embodiments, the core comprises about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80. In some embodiments, the core comprises about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP-VA64, HPMC (e.g., HPMC E3LV) or a combination thereof.

[0022] In some embodiments, the core comprises over 85% by weight of the pharmaceutical composition. In some embodiments, wherein the core comprises about 90-97 % by weight of the pharmaceutical composition. In some embodiments, the shell comprises a protective layer and enteric coating.

[0023] In some embodiments, the shell comprises less than 15% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 5-10% by weight of the pharmaceutical composition.

[0024] In some embodiments, the core comprises an intragranular component and an extragranular component. In some embodiments, the core comprises the intragranular component in an amount of at least 50% by weight (wt%). In some embodiments, the core comprises the intragranular component in an amount of about 10 wt% to about 99 wt%. In some embodiments, the core comprises the intragranular component in an amount of about 55 wt% to about 95 wt%. In some embodiments, the core comprises the intragranular component in an amount of about 86 wt%.

[0025] In some embodiments, the core comprises the extragranular component in an amount of about 1 wt% to about 50 wt%. In some embodiments, the core comprises the extragranular component in an amount of about 5 wt% to about 25 wt%. In some embodiments, the core comprises the extragranular component in an amount of about 10 wt% to about 20 wt%. In some embodiments, the core comprises the extragranular component in an amount of about 14 wt%.WSGR Docket No. 51503-780.601

[0026] In some embodiments, the intragranular component comprises the ASD, a filler, a binder, a glidant, and a lubricant. In some embodiments, the intragranular component comprises the ASD, mannitol, crospovidone, silico dioxide (e.g., untreated fumed colloidal silicon dioxide), and sodium stearyl fumarate.

[0027] In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 60 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 60 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 60 wt% mannitol, about 4 wt% crospovidone, about 1 wt% silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV).

[0028] In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 60.5 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 60.5 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 60.5 wt% mannitol, about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV). In some embodiments, the intragranular component comprises about 23.3 wt% of the ASD, about 70.4 mannitol, about 4.7 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6% wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV). In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 64.5 wt% mannitol (e.g., mannitol M100), about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 64.5 wt% mannitol, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 64.5 wt% mannitol about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarateWSGR Docket No. 51503-780.601relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP VA64. In some embodiments, the intragranular component comprises about 22.7 wt% of the ASD, about 73.3 wt% mannitol, about 2.3 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6 wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP VA 64.

[0029] In some embodiments, the intragranular component comprises the ASD, mannitol, starch, crospovidone, silico dioxide (e.g., untreated fumed colloidal silicon dioxide), and sodium stearyl fumarate. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 45 wt% mannitol (e.g., mannitol M100), about 15 wt% starch (e.g., starch 1500), about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 45 wt% mannitol, about 15 wt% starch, about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 45 wt% mannitol, about 15 wt% starch, about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV). In some embodiments, the intragranular component comprises about 23.4 wt% of the ASD, about 52.7 wt% mannitol, about 17.6 wt% starch, about 4.7 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6 wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 48 wt% mannitol, about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core.

[0030] In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 48 wt% mannitol, about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80. In some embodiments, the intragranular component comprises about 20 wt% of the ASD, about 48 wt% mannitol, about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about:80, wherein the polymer comprises PVP VA64. In some embodiments, the intragranular component comprises about 22.9 wt% of the ASD, about 54.9 wt% mannitol M100, about 18.3 wt% starch 1500, about 2.3 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6 wt% sodium stearyl fumarate relative to the intragranularWSGR Docket No. 51503-780.601component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises PVP VA64.

[0031] In some embodiments, the extragranular component comprises at least a portion of the filler, at least a portion of the binder, at least portion of the glidant, at least a portion of the lubricant, or a combination thereof. In some embodiments, the extragranular component comprises a filler, a binder, and a lubricant. In some embodiments, the extragranular component comprises mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the extragranular component comprises about 10 wt% mannitol (e.g., mannitol M200), about 3.5 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the extragranular component comprises about 10 wt% mannitol, about 4 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the extragranular component comprises about 10 wt% mannitol, about 1.5 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the extragranular component comprises about 10 wt% mannitol, about 2 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core. In some embodiments, the extragranular component comprises about 9.5 wt% mannitol, about 4 wt% crospovidone, and about 1 wt% sodium stearyl fumarate relative to the core. In some embodiments, the extragranular component comprises about 71.4 wt% mannitol, about 25 wt% crospovidone, and about 3.6 wt% sodium stearyl fumarate based on the total weight of the extragranular component. In some embodiments, the extragranular component comprises about 69 wt% mannitol about 27.6 wt% crospovidone, and about 3.4 wt% sodium stearyl fumarate based on the total weight of the extragranular component. In some embodiments, the extragranular component comprises about 83.3 wt% mannitol, about 12.5 wt% crospovidone, and about 4.2 wt% sodium stearyl fumarate based on the total weight of the extragranular component. In some embodiments, the extragranular component comprises about 80 wt% mannitol, about 16 wt% crospovidone, and about 4 wt% sodium stearyl fumarate based on the total weight of the extragranular component. In some embodiments, the extragranular component comprises about 66 wt% mannitol, about 28 wt% crospovidone, and about 7 wt% sodium stearyl fumarate based on the total weight of the extragranular component.

[0032] In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises polyvinylpyrrolidone-co-vinyl acetate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), a methacrylate copolymer (such as methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer), or a combination thereof. In some embodiments, the pharmaceutical composition comprises a Spray Dry Intermediate (SDI), and wherein the SDI comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 50%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprisesWSGR Docket No. 51503-780.601polyvinylpyrrolidone-co-vinyl acetate. In some embodiments, the pharmaceutical composition comprises a Spray Dry Intermediate (SDI), and wherein the SDI comprises about 20% wt of the Compound B and 80% wt of polyvinylpyrrolidone-co-vinyl acetate. In some embodiments, the pharmaceutical composition comprises a Spray Dry Intermediate (SDI), and wherein the SDI comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises HPMC. In some embodiments, the pharmaceutical composition comprises a Spray Dry Intermediate (SDI), and wherein the SDI comprises about 20% wt of the Compound B and about 80% wt of HPMC.

[0033] In some embodiments, the pharmaceutical composition comprises a core and optionally a shell, wherein: the core comprises, by weight, about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 60-80% of mannitol, about 4-12% of crospovidone, about 0.5-2% of silicon dioxide, and about 0.5-2% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition.

[0034] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 71% of mannitol, about 7% of crospovidone, about 1% of silicon dioxide, and about 1% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 95% wt of the pharmaceutical composition.

[0035] In some embodiments, the pharmaceutical composition comprises a core and optionally a shell, wherein: the core comprises, by weight, about 10-40% of an ASD, wherein the ASD comprises about 10-40% of Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 60-90% of a polymer (such as HPMC); about 50-90% of a filler (such as mannitol); about 1-15% of a binder (such as crospovidone); about 0.1-5% of a glidant, and about 0.1-5% of a lubricant; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises over 80% wt of the pharmaceutical composition.

[0036] In some embodiments, the pharmaceutical composition comprises a core and optionally a shell, wherein: the core comprises, by weight, about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 65-85% of mannitol, about 1-5% of crospovidone, about 0.5-2% of silicon dioxide, and about 0.5-2% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition.

[0037] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 75% of mannitol, about 3% of crospovidone, about 1% of silicon dioxide, and about 1% of sodium stearyl fumarate; and the shellWSGR Docket No. 51503-780.601comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition.

[0038] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 70-71% (e.g., 70.5%) of mannitol, about 7-8% (e.g., 7.5%) of crospovidone, about 1% of silicon dioxide, and about 1% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition.

[0039] In some embodiments, the pharmaceutical composition comprises a core and optionally a shell, wherein: the core comprises, by weight, about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 45-65% of mannitol, about 5-25% of starch, about 4-12% of crospovidone, about 0.5-2% of silicon dioxide, and about 0.5-2% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition.

[0040] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 55% of mannitol, about 15% of starch, about 8% of crospovidone, about 1% of silicon dioxide, and about 1% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition.

[0041] In some embodiments, the pharmaceutical composition comprises a core and optionally a shell, wherein: the core comprises, by weight, about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 65-85% of mannitol, about 1-7% of crospovidone, about 0.5-2% of silicon dioxide, and about 0.5-2% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition.

[0042] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 74-75% (e.g., 74.5%) of mannitol, about 3-4% (e.g., 3.5%) of crospovidone, about 1% of silicon dioxide, and about 1% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition.

[0043] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 50-70% of mannitol, about 5-25% of starch, about 1-7% of crospovidone, about 0.5-2% of silicon dioxide, and about 0.5-2% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition.WSGR Docket No. 51503-780.601

[0044] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 58% of mannitol, about 16% of starch, about 4% of crospovidone, about 1% of silicon dioxide, and about 1% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition.

[0045] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 60-80% of mannitol, about 4-12% of crospovidone, about 0.5-2% of silicon dioxide, and about 0.5-3% of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition.

[0046] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 69-70% (e.g., 69.5%) of mannitol, about 8% of crospovidone, about 1% of silicon dioxide, and about 0.5-1.5 % (e.g., 0.5 % or 1.5%) of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition.

[0047] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein: the core comprises, by weight, about 20% of an SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC; about 69.5% of mannitol, about 8% of crospovidone, about 1% of silicon dioxide, and about 1.5 % of sodium stearyl fumarate; and the shell comprises a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt (e.g., about 92%) of the pharmaceutical composition.

[0048] In some embodiments, the pharmaceutical composition comprises a core and a shell, wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the core): about 20 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and wherein in the ASD is an SDI; about 60 wt% mannitol Ml 00; about 4 wt% crospovidone; about 1 wt% untreated fumed colloidal silicon dioxide; and about 0.5 wt% sodium stearyl fumarate; and wherein the intragranular component comprises (relative to the core): about 9.5 wt% mannitol M200; about 4 wt% crospovidone; about 1 wt% sodium stearyl fumarate.

[0049] In some embodiments, the shell comprises, relative to the pharmaceutical composition, about 0.5-5 wt% of a protective layer (e.g., a seal coat), optionally comprising polyvinyl alcohol (PVA), HPMC, or a combination thereof; and about 2-12 wt% of an enteric coating, optionally comprising polymethacrylate (e.g., L100-55 grade). In some embodiments, the shell comprises, relative to the pharmaceutical composition, about 1.5-2.5 wt% of a protective layer (e.g., a seal coat), optionally comprising polyvinyl alcohol (PVA), HPMC, or a combination thereof; and about 5-8 wt% of an entericWSGR Docket No. 51503-780.601coating, optionally comprising polymethacrylate (e.g., L100-55 grade). In some embodiments, the shell comprises, relative to the pharmaceutical composition, about 2 wt% of a protective layer (e.g., a seal coat), optionally comprising polyvinyl alcohol (PVA), HPMC, or a combination thereof; and about 7 wt% of an enteric coating, optionally comprising polymethacrylate L100-55 grade. In some embodiments, the protective layer (e.g., seal coat) comprises polyvinyl alcohol (PVA), HPMC, or a combination thereof, and wherein the enteric coating comprises a polymethacrylate copolymer (e.g., a copolymer of methacrylic acid).

[0050] In some embodiments, the pharmaceutical composition comprises a core comprising about 92% wt of the composition and a shell comprising about 8% wt of the composition, wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the pharmaceutical composition): about 18 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and wherein in the ASD is optionally an SDI; about 55 wt% mannitol (e.g., M100); about 3-4 wt% crospovidone; about 0.5-1 wt% untreated fumed colloidal silicon dioxide; and about 0.1-0.5 wt% sodium stearyl fumarate; and wherein the extragranular component comprises (relative to the pharmaceutical composition): about 9 wt% mannitol M200; about 3-4 wt% crospovidone; about 0.1 -0.5 wt% sodium stearyl fumarate; and wherein the shell comprises (relative to the pharmaceutical composition): about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6 wt% of an enteric coating comprising polymethacrylate L100-55 grade.

[0051] In some embodiments, the pharmaceutical composition comprises a core comprising about 92% wt of the composition and a shell comprising about 8% wt of the composition, wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the pharmaceutical composition): about 18 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and wherein in the ASD is an SDI; about 55 wt% mannitol (e.g., M100); about 3-4 wt% crospovidone; about 0.5-1 wt% untreated fumed colloidal silicon dioxide; and about 0.1-0.5 wt% sodium stearyl fumarate; and wherein the extragranular component comprises (relative to the pharmaceutical composition): about 9 wt% mannitol (e.g., M200); about 3-4 wt% crospovidone; about 0.5-1 wt% sodium stearyl fumarate; and wherein the shell comprises (relative to the pharmaceutical composition): about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6-7 wt% of an enteric coating comprising polymethacrylate (e.g., L 100-55 grade).

[0052] In some embodiments, the pharmaceutical composition comprises a core comprising about 91-92% wt of the composition and a shell comprising about 8-9% wt of the composition, wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the core): about 20 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and optionally wherein in the ASD is an SDI; about 60 wt% mannitol (e.g., M100); about 4 wt% crospovidone; about 1 wt% silicon dioxide; and aboutWSGR Docket No. 51503-780.6010.5 wt% sodium stearyl fumarate; and wherein the extragranular component comprises (relative to the core): about 9.5 wt% mannitol (e.g., M200); about 4 wt% crospovidone; about 1 wt% sodium stearyl fumarate; and wherein the shell comprises (relative to the pharmaceutical composition): about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6-7 wt% of an enteric coating comprising polymethacrylate (e.g., L100-55 grade).

[0053] In some embodiments, the pharmaceutical composition comprises about 0.1 to about 20 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 to about 15 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, wherein the pharmaceutical composition comprises about 1 to about 10 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 4 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 5 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 6 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 8 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises about 16 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0054] In some embodiments, the ASD or SDI has a glass transition temperature (Tg) of about 50 °C or greater at 0.0% relative humidity. In some embodiments, the ASD or SDI has Tgof about 75 °C or greater at 0.0% relative humidity. In some embodiments, the ASD or SDI has Tgof about 90 °C or greater at 0.0% relative humidity. In some embodiments, the ASD or SDI has Tgof about 100 °C or greater at 0.0% relative humidity. In some embodiments, the ASD or SDI has Tgof 105 °C at 0.0% relative humidity. In some embodiments, the ASD or SDI has Tgof about 113 °C at 0.0% relative humidity.

[0055] In some embodiments, the ASD or SDI provides a maximum concentration of solubilized Compound B after the gastric phase of a non-sink dissolution assay (CmaxGB) of greater than about 100 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 200 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 500 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 600 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 767 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 607 μg Compound B / mL.WSGR Docket No. 51503-780.601

[0056] In some embodiments, the ASD or SDI provides a maximum concentration of solubilized Compound B after the intestinal phase of a non-sink dissolution assay (CmaxIB) of greater than about 100 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 200 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 300 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 370 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 345 pg Compound B / mL.

[0057] In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±30% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDL In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±20% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDL In some embodiments, the ASD or SDI comprises less than 10% total impurities as measured by high-performance liquid chromatography (HPLC) after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than 5% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH. In some embodiments, the ASD or SDI comprises less than 3% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH. In some embodiments, the ASD or SDI comprises less than 2% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH. In some embodiments, the ASD or SDI comprises at most about 1% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH. In some embodiments, the ASD or SDI comprises at most 0.5% about total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH. In some embodiments, after being stored for 2 months at 40°C / 75%RH, the ASD or SDI has an assay value of Compound B that is within ±20%, ±15%, ±10%, or ±5% of the initial assay value.

[0058] In some embodiments, the ASD or SDI has a Dv50 of about 0.1 μm to about 20 μm. In some embodiments, the ASD or SDI has a Dv50 of about 0.5 μm to about 10 μm. In some embodiments, the ASD or SDI has a Dv50 of about 1 μm to about 5 μm. In some embodiments, the ASD or SDI has a Dv50 of about 3 μm. In some embodiments, the ASD or SDI has a Dv50 of about 2 μm.

[0059] In some embodiments, the ASD or SDI remained amorphous for at least a month when stored at 25°C / 60%RH condition, as determined by X-ray powder diffraction (XRPD). In some embodiments, the ASD or SDI remained amorphous for at least two months when stored at 25°C / 60%RH condition, as determined by X-ray powder diffraction (XRPD). In some embodiments, the ASD or SDI remained amorphous for at least a month when stored at 40°C / 75%RH condition, as determined by X-ray powder diffraction (XRPD). In some embodiments, the ASD or SDI remained amorphous for at least two months when stored at 40°C / 75%RH condition, as determined by X-ray powder diffraction (XRPD).

[0060] In some embodiments, the ASD or SDI is chemically stable for at least 1 day when stored at 2-8 oC when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 2 days when stored at 2-8 oC when the ASD or SDI is wet. In some embodiments, the ASD or SDI isWSGR Docket No. 51503-780.601chemically stable for at least 3 days when stored at 2-8 oC when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 4 days when stored at 2-8 oC when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 5 days when stored at 2-8 oC when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 7 days when stored at 2-8 oC when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 8 days when stored at 2-8 oC when the ASD or SDI is wet.

[0061] In some embodiments, a chemically stable, wet ASD or SDI does not exhibit any degradation peak of Compound B as determined by HPLC. In some embodiments, the wet ASD or SDI has a total solid of about 1-10 wt%.

[0062] In some embodiments, the pharmaceutical composition provides a CmaxGB of less than about 20 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxGB of less than about 10 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxGB of less than about 1 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxGB of less than about 0.1 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxGB of about 0 μg Compound B / mL.

[0063] In some embodiments, the pharmaceutical composition provides a CmaxIB of greater than about 200 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxIB of greater than about 300 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxIB of greater than about 500 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxIB of about 520 μg Compound B / mL. In some embodiments, the pharmaceutical composition provides a CmaxIB of about 550 μg Compound B / mL.

[0064] In some embodiments, the pharmaceutical composition comprises granules. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 of about 1250 μm to about 100 μm. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 of about 200 μm to about 1000 μm. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 about 300 μm to about 750 μm. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 of less than about 700 μm. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 of about 500 μm to about 700 μm. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 of less than about 600 μm.

[0065] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the pharmaceutical composition is a capsule.

[0066] In some embodiments, provided herein is a pharmaceutical composition selected from Formulations 1A-5A, 1A’-5A’, 1A”-5A”, 1B-5B, 1B’-5B’, 1B”-5B”, 4A(1)’, 4A(1)”, 4A(2)’, 4A(2)”, SDI 1 to SDI 8, and Formulations of Tables 30-32, 45-47, 52-53, 65, and 74-86. In some embodiments, provided herein is a pharmaceutical composition comprising the Formulation of Table 86.

[0067] Provided herein is some embodiments, is a method of modulating splicing comprising administering to cells a pharmaceutical composition provided herein, wherein the pharmaceuticalWSGR Docket No. 51503-780.601composition modulates splicing at a splice site sequence of a pre-mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or a functional RNA.

[0068] Provided herein is a method of treating a disease or condition comprising administering a pharmaceutical composition provided herein, to a subject in need thereof.

[0069] Provided herein is a method of using a pharmaceutical composition provided herein, in the manufacture of a medicament for the treatment of a condition or disease. In some embodiments, the disease or condition is Huntington’s Disease.INCORPORATION BY REFERENCE

[0070] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0071] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure are obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0072] FIG. 1 illustrates a non-sink dissolution in biorelevant media for spray dry intermediate (SDI) formulations comprising Compound B and a polymer compared to bulk Compound B.

[0073] FIG. 2A illustrates an x-ray powder diffraction (XRPD) diffractogram of an SDI comprising Compound B and PVP-VA64 in different stability testing conditions.

[0074] FIG. 2B illustrates an XRPD diffractogram of an SDI comprising Compound B and HPMC E3LV in different stability testing conditions.

[0075] FIG. 2C illustrates an XRPD diffractogram of an SDI comprising Compound B and HPMCP HP55 in different stability testing conditions.

[0076] FIG. 2D illustrates an XRPD diffractogram of an SDI comprising Compound B and Eudragit LI 00-55 in different stability testing conditions.

[0077] FIG. 3 illustrates an XRPD diffractogram of compositions PK SDI 1 and PK SDI 2, each comprising Compound B and a polymer.

[0078] FIG. 4 illustrates a non-sink dissolution in biorelevant media for PK SDIs comprising Compound B and a polymer compared to bulk Compound B.

[0079] FIG. 5 illustrates a non-sink dissolution in biorelevant media for tablets used in PK testing comprising Compound B and a polymer.

[0080] FIG. 6 illustrates a process flow chart for the manufacture of tablet comprising 8 mg Compound B.

[0081] FIG. 7 illustrates a non-sink dissolution in biorelevant media for tablets comprising 8 mg Compound B.WSGR Docket No. 51503-780.601

[0082] FIG. 8A illustrates an XRPD diffractogram of a wet SDI comprising Compound B and HPMC E3LV.

[0083] FIG. 8B illustrates an XRPD diffractogram of a wet SDI comprising Compound B and PVP-VA64.

[0084] FIG. 9 illustrates a granulation particle size distribution for tablets comprising Compound B in different manufacturing conditions.

[0085] FIG. 10 illustrates a granulation particle size distribution for tablets comprising Compound B in different manufacturing conditions.

[0086] FIG. 11 illustrates a non-sink dissolution in biorelevant media for tablets comprising 8 mg Compound B and a polymer.DETAILED DESCRIPTION

[0087] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0088] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.Definitions

[0089] The terms “compound(s) of this disclosure”, “compound(s) of the present disclosure”, “small molecule splicing modulator(s)”, “splicing modulator(s)”, “compound(s) that modify splicing” and “compound(s) modifying splicing”, or “SMSM” are interchangeably used herein and refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0090] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise.

[0091] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes (p.o.), intraduodenal routes (i.d.), parenteral injection (including intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intravascular or infusion (inf.), topical (top.) and rectal (p.r.) administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0092] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens inWSGR Docket No. 51503-780.601which the agents are administered by the same or different route of administration or at the same or different time.

[0093] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated; for example a reduction and / or alleviation of one or more signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses can be an amount of an agent that provides a clinically significant decrease in one or more disease symptoms. An appropriate “effective” amount may be determined using techniques, such as a dose escalation study, in individual cases.

[0094] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in amount, potency or duration a desired effect. For example, in regard to enhancing splicing of a target, the term “enhancing” can refer to the ability to increase or prolong splicing, either in amount, potency or duration, of a target.

[0095] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. The term “animal” as used herein comprises human beings and non-human animals. In one embodiment, a “non-human animal” is a mammal, for example a rodent such as rat or a mouse. In one embodiment, a non-human animal is a mouse.

[0096] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g., a human in need thereof.

[0097] The term “pharmaceutical combination” as used herein, means a product that results from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0098] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.WSGR Docket No. 51503-780.601“Pharmaceutically acceptable” can refer to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i. e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0099] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives or lubricants used in formulating pharmaceutical products.

[0100] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. A “pharmaceutically acceptable salt” can refer to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and / or does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting an SMSM compound of Formula (I) with an acid. Pharmaceutically acceptable salts are also obtained by reacting a compound of Formula (I) with a base to form a salt.

[0101] The term “nucleic acid” as used herein generally refers to one or more nucleobases, nucleosides, or nucleotides, and the term includes polynucleobases, polynucleosides, and polynucleotides.

[0102] As used herein, a “small molecular weight compound” can be used interchangeably with “small molecule” or “small organic molecule”. Small molecules refer to compounds other than peptides or oligonucleotides; and typically have molecular weights of less than about 2000 Daltons, e.g., less than about 900 Daltons.

[0103] As used herein, the term “Dv50” refers to a particle size distribution in which 50% of the particles, by volume, have a particle diameter less than the Dv50 value, and in which 50% of the particles, by volume, have a particle diameter larger than the Dv50 value.

[0104] As used herein, the term “Dv90” refers to a particle size distribution in which 90% of the particles, by volume, have a particle diameter less than the Dv90 value, and in which 10% of the particles, by volume, have a particle diameter larger than the Dv90 value.

[0105] As used herein, the term “Dv10” refers to a particle size distribution in which 10% of the particles, by volume, have a particle diameter less than the Dv10 value, and in which 90% of the particles, by volume, have a particle diameter larger than the Dv10 value.

[0001] The term “about” is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. For example, “about” can refer to within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can refer to a range of up to ±20%, up to ±10%, up to ±5%, or up to ±1% of a given value.WSGR Docket No. 51503-780.601Small Molecule Splicing Modulators (SMSMs)

[0106] Described herein are compounds modifying splicing of gene products for use in the treatment, prevention and / or delay of progression of diseases or conditions.

[0107] In one aspect, described herein is a compound that has the structure of, or a pharmaceutically acceptable salt thereof.

[0108] In one aspect, described herein is Compound B, or a pharmaceutically acceptable salt or stereoisomer thereof:Compound B.

[0109] In one aspect, described herein is Compound B. In one aspect, described herein is a compound that is a pharmaceutically acceptable salt of Compound B. In another aspect, described herein is the compound 6-(6-(((lR,2R,3S,5S)-2-Fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2 -methylbenzo [d] oxazol-5 -ol.

[0110] In some embodiments, a stereoisomer of Compound B is(Compound A).

[0111] In one aspect, described herein is the compound 6-(6-(((lS,2S,3A,5A)-2-fluoro-9-azabicyclo [3.3. l]nonan-3 -yl)(methyl)amino)pyridazin-3 -y 1 )-2-methy 1 benzo[ d\ oxazol-5 -ol.

[0112] In one aspect, disclosed herein is a method of modulating splicing comprising contacting a compound of the present disclosure to cells, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or a functional RNA.

[0113] In one aspect, disclosed herein is a method of treating a disease or condition comprising administering a compound of the present disclosure.

[0114] The compound described herein may be formed as, and / or used as, a pharmaceutically acceptable salt. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganicWSGR Docket No. 51503-780.601acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethane sulfonic acid, benzene sulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0115] In some embodiments, described herein include a compound and pharmaceutical formulations for modifying splicing of gene products, such as HTT pre-m RNA for use in the treatment, prevention, and / or delay of progression of diseases or conditions (e.g., Huntington’s disease). In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound described herein for use in the treatment, prevention, and / or delay of progression of Huntington’s disease. In some embodiments, a compound described herein can be administered for treatment, prevention, and / or delay of progression of Huntington’s disease. In some embodiments, a subject is affected by Huntington’s disease associated with the HTT gene. In some embodiments, a subject is affected by Huntington’s disease associated with a splicing product of the HTT pre-mRNA. In some embodiments, the splicing product of the HTT pre-mRNA is an aberrant splicing product. In some embodiments, the splicing product of the HTT pre-mRNA encodes an aberrant polypeptide. In some embodiments, the splicing product of the HTT pre-mRNA is an aberrant splicing product resulted from a mutation in the HTT gene. In some embodiments, the splicing product of the HTT pre-mRNA may comprise a string of CAG repeats. In some embodiments, the splicing product of the HTT pre-mRNA may comprise an aberrant expansion of a string of CAG repeats. In some embodiments, the splicing product of the HTT pre-mRNA may comprise an aberrant expansion of a string of CAG repeats resulted from a mutation in the HTT gene.

[0116] In some embodiments, the compound and methods of use described herein can modulate splicing, such as alternative splicing of a polynucleotide encoded by HTT gene. In some embodiments,WSGR Docket No. 51503-780.601alternative splicing of the HTT pre-mRNA may lead to the expression of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 isoforms of the huntingtin protein. In some embodiments, the HTT gene may comprise a mutation. In some embodiments, the HTT gene may comprise a mutation associated with expansion of a CAG repeat. In some embodiments, the splice modulating compounds and methods of use described herein can modulate splicing of the HTT pre-mRNA that lead to inclusion of a cryptic exon (e.g., a poison exon) that is normally not included in the HTT spliced product, e.g., mRNA. In some embodiments, the cryptic exon (e.g., a poison exon) included in the HTT spliced product may lead to degradation of the HTT spliced product through nonsense-mediated decay (NMD) mediated RNA degradation. In a preferred embodiment, alternative splicing of the HTT pre-mRNA may lead to inclusion of a cryptic exon that is not normally included in between exon 49 and exon 50 of the HTT mRNA. In a preferred embodiment, alternative splicing of the HTT pre-mRNA may promote the inclusion of a poison exon 49b. In some embodiments, the HTT pre-mRNA comprises the sequence AGAguaaggg (SEQ ID NO: 1). In a preferred embodiment, the compounds described herein bind to the 5’ss sequence AGAguaaggg (SEQ ID NO: 1).

[0117] Described herein is a compound modifying splicing of gene products wherein the compound induces a post-transcriptionally unstable variant or transcript of a gene product. Described herein is a compound modifying splicing of gene products wherein the compound represses a transcript of a gene product. In some embodiments, an HTT transcript harbors a poison exon. In some embodiments, the poison exon results in a frame-shift in a downstream exon, for example in an exon immediately following the poison exon. In some embodiments, the frame-shift in a downstream exon contains an in-frame stop codon that would not be in frame in the absence of inclusion of the poison exon. In some embodiments, the poison exon comprises an in-frame premature termination codon (PTC). In some embodiments, the poison exon triggers NMD and degradation of the transcript. In some embodiments, the gene product is HTT.Methods of Making Compounds

[0118] Compound B, 6-(6-(((1R,2R,3S,5S)-2-Fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5-ol. can be made by the techniques and processes known in the art, for example as described in Example 1.Pharmaceutical Formulations

[0119] Provided in some embodiments herein is a pharmaceutical composition described herein. In some embodiments, the pharmaceutical composition comprises a compound described herein, such as a Small Molecule Splicing Modulators (SMSMs) described herein. In some embodiments, the pharmaceutical composition comprises the compound 6-(6-((2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol. In some embodiments, the pharmaceutical composition comprises the compound of Compound B, 6-(6-(((lR,2R,3S,5S)-2-Fluoro-9-azabicyclo[3.3. l]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5-ol. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound described herein. In some embodiments, the pharmaceutical composition comprises a stereoisomer of a compound described herein. In some embodiments, the pharmaceutical compositionWSGR Docket No. 51503-780.601comprises a pharmaceutically acceptable excipient described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier described herein. In some embodiments, the pharmaceutical composition is in a solid dosage form.

[0120] Provided in some embodiments herein is a pharmaceutical composition comprising a compounddescribed herein, the compound having a structureof (Compound B).

[0121] Provided in some embodiments herein is a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutically acceptable excipient comprises a polymer, such as a polymer provided herein. In some embodiments, the pharmaceutically acceptable carrier comprises a polymer, such as a polymer provided herein.

[0122] Provided herein is some embodiments is a pharmaceutical composition comprising an amorphous solid dispersion (ASD). In some embodiments, the ASD comprises a compound. In some embodiments, the ASD comprises a compound described herein, such as an SMSM. In some embodiments, the ASD comprises the compound of Compound B, 6-(6-(((lR,2R,3S,5S)-2-Fluoro-9-azabicyclo[3.3. l]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5-ol. In some embodiments, the ASD comprises a pharmaceutically acceptable salt of the Compound B. In some embodiments, the ASD comprises a stereoisomer of the Compound B. In some embodiments, the ASD comprises a polymer, such as a polymer described herein. In some embodiments, the ASD comprises a compound, such as a compound described herein, and a polymer, such as a polymer described herein. In some embodiments, the ASD comprises an SMSM and a polymer. In some embodiments, the ASD comprises the compound of Compound B, 6-(6-(((lR,2R,3S,5S)-2-Fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5-ol, and a polymer. In some embodiments, the ASD comprises a pharmaceutically acceptable salt of the Compound B and the polymer. In some embodiments, the ASD comprises a stereoisomer of the Compound B and the polymer. In some embodiments, the ASD is an SDI. In some embodiments, the ASD is not an SDI. An ASD can be prepared by any suitable method in the art, such as solvent-based methods, such as spray drying and solvent casting, or melt-based methods, like hot-melt extrusion and melt granulation.

[0123] Provided in some embodiments herein is an ASD comprising a Spray Dry Intermediate. In some embodiments, an ASD described herein is a Spray Dry Intermediate (SDI) described herein.

[0124] In some embodiments, a pharmaceutical composition described herein comprises an SDI described herein. In some embodiments, the SDI comprises a compound described herein, such as the compound of Compound B. In some embodiments, the SDI comprises Compound B. In some embodiments, the SDI comprises a pharmaceutically acceptable salt of the Compound B. In some embodiments, the SDI comprises a stereoisomer of the Compound B. In some embodiments, the SDIWSGR Docket No. 51503-780.601comprises a polymer described herein. In some embodiments, the SDI comprises the Compound B and the polymer. In some embodiments, the SDI comprises a pharmaceutically acceptable salt of the Compound B and the polymer. In some embodiments, the SDI comprises a stereoisomer of the Compound B and the polymer.

[0125] In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof. In some embodiment, the ASD or the SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and a polymer. In some embodiments, the ASD or the SDI comprises the polymer in an amorphous state. In some embodiments, the ASD or the SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer in an amorphous state.

[0126] In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 1:99 to about 50:50. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 50:50 to about 90: 10. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 5:95 to about 60:40. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 10:90 to about 30:70. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 11:89 to about 29:71. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 12:88 to about 28:72. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 13:87 to about 27:73. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 14:86 to about 26:74. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 15:85 to about 25:75. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 16:84 to about 24:76. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 17:83 to about 23:77. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 18:82 to about 22:78. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 19: 81 to about 21: 79. In some embodiments, the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt orWSGR Docket No. 51503-780.601stereoisomer thereof and the polymer at a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.

[0127] In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises about 5% to 50% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 50% to 95% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises polyvinylpyrrolidone-co-vinyl acetate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), a methacrylate copolymer (such as methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer), or a combination thereof. In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises about 15% to 45% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 55% to 85% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises polyvinylpyrrolidone-co-vinyl acetate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), a methacrylate copolymer (such as methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer), or a combination thereof. In some embodiments, the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises polyvinylpyrrolidone-co-vinyl acetate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), a methacrylate copolymer (such as methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer), or a combination thereof.

[0128] In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 1% to about 70% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 5% to about 50% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 10% to about 30% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 11% to about 29% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 12% to about 28% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 13% to about 27% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 14% to about 26% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 15% to about 25% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 16% to about 24% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 17% to about 23% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 18% to about 22% by weight. In some embodiments,WSGR Docket No. 51503-780.601the ASD or SDI is present in the pharmaceutical composition in an amount of about 19% to about 21% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 15% to about 20% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 17% to about 20% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 18% to about 20% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 20% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 19% by weight. In some embodiments, the ASD or SDI is present in the pharmaceutical composition in an amount of about 18% by weight.

[0129] Provided in some embodiments herein is a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier. Provided in some embodiments herein is a pharmaceutical composition comprising a pharmaceutically acceptable excipient. Provided in some embodiments herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0130] In some embodiments, the pharmaceutically acceptable excipient or carrier comprises a polymer, a binder, a filler, a glidant, a lubricant, or a combination thereof. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises a polymer. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises a binder. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises a filler. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises a glidant. In some embodiments, the pharmaceutically acceptable excipient or carrier comprises a lubricant.

[0131] Provided in some embodiments herein is a pharmaceutical composition comprising a polymer. The polymer can be a pharmaceutically acceptable excipient or carrier. In some embodiments, the polymer is a copolymer. In some embodiment, the polymer is an anionic copolymer, such as an anionic copolymer. In some embodiments, the polymer is a cationic polymer, such as a cationic copolymer. In some embodiments, the polymer is an acidic, a neutral, or a basic polymer. In some embodiments, the polymer is an acidic polymer. In some embodiments, the polymer is a neutral polymer. In some embodiments, the polymer is a hydrophilic polymer. In some embodiments, the polymer is ionized at a pH above about pH 5.5. In some embodiments, the polymer is ionized at a pH above about pH 6.0.

[0132] In some embodiments, the polymer comprises polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co-vinyl acetate (PVP-VA64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam -polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus), methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit L100), methacrylic acid-ethyl acrylate copolymer (e.g., sold under the trade name Eudragit L100-55), or a combination thereof. In some embodiments, the polymer comprises PVP-VA64, HPMC, HPMCP, methacrylic acid-ethyl acrylate copolymer (e.g., sold under the trade name Eudragit L100-55), or a combination thereof. In some embodiments, the polymer is selected from the group consisting of PVP-VA64, HPMC, HPMCP, and methacrylic acid-ethyl acrylate copolymer (e.g., sold under the trade name Eudragit L100-55). In someWSGR Docket No. 51503-780.601embodiments, the polymer is selected from the group consisting of PVP-VA64 and HPMC. In some embodiments, the polymer comprises PVP-VA64, HPMC, or a combination thereof. In some embodiments, the polymer comprises PVP. In some embodiments, the polymer comprises PVP K30 grade (PVP K30). In some embodiments, the polymer comprises PVP-VA64. In some embodiments, the polymer comprises HPMC. In some embodiments, the polymer comprises HPMCAS. In some embodiments, the polymer comprises HPMCP. In some embodiments, the polymer comprises polyvinyl caprolactam -polyvinyl acetate -polyethylene glycol graft copolymer (e.g., sold under the trade name Soluplus). In some embodiments, the polymer comprises polymethacrylate (e.g., methacrylic acid-methyl methacrylate copolymer or methacrylic acid-methyl methacrylate copolymer). In some embodiments, the polymer comprises methacrylic acid-methyl methacrylate copolymer (e.g., sold under the trade name Eudragit LI 00). In some embodiments, the polymer comprises methacrylic acid-methyl methacrylate copolymer, sold under the trade name of Eudragit L100. In some embodiments, the polymer comprises methacrylic acid-ethyl acrylate copolymer (e.g., sold under the trade name Eudragit L100-55). In some embodiments, the polymer comprises methacrylic acid-ethyl acrylate copolymer, sold under the trade name of Eudragit LI 00-55.

[0133] In some embodiments, the ASD or SDI comprises about 30% to about 70% wt of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 30% to about 70% wt of a polymer.

[0134] In some embodiments, the ASD or SDI comprises about 10% to about 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 70% to about 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer (e.g., polyvinylpyrrolidone-co-vinyl acetate or HPMC).

[0135] In some embodiments, the SDI comprises about 10% to about 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 70% to about 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of polyvinylpyrrolidone-co-vinyl acetate (e.g., PVP-VA64). In some embodiments, the SDI comprises about 20% wt of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 80% wt of polyvinylpyrrolidone-co-vinyl acetate (e.g., PVP-VA64).

[0136] In some embodiments, the SDI comprises about 10% to about 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 70% to about 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of HPMC (e.g., HPMC E3LV). In some embodiments, the SDI comprises about 20% wt of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 80% wt of HPMC (e.g., HPMC E3LV).

[0137] Provided in some embodiments herein is a pharmaceutical composition comprising a binder, a filler, a glidant, a lubricant, or a combination thereof. In some embodiments, the pharmaceutical composition comprises a binder. In some embodiments, the pharmaceutical composition comprises aWSGR Docket No. 51503-780.601filler. In some embodiments, the pharmaceutical composition comprises a glidant. In some embodiments, the pharmaceutical composition comprises a lubricant.

[0138] In some embodiments, the binder comprises a polymer. In some embodiments, the binder comprises crospovidone (e.g., Kollidon). In some embodiments, the binder comprises Kollidon. In some embodiments, the binder comprises crospovidone CL grade (e.g., Kollidon CL). In some embodiments, the binder comprises Kollidon CL. In some embodiments, the binder comprises crospovidone CL-F grade (e.g., Kollidon CL-F). In some embodiments, the binder comprises Kollidon CL-F.

[0139] In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 1% to about 15% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 2% to about 10% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 2% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 2.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 3% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 3.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 4% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 4.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 5.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 6% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 6.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 7% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 7.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 8% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 8.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 9% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 9.5% by weight. In some embodiments, the binder is present in the pharmaceutical composition in an amount of about 10% by weight.

[0140] In some embodiments, the filler comprises lactose, cellulose, sucrose, mannitol, starch, or a combination thereof. In some embodiments, the filler comprises lactose. In some embodiments, the filler comprises cellulose. In some embodiments, the filler comprises sucrose. In some embodiments, the filler comprises mannitol (e.g., Parteck). In some embodiments, the filler comprises mannitol M100 grade (e.g., Parteck Ml 00). In some embodiments, the filler comprises Parteck Ml 00. In some embodiments, the filler comprises mannitol M200 grade (e.g., Parteck M200). In some embodiments, the filler comprises Parteck M200. In some embodiments, the filler comprises starch. In some embodiments, the filler comprises calcium phosphate.WSGR Docket No. 51503-780.601

[0141] In some embodiments, the filler comprises mannitol (e.g., Parteck) and starch. In some embodiments, the filler comprises mannitol M100 grade (e.g., Parteck M100) and starch. In some embodiments, the filler comprises mannitol M200 grade (e.g., Parteck M200) and starch. In some embodiments, the filler comprises mannitol M100 grade (e.g., Parteck M100), mannitol M200 grade (e.g., Parteck M200), starch, or a combination thereof. In some embodiments, the filler comprises mannitol M100 grade (e.g., Parteck M100) and mannitol M200 grade (e.g., Parteck M200). In some embodiments, the filler comprises mannitol M100 grade (e.g., Parteck M100), mannitol M200 grade (e.g., Parteck M200), and starch.

[0142] In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 5% to about 99% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 30% to about 90% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 40% to about 90% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 40% to about 90% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 50% to about 80% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 55% to about 75% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 60% to about 75% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 60% to about 70% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 53% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 55% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 57% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 59% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 60% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 61% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 62% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 63% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 64% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 65% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 66% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 67% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 68% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 69% by weight. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 70% by weight.

[0143] In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.01% to about 20% by weight. In some embodiments, the glidant comprises silicon dioxide (e.g.,WSGR Docket No. 51503-780.601fumed silica). In some embodiments, the glidant comprises fumed silica. In some embodiments, the glidant comprises untreated fumed colloidal silicon dioxide (e.g., Cab-O-Sil). In some embodiments, the glidant comprises Cab-O-Sil. In some embodiments, the glidant comprises untreated fumed colloidal silicon dioxide M-5P grade (e.g., Cab-O-Sil M-5P). In some embodiments, the glidant comprises Cab-O-Sil M-5P grade.

[0144] In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.1% to about 5% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.1% to about 4% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.1% to about 3% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.5% to about 2% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.5% to about 1.5% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.5% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.6% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.7% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.8% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.9% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.0% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.1% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.2% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.3% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.4% by weight. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.5% by weight.

[0145] In some embodiments, the lubricant comprises talc, magnesium stearate, sodium stearyl fumarate, or a combination thereof. In some embodiments, the lubricant comprises talc. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the lubricant comprises sodium stearyl fumarate (e.g., Pruv). In some embodiments, the lubricant comprises Pruv. In some embodiments, the lubricant comprises sodium stearyl fumarate SSF grade (e.g., Pruv SSF). In some embodiments, the lubricant comprises Pruv SSF.

[0146] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.01% to about 20% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% to about 5% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% to about 4% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% to about 3% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% to about 2% by weight. In some embodiments, the lubricant isWSGR Docket No. 51503-780.601present in the pharmaceutical composition in an amount of about 0.5% to about 1.5% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.6% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.7% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.8% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.9% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.0% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.1% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.2% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.3% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.4% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.5% by weight.

[0147] Provided herein in some embodiments is a pharmaceutical composition comprising a core-shell structure. In some embodiments, a pharmaceutical composition provided herein comprises a core. In some embodiments, a pharmaceutical composition provided herein comprises a shell.

[0148] In some embodiments, the core comprises over about 10%, about 20%, about 30% or about 40% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 50% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 60% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 70% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 75% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 80% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 82% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 85% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 87% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 90% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 91% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 92% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 95% by weight of the pharmaceutical composition. In some embodiments, the core comprises over about 97% by weight of the pharmaceutical composition.

[0149] In some embodiments, the core comprises about 50% to about 99% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 60% to about 99% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 70% to about 99% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 80% to about 99% by weight of the pharmaceutical composition. In some embodiments, the core comprisesWSGR Docket No. 51503-780.601about 85% to about 99% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 90% to about 99% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 90% to about 97% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 91% to about 97% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 90% to about 95% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 95% to about 99% by weight of the pharmaceutical composition.

[0150] In some embodiments, the core comprises about 90% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 91% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 92% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 93% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 94% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 95% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 96% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 97% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 98% by weight of the pharmaceutical composition. In some embodiments, the core comprises about 99% by weight of the pharmaceutical composition.

[0151] In some embodiments, the ASD or SDI is present in the core in an amount of about 1% to about 90% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 1% to about 50% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 50% to about 99% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 5% to about 40% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 3% to about 35% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 10% to about 30% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 11% to about 29% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 12% to about 28% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 13% to about 27% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 14% to about 16% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 15% to about 25% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 16% to about 24% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 17% to about 23% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 18% to about 22% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 19% to about 21% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 17% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 18% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 19% by weight. In some embodiments, the ASD or SDI isWSGR Docket No. 51503-780.601present in the core in an amount of about 20% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 21% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 22% by weight. In some embodiments, the ASD or SDI is present in the core in an amount of about 23% by weight. In some embodiments, the ASD is an SDI.

[0152] Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising a pharmaceutically acceptable excipient or carrier. In some embodiments, the core comprises a pharmaceutically acceptable excipient. In some embodiments, the core comprises a pharmaceutically acceptable carrier.

[0153] In some embodiments, the core comprises a polymer, a binder, a filler, a glidant, a lubricant, or a combination thereof. In some embodiments, the core comprises a polymer. In some embodiments, the core comprises a binder. In some embodiments, the core comprises a filler. In some embodiments, the core comprises a glidant. In some embodiments, the core comprises a lubricant.

[0154] In some embodiments, the binder is present in the core in an amount of about 0.1% to about 40% by weight. In some embodiments, the binder is present in the core in an amount of about 1% to about 15% by weight. In some embodiments, the binder is present in the core in an amount of about 2% to about 10% by weight. In some embodiments, the binder is present in the core in an amount of about 3% to about 9% by weight. In some embodiments, the binder is present in the core in an amount of about 2% by weight. In some embodiments, the binder is present in the core in an amount of about 2.5% by weight. In some embodiments, the binder is present in the core in an amount of about 3% by weight. In some embodiments, the binder is present in the core in an amount of about 3.5% by weight. In some embodiments, the binder is present in the core in an amount of about 4% by weight. In some embodiments, the binder is present in the core in an amount of about 4.5% by weight. In some embodiments, the binder is present in the core in an amount of about 5% by weight. In some embodiments, the binder is present in the core in an amount of about 5.5% by weight. In some embodiments, the binder is present in the core in an amount of about 6% by weight. In some embodiments, the binder is present in the core in an amount of about 6.5% by weight. In some embodiments, the binder is present in the core in an amount of about 7% by weight. In some embodiments, the binder is present in the core in an amount of about 7.5% by weight. In some embodiments, the binder is present in the core in an amount of about 8% by weight. In some embodiments, the binder is present in the core in an amount of about 8.5% by weight. In some embodiments, the binder is present in the core in an amount of about 9% by weight. In some embodiments, the binder is present in the core in an amount of about 9.5% by weight. In some embodiments, the binder is present in the core in an amount of about 10% by weight.

[0155] In some embodiments, the filler is present in the core in an amount of about 30% to about 90% by weight. In some embodiments, the filler is present in the core in an amount of about 0.1% to about 30% by weight. In some embodiments, the filler is present in the core in an amount of about 20% to about 99% by weight. In some embodiments, the filler is present in the core in an amount of about 40% to about 90% by weight. In some embodiments, the filler is present in the core in an amount of aboutWSGR Docket No. 51503-780.60140% to about 90% by weight. In some embodiments, the filler is present in the core in an amount of about 50% to about 80% by weight. In some embodiments, the filler is present in the core in an amount of about 55% to about 75% by weight. In some embodiments, the filler is present in the core in an amount of about 60% to about 75% by weight. In some embodiments, the filler is present in the core in an amount of about 60% to about 70% by weight. In some embodiments, the filler is present in the core in an amount of about 65% to about 75% by weight. In some embodiments, the filler is present in the core in an amount of about 53% by weight. In some embodiments, the filler is present in the core in an amount of about 55% by weight. In some embodiments, the filler is present in the core in an amount of about 57% by weight. In some embodiments, the filler is present in the core in an amount of about 59% by weight. In some embodiments, the filler is present in the core in an amount of about 60% by weight. In some embodiments, the filler is present in the core in an amount of about 61% by weight. In some embodiments, the filler is present in the core in an amount of about 62% by weight. In some embodiments, the filler is present in the core in an amount of about 63% by weight. In some embodiments, the filler is present in the core in an amount of about 64% by weight. In some embodiments, the filler is present in the core in an amount of about 65% by weight. In some embodiments, the filler is present in the core in an amount of about 66% by weight. In some embodiments, the filler is present in the core in an amount of about 67% by weight. In some embodiments, the filler is present in the core in an amount of about 68% by weight. In some embodiments, the filler is present in the core in an amount of about 69% by weight. In some embodiments, the filler is present in the core in an amount of about 70% by weight. In some embodiments, the filler is present in the core in an amount of about 71% by weight. In some embodiments, the filler is present in the core in an amount of about 72% by weight. In some embodiments, the filler is present in the core in an amount of about 73% by weight. In some embodiments, the filler is present in the core in an amount of about 74% by weight. In some embodiments, the filler is present in the core in an amount of about 75% by weight. In some embodiments, the filler is present in the core in an amount of about 77% by weight. In some embodiments, the filler is present in the core in an amount of about 79% by weight. In some embodiments, the filler is present in the core in an amount of about 80% by weight.

[0156] In some embodiments, the glidant is present in the core in an amount of about 0.01% to about 15% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.1% to about 5% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.1% to about 4% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.1% to about 3% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.5% to about 2% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.5% to about 1.5% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.5% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.6% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.7% by weight. In some embodiments, the glidant is present in the core in an amount of about 0.8% byWSGR Docket No. 51503-780.601weight. In some embodiments, the glidant is present in the core in an amount of about 0.9% by weight. In some embodiments, the glidant is present in the core in an amount of about 1.0% by weight. In some embodiments, the glidant is present in the core in an amount of about 1.1% by weight. In some embodiments, the glidant is present in the core in an amount of about 1.2% by weight. In some embodiments, the glidant is present in the core in an amount of about 1.3% by weight. In some embodiments, the glidant is present in the core in an amount of about 1.4% by weight. In some embodiments, the glidant is present in the core in an amount of about 1.5% by weight.

[0157] In some embodiments, the glidant is present in the lubricant in an amount of about 0.01% to about 15% by weight. In some embodiments, the lubricant is present in the core in an amount of about 0.1% to about 5% by weight. In some embodiments, the lubricant is present in the core in an amount of about 0.1% to about 4% by weight. In some embodiments, the lubricant is present in the core in an amount of about 0.1% to about 3% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% to about 2% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% to about 1.5% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.6% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.7% by weight. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.8% by weight. In some embodiments, the lubricant is present in the core in an amount of about 0.9% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.0% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.1% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.2% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.3% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.4% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.5% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.6% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.7% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.8% by weight. In some embodiments, the lubricant is present in the core in an amount of about 1.9% by weight. In some embodiments, the lubricant is present in the core in an amount of about 2.0% by weight.

[0158] Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising the ASD or SDI, a filler, a binder, a glidant, a lubricant, or a combination thereof.Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising the ASD or SDI, a filler (e.g., mannitol or starch), a binder (e.g., crospovidone), a glidant (e.g., silicon dioxide), a lubricant (e.g., sodium stearyl fumarate), or a combination thereof. Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising the ASD or SDI, mannitol, starch, crospovidone, untreated fumed colloidal silicon dioxide, sodium stearylWSGR Docket No. 51503-780.601fumarate, or a combination thereof. In some embodiments, a pharmaceutical composition provided herein comprises a core, the core comprising the ASD or SDI, mannitol, starch, crospovidone, untreated fumed colloidal silicon dioxide, sodium stearyl fumarate, or a combination thereof. In some embodiments, the pharmaceutical composition provided herein comprises a core, the core comprising the ASD or SDI, mannitol, starch, crospovidone, untreated fumed colloidal silicon dioxide, and sodium stearyl fumarate. In some embodiments, the pharmaceutical composition provided herein comprises a core, the core comprising the ASD or SDI, mannitol, crospovidone, untreated fumed colloidal silicon dioxide, and sodium stearyl fumarate. In some embodiments, the ASD is an SDI.

[0159] In some embodiments, a composition provided herein comprises a core, the core comprising about 10 wt% to about 50 wt% of the ASD or SDI, about 50 wt% to about 80 wt% of a filler, about 2 wt% to about 15 wt% of a binder, about 0.1 wt% to about 5 wt% of a glidant, and about 0.1 wt% to about 5 wt% of a lubricant. In some embodiments, a composition provided herein comprises a core, the core comprising about 15 wt% to about 25 wt% of the ASD or SDI, about 65 wt% to about 75 wt% of a filler, about 5 wt% to about 10 wt% of a binder, about 0.5 wt% to about 2 wt% of a glidant, and about 0.5 wt% to about 2 wt% of a lubricant. In some embodiments, a composition provided herein comprises a core, the core comprising about 15 wt% to about 25 wt% of the ASD or SDI, about 65 wt% to about 75 wt% of mannitol, about 5 wt% to about 10 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.5 wt% to about 2 wt% of sodium stearyl fumarate. In some embodiments, the ASD is an SDI.

[0160] In some embodiments, a composition provided herein comprises a core, the core comprising about 20 wt% of the ASD or SDI, about 71 wt% mannitol (e.g., mannitol M200), about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% of sodium stearyl fumarate. In some embodiments, the ASD is an SDI.

[0161] In some embodiments, a composition provided herein comprises a core, the core comprising about 20 wt% of the ASD or SDI, about 71 wt% mannitol (e.g., mannitol M200), about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64 or HPMC E3LV) in a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.

[0162] In some embodiments, a composition provided herein comprises a core, the core comprising about 20 wt% of the ASD or SDI, about 71 wt% mannitol (e.g., mannitol M200), about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and PVP-VA64 in a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.

[0163] In some embodiments, a composition provided herein comprises a core, the core comprising about 20 wt% of the ASD or SDI, about 71 wt% mannitol (e.g., mannitol M200), about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and HPMC E3LV in a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.WSGR Docket No. 51503-780.601

[0164] In some embodiments, a composition provided herein comprises a core, the core comprising about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide, and about 1.5 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and HPMC in a weight ratio of about 20:80. In some embodiments, a composition provided herein comprises a core, the core comprising about 20 wt% of the ASD or SDI, about 69.5 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide, and about 1.5 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and HPMC in a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.

[0165] Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising an intragranular component and an extragranular component. In some embodiments, the core comprises an intragranular component. In some embodiments, the core comprises an extragranular component. In some embodiments, the core comprises granules.

[0166] In some embodiments, the intragranular component comprises over about 10%, about 20%, about 30%, or about 40% by weight of the core. In some embodiments, the intragranular component comprises over about 50% by weight of the core. In some embodiments, the intragranular component comprises over about 60% by weight of the core. In some embodiments, the intragranular component comprises over about 70% by weight of the core. In some embodiments, the intragranular component comprises over about 75% by weight of the core. In some embodiments, the intragranular component comprises over about 80% by weight of the core. In some embodiments, the intragranular component comprises over about 82% by weight of the core. In some embodiments, the intragranular component comprises over about 85% by weight of the core. In some embodiments, the intragranular component comprises over about 87% by weight of the core. In some embodiments, the intragranular component comprises over about 90% by weight of the core. In some embodiments, the intragranular component comprises over about 95% by weight of the core.

[0167] In some embodiments, the intragranular component comprises about 10% to about 99% by weight of the core. In some embodiments, the intragranular component comprises about 50% to about 99% by weight of the core. In some embodiments, the intragranular component comprises about 55% to about 95% by weight of the core. In some embodiments, the intragranular component comprises about 60% to about 95% by weight of the core. In some embodiments, the intragranular component comprises about 70% to about 95% by weight of the core. In some embodiments, the intragranular component comprises about 80% to about 90% by weight of the core. In some embodiments, the intragranular component comprises about 82% to about 89% by weight of the core. In some embodiments, the intragranular component comprises about 83% to about 88% by weight of the core.

[0168] In some embodiments, the intragranular component comprises about 80% by weight of the core. In some embodiments, the intragranular component comprises about 81% by weight of the core. In some embodiments, the intragranular component comprises about 82% by weight of the core. In some embodiments, the intragranular component comprises about 83% by weight of the core. In some embodiments, the intragranular component comprises about 84% by weight of the core. In someWSGR Docket No. 51503-780.601embodiments, the intragranular component comprises about 85% by weight of the core. In some embodiments, the intragranular component comprises about 86% by weight of the core. In some embodiments, the intragranular component comprises about 87% by weight of the core. In some embodiments, the intragranular component comprises about 88% by weight of the core. In some embodiments, the intragranular component comprises about 89% by weight of the core.

[0169] Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising an intragranular component. In some embodiments, the intragranular component comprises at least a portion of the filler, at least a portion of the binder, at least a portion of the glidant, at least a portion of the lubricant, or a combination thereof. In some embodiments, the intragranular component comprises the ASD or SDI, a filler, a binder, a glidant, a lubricant, or a combination thereof. In some embodiments, the intragranular component comprises the ASD or SDI, a filler (e.g., mannitol or starch), a binder (e.g., crospovidone), a glidant (e.g., silicon dioxide), a lubricant (e.g., sodium stearyl fumarate), or a combination thereof. In some embodiments, the intragranular component comprises the ASD or SDI, mannitol, starch, crospovidone, untreated fumed colloidal silicon dioxide, sodium stearyl fumarate, or a combination thereof. In some embodiments, the intragranular component comprises the ASD or SDI, mannitol, starch, crospovidone, untreated fumed colloidal silicon dioxide, sodium stearyl fumarate, or a combination thereof. In some embodiments, the intragranular component comprises the ASD or SDI, mannitol, starch, crospovidone, untreated fumed colloidal silicon dioxide, and sodium stearyl fumarate. In some embodiments, the intragranular component comprises the ASD or SDI, mannitol, crospovidone, untreated fumed colloidal silicon dioxide, and sodium stearyl fumarate. In some embodiments, the ASD is an SDI.

[0170] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 15 wt% to about 25 wt% of the ASD or SDI, about 40 wt% to about 70 wt% of mannitol, about 1 wt% to about 5 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the core. In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 15 wt% to about 25 wt% of the ASD or SDI, about 40 wt% to about 70 wt% of mannitol, about 1 wt% to about 5 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64 or HPMC E3LV) in a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.

[0171] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 15 wt% to about 25 wt% of the ASD or SDI, about 40 wt% to about 50 wt% of mannitol, about 10 wt% to about 20 wt% of starch, about 1 wt% to about 5 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relativeWSGR Docket No. 51503-780.601to the core. In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 15 wt% to about 25 wt% of the ASD or SDI, about 40 wt% to about 50 wt% of mannitol, about 10 wt% to about 20 wt% of starch, about 1 wt% to about 5 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64 or HPMC E3LV) in a weight ratio of about 20:80. In some embodiments, the ASD is an SDI.

[0172] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 20 wt% of the ASD or SDI, about 60.5 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.5 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., HPMC E3LV) in a weight ratio of about 20:80 relative to the core. In some embodiments, the ASD is an SDI.

[0173] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 20 wt% of the ASD or SDI, about 64.5 wt% mannitol (e.g., mannitol M100), about 2 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.5 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64) in a weight ratio of about 20:80 relative to the core. In some embodiments, the ASD is an SDI.

[0174] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 20 wt% of the ASD or SDI, about 45 wt% mannitol (e.g., mannitol M100), about 15 wt% starch, about 4 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.5 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., HPMC E3LV) in a weight ratio of about 20:80 relative to the core. In some embodiments, the ASD is an SDI.

[0175] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 20 wt% of the ASD or SDI, about 48 wt% mannitol (e.g., mannitol M100), about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.5 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64) in a weight ratio of about 20:80 relative to the core. In some embodiments, the ASD is an SDI.

[0176] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 17 wt% to about 27 wt% of the ASD or SDI, about 50 wt% to about 80 wt% of mannitol, about 1 wt% to about 5 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the intragranular component. In some embodiments, the ASD is an SDI.WSGR Docket No. 51503-780.601

[0177] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 17 wt% to about 27 wt% of the ASD or SDI, about 50 wt% to about 60 wt% of mannitol, about 15 wt% to about 25 wt% of starch, about 1 wt% to about 5 wt% of crospovidone, about 0.5 wt% to about 2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the intragranular component. In some embodiments, the ASD is an SDI.

[0178] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 23.3 wt% of the ASD or SDI, about 70.4 wt% mannitol (e.g., mannitol M100), about 4.7 wt% crospovidone, about 1.2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.6 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., HPMC E3LV) in a weight ratio of about 20:80 relative to the intragranular component. In some embodiments, the ASD is an SDI.

[0179] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 22.7 wt% of the ASD or SDI, about 73.3 wt% mannitol (e.g., mannitol M100), about 2.3 wt% crospovidone, about 1.1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.6 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64) in a weight ratio of about 20:80 relative to the intragranular component. In some embodiments, the ASD is an SDI.

[0180] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 23.4 wt% of the ASD or SDI, about 52.6 wt% mannitol (e.g., mannitol M100), about 17.5 wt% starch, about 4.7 wt% crospovidone, about 1.2 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.6 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., HPMC E3LV) in a weight ratio of about 20:80 relative to the intragranular component. In some embodiments, the ASD is an SDI.

[0181] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 22.9 wt% of the ASD or SDI, about 54.9 wt% mannitol (e.g., mannitol M100), about 18.3 wt% starch, about 2.3 wt% crospovidone, about 1.1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.6 wt% of sodium stearyl fumarate; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64) in a weight ratio of about 20:80 relative to the intragranular component. In some embodiments, the ASD is an SDI.

[0182] In some embodiments, a composition provided herein comprises a core, the core comprising an intragranular component, the intragranular component comprising about 20 wt% of the ASD or SDI, about 60 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 0.5 wt% of sodium stearyl fumarate; the ASDWSGR Docket No. 51503-780.601or SDI comprising the Compound B and the polymer (e.g., HPMC) in a weight ratio of about 20:80 relative to the intragranular component. In some embodiments, the ASD is an SDI.

[0183] In some embodiments, the extragranular component comprises less than about 90%, about 80%, about 70%, or about 60% by weight of the core. In some embodiments, the extragranular component comprises less than about 50% by weight of the core. In some embodiments, the extragranular component comprises less than about 40% by weight of the core. In some embodiments, the extragranular component comprises less than about 30% by weight of the core. In some embodiments, the extragranular component comprises less than about 20% by weight of the core. In some embodiments, the extragranular component comprises less than about 18% by weight of the core. In some embodiments, the extragranular component comprises less than about 17% by weight of the core. In some embodiments, the extragranular component comprises less than about 16% by weight of the core. In some embodiments, the extragranular component comprises less than about 15% by weight of the core.

[0184] In some embodiments, the extragranular component comprises about 1% to about 50% by weight of the core. In some embodiments, the extragranular component comprises about 1% to about 40% by weight of the core. In some embodiments, the extragranular component comprises about 1% to about 30% by weight of the core. In some embodiments, the extragranular component comprises about 5% to about 25% by weight of the core. In some embodiments, the extragranular component comprises about 7% to about 22% by weight of the core. In some embodiments, the extragranular component comprises about 10% to about 20% by weight of the core.

[0185] In some embodiments, the extragranular component comprises about 10% by weight of the core. In some embodiments, the extragranular component comprises about 11% by weight of the core. In some embodiments, the extragranular component comprises about 12% by weight of the core. In some embodiments, the extragranular component comprises about 13% by weight of the core. In some embodiments, the extragranular component comprises about 14% by weight of the core. In some embodiments, the extragranular component comprises about 15% by weight of the core. In some embodiments, the extragranular component comprises about 16% by weight of the core. In some embodiments, the extragranular component comprises about 17% by weight of the core. In some embodiments, the extragranular component comprises about 18% by weight of the core. In some embodiments, the extragranular component comprises about 19% by weight of the core.

[0186] Provided in some embodiments herein is a pharmaceutical composition comprising a core, the core comprising an extragranular component. In some embodiments, the extragranular component comprises at least a portion of the filler, at least a portion of the binder, at least a portion of the glidant, at least a portion of the lubricant, or a combination thereof. In some embodiments, the extragranular component comprises at least a portion of the filler, at least a portion of the binder, at least a portion of the lubricant, or a combination thereof. In some embodiments, the extragranular component comprises a filler, a binder, a lubricant, or a combination thereof. In some embodiments, the extragranular component comprises a filler (e.g., mannitol or starch), a binder (e.g., crospovidone), a lubricant (e.g., sodium stearylWSGR Docket No. 51503-780.601fumarate), or a combination thereof. In some embodiments, the extragranular component comprises mannitol, crospovidone, and sodium stearyl fumarate.

[0187] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 5 wt% to about 15 wt% of mannitol, about 1 wt% to about 5 wt% of crospovidone, and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the core. In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 5 wt% to about 15 wt% of mannitol, about 1 wt% to about 5 wt% of crospovidone, and about 0.1 wt% to about 1 wt% of sodium stearyl fumarate relative to the core; the ASD or SDI comprising the Compound B and the polymer (e.g., PVP-VA64 or HPMC E3LV) in a weight ratio of about 20:80.

[0188] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 10 wt% mannitol (e.g., mannitol M200), about 3.5 wt% crospovidone and about 0.5 wt% of sodium stearyl fumarate relative to the core.

[0189] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 10 wt% mannitol (e.g., mannitol M200), about 4 wt% crospovidone, and about 0.5 wt% of sodium stearyl fumarate relative to the core.

[0190] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 10 wt% mannitol (e.g., mannitol M200), about 1.5 wt% crospovidone, and about 0.5 wt% of sodium stearyl fumarate relative to the core.

[0191] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 10 wt% mannitol (e.g., mannitol M200), about 2 wt% crospovidone, and about 0.5 wt% of sodium stearyl fumarate relative to the core.

[0192] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 9.5 wt% mannitol (e.g., mannitol M200), about 4 wt% crospovidone, and about 1 wt% of sodium stearyl fumarate relative to the core.

[0193] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 60 wt% to about 90 wt% of mannitol, about 5 wt% to about 35 wt% of crospovidone, and about 1 wt% to about 10 wt% of sodium stearyl fumarate relative to the extragranular component.

[0194] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 71.4 wt% mannitol (e.g., mannitol M200), about 25.0 wt% crospovidone and about 3.6 wt% of sodium stearyl fumarate relative to the extragranular component.WSGR Docket No. 51503-780.601

[0195] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 69.0 wt% mannitol (e.g., mannitol M200), about 27.6 wt% crospovidone, and about 3.5 wt% of sodium stearyl fumarate relative to the extragranular component.

[0196] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 83.3 wt% mannitol (e.g., mannitol M200), about 12.5 wt% crospovidone, and about 4.2 wt% of sodium stearyl fumarate relative to the extragranular component.

[0197] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 80 wt% mannitol (e.g., mannitol M200), about 16 wt% crospovidone, and about 4 wt% of sodium stearyl fumarate relative to the extragranular component.

[0198] In some embodiments, a composition provided herein comprises a core, the core comprising an extragranular component, the extragranular component comprising about 65.5 wt% mannitol (e.g., mannitol M200), about 27.6 wt% crospovidone, and about 6.9 wt% of sodium stearyl fumarate relative to the extragranular component.

[0199] Provided in some embodiments herein is a pharmaceutical composition comprising a shell. In some embodiments, the shell comprises a protective layer (e.g., a seal coat). In some embodiments, the shell comprises a coating. In some embodiments, the shell comprises an enteric coating. In some embodiments, the shell comprises a protective layer (e.g., a seal coat) and an enteric coating. In some embodiments, the shell comprises one or more coats of the protective layer, the enteric coating, or both. For example, the shell can comprise two coats of the protective layer and one coat of the enteric coating. In some embodiments, the protective layer comprises one or more coats (e.g., two coats). In some embodiments, the enteric coating comprises one or more coats (e.g., two coats). In some embodiments, the protective layer (e.g., the seal coat) is a sub-coat. In some embodiments, the enteric coating is atop coat. In some embodiments, the protective layer (e.g., the seal coat) is atop coat. In some embodiments, the enteric coating is a sub-coat.

[0200] In some embodiments, a coating disclosed herein is manufactured with a spray rate of about 3 to 20 g / min. In some embodiments, a coating disclosed herein is manufactured with a spray rate of about 5 to 15 g / min. In some embodiments, a coating disclosed herein is manufactured with a spray rate of about 6 to 12 g / min. In some embodiments, a coating disclosed herein is manufactured with a spray rate of about 6 to 10 g / min. In some embodiments, a coating disclosed herein is manufactured with a spray rate of about 6 to 9 g / min. In some embodiments, a coating disclosed herein is manufactured with a spray rate of about 6.5 to 8.5 g / min. In some embodiments, a coating disclosed herein is manufactured with an inlet temperature of about 30-80 °C. In some embodiments, a coating disclosed herein is manufactured with an inlet temperature of about 35-75 °C. In some embodiments, a coating disclosed herein is manufactured with an inlet temperature of about 40-70 °C. In some embodiments, a coating disclosed herein is manufactured with an inlet temperature of about 43-67 °C. In some embodiments, a coating disclosedWSGR Docket No. 51503-780.601herein is manufactured with an inlet temperature of about 50-70 °C. In some embodiments, a coating disclosed herein is manufactured with an inlet temperature of about 50-60 °C. In some embodiments, a coating disclosed herein is manufactured with an inlet temperature of about 53-56 °C. In some embodiments, a coating disclosed herein is manufactured with an exhaust air temperature of about 25-80 °C. In some embodiments, a coating disclosed herein is manufactured with an exhaust air temperature of about 35-70 °C. In some embodiments, a coating disclosed herein is manufactured with an exhaust air temperature of about 35-60 °C. In some embodiments, a coating disclosed herein is manufactured with an exhaust air temperature of about 40-50 °C. In some embodiments, a coating disclosed herein is manufactured with an exhaust air temperature of about 43-48 °C.

[0201] In some embodiments, the protective layer (e.g., a seal coat) comprises polyvinyl alcohol (PVA), HPMC, or a combination thereof. In some embodiments, the enteric coating comprises polymethacrylate (e.g., a copolymer of methacrylic acid). In some embodiments, the enteric coating comprises polymethacrylate L100-55 grade. In some embodiments, the enteric coating comprises a polymer that is sold under the trade name Eudragit L100-55.

[0202] In some embodiments, the shell comprises less than 50% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 40% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 30% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 25% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 20% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 17% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 15% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 13% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 12% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 11% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 10% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 9% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 8% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 7% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 6% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 5% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 4% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 3% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 2% by weight of the pharmaceutical composition. In some embodiments, the shell comprises less than 1% by weight of the pharmaceutical composition.

[0203] In some embodiments, the shell comprises 1% to 50% by weight of the pharmaceutical composition. In some embodiments, the shell comprises 1% to 40% by weight of the pharmaceutical composition. In some embodiments, the shell comprises 1% to 30% by weight of the pharmaceuticalWSGR Docket No. 51503-780.601composition. In some embodiments, the shell comprises 1% to 25% by weight of the pharmaceutical composition. In some embodiments, the shell comprises 1% to 20% by weight of the pharmaceutical composition. In some embodiments, the shell comprises 1% to 15% by weight of the pharmaceutical composition. In some embodiments, the shell comprises 1% to 10% by weight of the pharmaceutical composition. In some embodiments, the shell comprises 5% to 10% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 9% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 8% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 7% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 6% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 5% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 4% by weight of the pharmaceutical composition. In some embodiments, the shell comprises about 3% by weight of the pharmaceutical composition.

[0204] In some embodiments, the protective layer (e.g., a seal coat) comprises about 0.5% to about 10% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 0.01% to about 10% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 0.1% to about 10% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 0.5% to about 7% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 0.5% to about 5% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 1% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 2% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 3% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 4% by weight of the pharmaceutical composition. In some embodiments, the protective layer (e.g., a seal coat) comprises about 5% by weight of the pharmaceutical composition.

[0205] In some embodiments, the enteric coating comprises about 0.5% to about 25% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 0.01% to about 10% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 0.1% to about 10% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 1% to about 20% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 5% to about 15% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 5% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 6% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 7% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises aboutWSGR Docket No. 51503-780.6018% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 9% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 10% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 11% by weight of the pharmaceutical composition. In some embodiments, the enteric coating comprises about 12% by weight of the pharmaceutical composition. In some embodiments, the weight of each layer of coating is calculated based on the total weight of the tablet before such layer of the coating. In some embodiments, the weight of each layer of coating is calculated based on the total weight of the tablet.

[0206] Provided in some embodiments herein is a pharmaceutical composition comprising a core and optionally a shell, the core comprising, by weight, about 15-25% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 60-80% of mannitol; about 4-12% of crospovidone; about 0.5-2% of silicon dioxide; and about 0.5-2% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 71% of mannitol; about 7% of crospovidone; about 1% of silicon dioxide; and about 1% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 70-71% (e.g., 70.5%) of mannitol; about 7-8% (e.g., 7.5%) of crospovidone; about 1% of silicon dioxide; and about 1% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition. In some embodiments, the SDI is an ASD.

[0207] Provided in some embodiments herein is a pharmaceutical composition comprising a core and optionally a shell, the core comprising, by weight, about 15-25% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 45-65% of mannitol; about 5-25% of starch; about 4-12% crospovidone; about 0.5-2% of silicon dioxide; and about 0.5-2% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 55% of mannitol; about 15% of the starch; about 8% of crospovidone; about 1% of silicon dioxide; and about 1% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition. In some embodiments, the SDI is an ASD.

[0208] Provided in some embodiments herein is a pharmaceutical composition comprising a core and optionally a shell, the core comprising, by weight, about 15-25% of an SDI, the SDI comprising aboutWSGR Docket No. 51503-780.60120% of the Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 65-85% of mannitol; about 1-5% of crospovidone; about 0.5-2% of silicon dioxide; and about 0.5-2% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 75% of mannitol; about 3% of crospovidone; about 1% of silicon dioxide; and about 1% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition. In some embodiments, the SDI is an ASD.

[0209] Provided in some embodiments herein is a pharmaceutical composition comprising a core and optionally a shell, the core comprising, by weight, about 15-25% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 65-85% of mannitol; about 1-7% of crospovidone; about 0.5-2% of silicon dioxide; and about 0.5-2% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 74-75% (e.g., 74.5%) of mannitol; about 3-4% (e.g., 3.5%) of crospovidone; about 1% of silicon dioxide; and about 1% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition. In some embodiments, the SDI is an ASD.

[0210] Provided in some embodiments herein is a pharmaceutical composition comprising a core and optionally a shell, the core comprising, by weight, about 15-25% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 50-70% of mannitol; about 5-25% of starch; about 1-7% of crospovidone; about 0.5-2% of silicon dioxide; and about 0.5-2% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate; about 58% of mannitol; about 16% of starch; about 4% of crospovidone; about 1% of silicon dioxide; and about 1% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition. In some embodiments, the SDI is an ASD.

[0211] Provided in some embodiments herein is a pharmaceutical composition comprising a core and optionally a shell, the core comprising, by weight, about 15-25% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 60-80% of mannitol; about 4-12% of crospovidone; about 0.5-2% of silicon dioxide; and about 0.5-3% of sodium stearyl fumarate; and theWSGR Docket No. 51503-780.601shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 85% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 69-70% (e.g., about 69.5%) of mannitol; about 8% of crospovidone; about 1% of silicon dioxide; and about 0.5-1.5% (e.g., 0.5%, 1.0%, or 1.5%) of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a core and a shell, the core comprising, by weight, about 20% of an SDI, the SDI comprising about 20% of the Compound B and about 80% of HPMC; about 69.5% of mannitol; about 8% of crospovidone; about 1% of silicon dioxide; and about 1.5% of sodium stearyl fumarate; and the shell comprising a film coating, optionally an enteric coating; wherein the core comprises about over 90% wt (e.g., about 92%) of the pharmaceutical composition. In some embodiments, the SDI is an ASD.

[0212] Provided herein in some embodiments is a pharmaceutical composition comprising a core and a shell, the core comprising an intragranular component and an extragranular component, wherein the intragranular component comprises, relative to the core, about 20 wt% of the ASD, and wherein the ASD comprises the Compound B an HPMC in a weight ratio of about 20:80; about 60 wt% mannitol M100; about 4 wt% crospovidone; about 1 wt% untreated fumed colloidal silicon dioxide; and about 0.5 wt% sodium stearyl fumarate; and wherein the intragranular component comprises, relative to the core, about 9.5 wt% mannitol M200; about 4 wt% crospovidone; about 1 wt% sodium stearyl fumarate. In some embodiments, the shell comprises about 2 wt% of a protective layer (e.g., a seal coat) and about 6-7 wt% of an enteric coating. In some embodiments, the shell comprises about 2 wt% of a protective layer (e.g., a seal coat) and about 7 wt% of an enteric coating. In some embodiments, the ASD is an SDI.

[0213] Provided herein in some embodiments is a pharmaceutical composition comprising a core comprising about 92% wt of the composition and a shell (e.g., a coating) comprising about 8% wt of the composition, wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the pharmaceutical composition) about 18 wt% of the ASD, and wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80; about 55 wt% mannitol M100; about 3-4 wt% crospovidone (e.g., about 3.7%); about 0.5-1 wt% (e.g., about 0.9%) untreated fumed colloidal silicon dioxide; and about 0.1 -0.5 wt% (e.g., about 0.5%) sodium stearyl fumarate; and wherein the intragranular component comprises, relative to the pharmaceutical composition about 9 wt% mannitol M200; about 3-4 wt% crospovidone (e.g., about 3.7%); about 0.1-0.5 wt% (e.g., about 0.5%) sodium stearyl fumarate; and wherein the shell comprises (relative to the pharmaceutical composition): about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6-7 wt% of an enteric coating comprising polymethacrylate L100-55 grade (e.g., a polymer sold under the trade name Eudragit L100-55). In some embodiments, the ASD is an SDI.WSGR Docket No. 51503-780.601

[0214] Provided herein, in some embodiments, is a pharmaceutical composition comprising a core comprising about 91-92% wt of the composition and a shell (e.g., a coating) comprising about 8-9% wt of the composition, wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the core) about 20 wt% of the ASD, and wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80; about 60 wt% mannitol (e.g., M100); about 4 wt% crospovidone; about 1 wt% silicon dioxide; and about 0.5 wt% sodium stearyl fumarate; and wherein the intragranular component comprises (relative to the core) about 9.5 wt% mannitol (e.g., M200); about 4 wt% crospovidone; about 1 wt% sodium stearyl fumarate; and wherein the shell comprises (relative to the pharmaceutical composition) about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6-7 wt% of an enteric coating comprising polymethacrylate L100-55 grade (e.g., a polymer sold under the trade name Eudragit L100-55). In some embodiments, the ASD is an SDI

[0215] In some embodiments, the pharmaceutical composition provided herein comprises about 0.1 to about 50 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 0.1 to about 40 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 0.1 to about 30 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 0.1 to about 20 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 0.5 to about 15 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 0.5 to about 12 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 1 to about 10 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 2 to about 8 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 16 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 15 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 14 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 13 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 12 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical compositionWSGR Docket No. 51503-780.601provided herein comprises about 11 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 10 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 9 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 8 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 7 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 6 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 5 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 4 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 3 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 2 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the pharmaceutical composition provided herein comprises about 1 mg of the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof. In some embodiments, the Compound B or a pharmaceutically acceptable salt of a stereoisomer thereof is Compound B.

[0216] In some embodiments, a pharmaceutical composition provided herein is a tablet (e.g., in tablet form). In some embodiments, a pharmaceutical composition provided herein is a capsule (e.g., in capsule form).

[0217] In some embodiments, a pharmaceutical composition comprises a tablet (e.g., a coated tablet). In some embodiments, the tablet comprises a core comprising about 100 mg of the composition and a shell comprising about 9 mg, wherein the core comprises an intragranular component comprising about 85.5 mg and an extragranular component comprising about 14.5 mg, wherein the intragranular component comprises: about 20 mg of the ASD, wherein the ASD comprises 4 mg of the Compound B and 16 mg of HPMC; about 60 mg of mannitol (e.g., M100); about 4 mg of crospovidone; about 1 mg of silicon dioxide; and about 0.5 mg sodium stearyl fumarate; and wherein the extragranular component comprises: about 9.5 mg of mannitol (e.g., M200); about 4 mg of crospovidone; about 1 mg of sodium stearyl fumarate; and wherein the shell comprises: about 2 mg of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 7 mg of an enteric coating comprising polymethacrylate (e.g., L100-55 grade). In some embodiments, the total weight of the tablet comprises about 109 mg.

[0218] In some embodiments, a pharmaceutical composition comprises a tablet (e.g., a coated tablet). In some embodiments, the tablet comprises a core comprising about 150 mg of the composition and a shell comprising about 13.5 mg, wherein the core comprises an intragranular component comprising aboutWSGR Docket No. 51503-780.601128.25 mg and an extragranular component comprising about 21.75 mg, wherein the intragranular component comprises: about 30 mg of the ASD, wherein the ASD comprises 6 mg of the Compound B and 24 mg of HPMC; about 90 mg of mannitol (e.g., M100); about 6 mg of crospovidone; about 1.5 mg of silicon dioxide; and about 0.75 mg sodium stearyl fumarate; and wherein the extragranular component comprises: about 14.25 mg of mannitol (e.g., M200); about 6 mg of crospovidone; about 1.5 mg of sodium stearyl fumarate; and wherein the shell comprises: about 3 mg of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 10.5 mg of an enteric coating comprising polymethacrylate (e.g., L100-55 grade). In some embodiments, the total weight of the tablet comprises about 163.5 mg.

[0219] In some embodiments, the pharmaceutical composition comprises a tablet (e.g., a coated tablet). In some embodiments, the tablet comprises a core comprising about 225 mg of the composition and a shell comprising about 20.25 mg, wherein the core comprises an intragranular component comprising about 192.375 mg and an extragranular component comprising about 32.625 mg, wherein the intragranular component comprises: about 45 mg of the ASD, wherein the ASD comprises 9 mg of the Compound B and 36 mg of HPMC; about 135 mg of mannitol (e.g., M100); about 9 mg of crospovidone; about 2.25 mg of silicon dioxide; and about 1.125 mg sodium stearyl fumarate; and wherein the extragranular component comprises: about 21.375 mg of mannitol (e.g., M200); about 9 mg of crospovidone; about 2.25 mg of sodium stearyl fumarate; and wherein the shell comprises: about 4.5 mg of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 15.75 mg of an enteric coating comprising polymethacrylate (e.g., L100-55 grade). In some embodiments, the total weight of the tablet comprises about 245.25 mg.

[0220] In some embodiments, the pharmaceutical composition comprises a tablet (e.g., a coated tablet). In some embodiments, the tablet comprises a core comprising about 200-250 mg of the composition. In some embodiments, the tablet comprises a core comprising about 150-300 mg of the composition. In some embodiments, the tablet comprises a shell comprising about 15-25 mg. In some embodiments, the core comprises an intragranular component comprising about 170-210 mg and an extragranular component comprising about 20-40. In some embodiments, the core comprises 9 mg of Compound B. In some embodiments, the core comprises Compound B or a pharmaceutically acceptable salt thereof that is equivalent to 9 mg of Compound B. In some embodiments, the core comprises 10-60 mg of a polymer. In some embodiments, the core comprises 25-45 mg of a polymer. In some embodiments, the core comprises 25-45 mg of HPMC. In some embodiments, the core comprises 100-200 mg of a filler. In some embodiments, the core comprises 140-170 mg of a filler. In some embodiments, the core comprises 156 mg of a filler. In some embodiments, the filler comprises mannitol. In some embodiments, the core comprises 10-30 mg of a binder. In some embodiments, the core comprises 15-21 mg of a binder. In some embodiments, the core comprises 18 mg of a binder. In some embodiments, the binder is crospovidone. In some embodiments, the core comprises 0.5-5 mg of a glidant. In some embodiments, the core comprises 2.25 mg of a glidant. In some embodiments, the glidant is silicon dioxide. In someWSGR Docket No. 51503-780.601embodiments, the glidant is Fumed Colloidal Silicon Dioxide. In some embodiments, the core comprises 0.5-8 mg of a lubricant. In some embodiments, the core comprises 3.4 mg of a lubricant. In some embodiments, the lubricant is Sodium Stearyl Fumarate. In some embodiments, the shell comprises a film coating. In some embodiments, the shell comprises a film coating and an enteric coating.

[0221] Provided in some embodiments herein is an ASD or an SDI that has a glass transition temperature (Tg). In some embodiments, the ASD or SDI has a Tgof about 50 °C. In some embodiments, the ASD or SDI has a Tgof about 75 °C. In some embodiments, the ASD or SDI has a Tgof about 90 °C. In some embodiments, the ASD or SDI has a Tgof about 100 °C. In some embodiments, the ASD or SDI has a Tgof about 100 °C. In some embodiments, the ASD or SDI has a Tgof about 103 °C. In some embodiments, the ASD or SDI has a Tgof about 105 °C. In some embodiments, the ASD or SDI has a Tgof about 107 °C. In some embodiments, the ASD or SDI has a Tgof about 109 °C. In some embodiments, the ASD or SDI has a Tgof about 111 °C. In some embodiments, the ASD or SDI has a Tgof about 113 °C. In some embodiments, the ASD or SDI has a Tgof about 115 °C. In some embodiments, the Tgis determined at 0.0% relative humidity. In some embodiments, the Tgis determined according to the conditions provided in Tables 25 and 26. In some embodiments, the ASD or SDI has a single glass transition temperature. In some embodiments, the ASD is an SDI.

[0222] In some embodiments, an ASD or SDI provided herein provides a maximum concentration of solubilized Compound B after the gastric phase of a non-sink dissolution assay (CmaxGB) of greater than about 100 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 200 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 300 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 400 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 500 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 550 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 600 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 650 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 700 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of greater than about 750 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 200-1000 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 500-900 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 600-800 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 600 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 607 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 610 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 630 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 650 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 670 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 690 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 710 pgWSGR Docket No. 51503-780.601Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 730 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 750 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 767 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxGB of about 770 pg Compound B / mL. In some embodiments, the ASD is an SDI

[0223] In some embodiments, an ASD or SDI provided herein provides a maximum concentration of solubilized Compound B after the intestinal phase of a non-sink dissolution assay (CmaxIB; e.g., a maximum concentration of solubilized Compound B in simulated intestinal fluid, CmaxFaSSIF) of greater than about 100 μg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 150 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 200 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 250 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 300 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 320 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of greater than about 350 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 150 -500 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 100 -1000 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 200 -800 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 250 -600 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 250 -550 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 300 -400 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 300 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 310 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 320 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 330 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 340 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 345 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 350 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 360 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 370 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 380 pg Compound B / mL. In some embodiments, the ASD or SDI provides a CmaxIB of about 390 pg Compound B / mL. In some embodiments, the ASD is an SDI

[0224] In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±50% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDI. In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±30% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDL In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±20% of the AUC35-210 FaSSIF provided by a corresponding composition ofWSGR Docket No. 51503-780.601Compound B without the ASD or SDI. In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±15% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDI. In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±10% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDI. In some embodiments, the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±5% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDI. In some embodiments, the ASD is an SDI.

[0225] Provided herein in some embodiments is an ASD or SDI comprising less than 20% total impurities as measured by high-performance liquid chromatography (HPLC) after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 15% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 12% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 10% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 9% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 8% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 7% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 6% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 5% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 4% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 3% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 2% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 1% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises less than about 0.5% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 5% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 5% total impurities as measured by HPCL after being stored for 2 months at aboutWSGR Docket No. 51503-780.60140°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 2% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 1.2% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 1% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 0.5% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 0.4% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 0.3% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 0.2% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD or SDI comprises about 0.1% total impurities as measured by HPCL after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging). In some embodiments, the ASD is an SDI

[0226] In some embodiments, after being stored for 2 months at 40°C / 75%RH, the ASD has an assay value of Compound B that is within ±20%, ±15%, ±10%, or ±5% of the initial assay value. In some embodiments, after being stored for 2 months at 40°C / 75%RH, the SDI has an assay value of Compound B that is within ±20%, ±15%, ±10%, or ±5% of the initial assay value.

[0227] In some embodiments, the ASD or SDI has a Dv50 of about 0.1 pm to about 20 pm. In some embodiments, the ASD or SDI has a Dv50 of about 20 pm to about 100 pm. In some embodiments, the ASD or SDI has a Dv50 of about 0.1 pm to about 15 pm. In some embodiments, the ASD or SDI has a Dv50 of about 0.5 μm to about 10 μm. In some embodiments, the ASD or SDI has a Dv50 of about 0.5 pm to about 7 pm. In some embodiments, the ASD or SDI has a Dv50 of about 1 μm to about 5 μm. In some embodiments, the ASD or SDI has a Dv50 of about 10 pm. In some embodiments, the ASD or SDI has a Dv50 of about 9 pm. In some embodiments, the ASD or SDI has a Dv50 of about 8 pm. In some embodiments, the ASD or SDI has a Dv50 of about 7 pm. In some embodiments, the ASD or SDI has a Dv50 of about 6 pm. In some embodiments, the ASD or SDI has a Dv50 of about 5 pm. In some embodiments, the ASD or SDI has a Dv50 of about 4 pm. In some embodiments, the ASD or SDI has a Dv50 of about 3 μm. In some embodiments, the ASD or SDI has a Dv50 of about 2 μm. In some embodiments, the ASD or SDI has a Dv50 of about 1 pm. In some embodiments, the ASD is an SDI

[0228] Provided herein in some embodiments is an ASD or SDI that remains amorphous for at least a month when stored at 25°C / 60%RH condition, as determined by X-ray powder diffraction (XRPD). In some embodiments, the ASD or SDI remains amorphous for at least two months when stored at 25°C / 60%RH condition, as determined by XRPD. In some embodiments, the ASD or SDI remains amorphous for at least a month when stored at 40°C / 75%RH condition, as determined by XRPD. In some embodiments, the ASD or SDI remains amorphous for at least two months when stored at 40°C / 75%RH condition, as determined by XRPD. In some embodiments, the ASD is an SDIWSGR Docket No. 51503-780.601

[0229] In some embodiments, a wet ASD or SDI as described herein has a total solid of about 1-30 wt%. In some embodiments, the wet ASD or SDI has a total solid of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wt%. In some embodiments, the wet ASD or SDI has a total solid of about 4 wt%. In some embodiments, the wet ASD or SDI has a total solid of about 8 wt%. In some embodiments, the wet ASD or SDI has a total solid of about 1-10 wt%.

[0230] In some embodiments, the ASD or SDI is chemically stable for at least 1 day when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 2 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 3 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 4 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 5 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 6 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 7 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 8 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 9 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD or SDI is chemically stable for at least 10 days when stored at 2-8 °C when the ASD or SDI is wet. In some embodiments, the ASD is an SDI.

[0231] In some embodiments, a chemically stable, wet ASD or SDI does not exhibit any degradation peak of Compound B as determined by HPLC.

[0232] Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 20 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 15 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 10 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 7 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 5 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 4 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 3 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 2 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 1 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 0.5 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 0.1 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of less than about 0.05 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providingWSGR Docket No. 51503-780.601a CmaxGB of less than about 0.01 μg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxGB of 0 pg Compound B / mL.

[0233] Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of greater than about 200 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of greater than about 300 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of greater than about 400 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of greater than about 500 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of greater than about 550 pg Compound B / mL.Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of about 500 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of about 520 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of about 550 pg Compound B / mL. Provided in some embodiments herein is a pharmaceutical composition providing a CmaxIB of about 570 pg Compound B / mL.

[0234] Provided herein in some embodiments is a pharmaceutical composition comprising granules. In some embodiments, the pharmaceutical composition comprises a granule size Dv90 of about 1250 μm to about 100 μm (e.g., a particle size distribution in which 90% of the particle, by volume, have a particle diameter that is less than the DV90 value). In some embodiment, the pharmaceutical composition comprises a granule size Dv90 of about 200 μm to about 1000 μm. In some embodiment, the pharmaceutical composition comprises a granule size Dv90 of about 300 pm to about 750 pm. In some embodiment, the pharmaceutical composition comprises a granule size Dv90 of about 500 μm to about 700 μm. In some embodiment, the pharmaceutical composition comprises a granule size Dv90 of less than about 700 μm. In some embodiment, the pharmaceutical composition comprises a granule size Dv90 of about 600 pm.

[0235] In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 20 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 15 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 10 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 8 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 5 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 4 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 3 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 2 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of less than about 1 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of about 5 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of about 4 wt%. In some embodiments, a pharmaceutical composition provided hereinWSGR Docket No. 51503-780.601comprises a water content of about 3 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of about 2 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of about 1.4 wt%. In some embodiments, a pharmaceutical composition provided herein comprises a water content of about 1 wt%.

[0236] In some embodiments, a pharmaceutical composition provided herein comprises less than about 25% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 20% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 15% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 10% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 8% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 5% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 4% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 3% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 2% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 1% total impurities. In some embodiments, a pharmaceutical composition provided herein comprises less than about 0.5% total impurities.EXAMPLES

[0237] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. The compound described herein can be synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology can be employed. The compound can be prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials and reagents used for the synthesis of the compound described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acres Organics, Fluka, and Fischer Scientific. The starting materials can be available from commercial sources or can be readily prepared. By way of example only, provided are schemes for preparing the Examples described herein.

[0238] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, ProtectiveWSGR Docket No. 51503-780.601Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).

[0239] Examples can be made using known techniques and further chemically modified, in some embodiments, to facilitate intranuclear transfer to, e.g., a splicing complex component, a spliceosome or a pre-mRNA molecule. One of ordinary skill in the art will appreciate the standard medicinal chemistry approaches for chemical modifications for intranuclear transfer (e.g., reducing charge, optimizing size, and / or modifying lipophilicity).Stereochemistry:

[0240] (±) or racemic indicates that the product is a racemic mixture of enantiomers. For example (±) ( 1S,2S,3R,5R) or racemic ( 1S,2S,3R,5R) indicates that the relative product stereochemistry shown is based on known stereochemistry of similar compounds and or reactions and the product is a racemic mixture of enantiomers of both (1S,2S,3A,5A) and ( 1R,2R,3S,5S) stereoisomers. A compound in which the absolute stereochemistry of separated enantiomers is undetermined is represented as being either of the single enantiomers, for example (1S,2S,3A,5A) or (1A,2A,3S,5S) or drawn as being either possible single enantiomer. In such cases, the product is pure and a single enantiomer, but absolute stereochemistry is not identified, but relative stereochemistry is known and indicated.Example 1: Synthesis of 6-(6-(((lA, 2S,3R, 57?)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[< / ]oxazol-5-ol (Compound A) and 6-(6-(((17?,27?,3iS,5iS)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[< / ]oxazol-5-ol (Compound B).dioxaneCompound BWSGR Docket No. 51503-780.601

[0241] Synthesis of 2-amino-4-methoxyphenol.

[0242] A mixture of 4-methoxy-2-nitrophenol (25.0 g, 0.15 mol) and Pd / C (2.5 g) in MeOH (500 mL) was stirred, degassed with hydrogen 3 times and then held with stirring at 20 °C under hydrogen for 2 d The reaction mixture was filtered and the cake was washed with MeOH (350 mL*3). The filtrated was combined and concentrated in vacuum to afford the product 2-amino-4-methoxyphenol as brown solid (20.0 g, yield 97.2 %). LCMS: m / z 140.1 [M+H]+; tR= 0.93 min.

[0243] Synthesis of 5-methoxy-2-methylbenzo[r / | oxazole.

[0244] A mixture of 2-amino-4-methoxyphenol (20.0 g, 0.14 mol) in trimethyl orthoacetate (50 mL) was heated to 100 °C with stirring and held for 1 h. The mixture was concentrated and the residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 60 mL / min, EA in PE 0 % ~ 35 %, 30 min, 35 %, 12 min, UV 254280) to give the desired product 5 -methoxy-2 -methylbenzo [aQ oxazole as orange oil (17.5 g, yield 74.6 %). LCMS: m / z 164.1 [M+H]+; tR= 1.41 min.

[0245] Synthesis of 6-bromo-5-methoxy-2-methylbenzo[< / ]oxazole.

[0246] NBS (19.6 g, 0.11 mol) was added to a mixture of 5-mcthoxy-2-mcthylbcnzo|t / |oxazolc (17.5 g, 0.11 mol) in AcOH (150 mL). This resulting mixture was stirred at 20 °C for 18 h. The mixture was quenched with ice water, neutralized with Na2COs aqueous, extracted with EtOAc (200 mL*3). The extracts were concentrated and the residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 60 mL / min, EA in PE 0 % ~ 10 %, 30 min, 20 %, 15 min, UV 254280) to give the desired product 6- bromo-5-methoxy-2 -methylbenzo [<7| oxazole as pink solid (20.5 g, yield 77.0 %). LCMS: m / z 242.1; 243.9 [M+H]+; tR= 1.70 min. ’HNMR (500 MHz, CDCWs) 57.68 (s, 1H), 7.17 (s, 1H), 3.93 (s, 3H), 2.61 (s, 3H).

[0247] Synthesis of 6-bromo-2-methylbenzo[< / ]oxazol-5-ol.

[0248] BBr, (210 mL, 1 mol / 1, 0.21 mol) was added to a mixture of 6-bromo-5-methoxy-2- mcthylbcnzo|t / | oxazole (20.5 g, 0.085 mol) in DCM (30 mL) at 0 °C. This resulting mixture was stirred at 0 °C for 10 min and then warmed to 20 °C with stirring and held for 3 d. The mixture was quenched with ice water, neutralized with NaHCOs aqueous, extracted with EtOAc (360 mL*3). The extracts were concentrated and the residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 80 mL / min, EA in PE 0 % ~ 50 %, 30 min, 40 %, 10 min, then MeOH in DCM 20% UV 254280) to give the desiredWSGR Docket No. 51503-780.601product 6-bromo-2-methylbenzo[<7]oxazol-5-ol as grey solid (19.0 g, yield 98.6 %). LCMS: m / z 228.0; 230.0 [M+H]+; tR= 1.50 min.

[0249] Synthesis of 6-bromo-5-(methoxymethoxy)-2-methylbenzo[< / | oxazole.

[0250] MOMBr (15.6 g, 0.12 mol) was added drop wise to a mixture of 6-bromo-2-methylbenzo[<7|oxazol-5-ol (19.0 g, 0.08 mol) and DIPEA (37.7 g, 0.19 mol) in ACN (300 m ) at 5 °C. This resulting mixture was stirred at 5 °C and held for 30 min. The mixture was quenched with ice water, extracted with EtOAc (200 mL*3). The extracts were washed with brine (300 mb) and concentrated. The residue was purified by combi-flash (Biotage, Silica gel column, 330 g, 60 mL / min, EA in PE 0 % ~ 15 %, 20 min, 15 %, 5 min, 15 % ~ 25 %, 10 min, 25 %, 15 min, UV 254280) to give the desired product 6-bromo-5-(methoxymethoxy)-2-methylbenzo[<7]oxazole as pink solid (18.0 g, yield 79.5 %). LCMS: m / z 272.0; 274.0 [M+H]+; tR= 1.77 min.

[0251] Synthesis of 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)benzo | z / | oxazole.

[0252] A mixture of 6-bromo-5-(methoxymethoxy)-2-methylbenzo[<7]oxazole (50 g, 0.02 mol), pinacolboron (28.0 g, 0.11 mol), PdCLdppf (1.1 g, 1.5 mmol) and KOAc (10.8 g, 0.11 mol) in 1, 4-dioxane (300 mb) was heated to 100 °C with stirring and held for 50 h. The mixture was quenched with ice water, extracted with EtOAc (200 mL*3). The extracts were washed with brine (200 mb) and concentrated. The residue was purified by combi-flash (Biotage, Silica gel column, 20 g, 30 mL / min, EA in PE 0 % ~ 15 %, 20 min, 15 %, 6 min, 15 % ~ 25 %, 15 min, 25 %, 10 min, UV 254280) to give the desired product 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)bcnzo|t / | oxazole as pink solid (4.0 g, yield 68.2 %). LCMS: m / z 320.2 [M+H]+; tR= 1.86 min.

[0253] Synthesis of tert-butyl (15,2iS,57?)-2-fluoro-3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate.F

[0254] LHMDS (94 mL, 94 mmol, 1 N solution in THF) was added to a stirred solution of tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (15 g, 62.8 mmol) in 150 mL of anhydrous THF at -78 °C under nitrogen atmosphere. After stirring for 30 min, NFSI (26.6 g, 75 mmol) in 100 mL of anhydrous THF was added dropwise. The mixture was then stirred at -78 °C for 4 h, quenchend with saturated NH4CI aqueous solution (30 mL), estracted with EtOAc (80 mL X 3). The combined organic phases were dried over anhydrous Na2SO4, conentrated and purified by silica gelchromatography (0-5%WSGR Docket No. 51503-780.601EtOAc / petroleum ether) to give 6.5 g of tert-butyl ( I. S'.2. S'.5 / )-2-fliioro-3-oxo-9-azabicyclo|3,3.1 |nonanc-9-carboxylate as a white solid (40% yield). LCMS: m / z 202.1 [M-55]+; tR= 1.75 min.

[0255] Synthesis of tert-butyl (liS,2iS,57?)-2-fluoro-3-(methylimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.F

[0256] Methylamine (58.5 mb, 117 mmol, 2N solution in THF) and Ti(zPrO)4 (32.8 g, 117 mmol) were added to a stirred solution of tert-butyl ( I. S'.2. S'.5 / )-2-fliioro-3-oxo-9-azabicyclo|3,3.1 |nonanc-9-carboxylate (20 g, 77 mmol) in THF (I L) under N2 protection. The reaction mixture was stirred at room temperature for 2 h. Water (I L) was added to quench the reaction. The mixture was extracted with EtOAc (IL X 3). The combined organic phases were washed with brine, dried over anhydrous ISfeSCL and concentrated to give the crude product (lS,2S,5A)-2-fluoro-3-(methylimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (20 g, 95% yield), which was directly used in next step. LCMS: m / z 272 [M+H]+; fe = 1.58, 1.80 min.

[0257] Synthesis of tert-butyl (liS,27?,37?,57?)-2-fluoro-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.i,XNHBkNz J

[0258] NaBFL (4 g, 104 mmol) was added to a stirred solution of ( I. S'.2. S'.5 / ?)-2-fluoro-3 -(meth l imino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (7 g, 26 mmol) and MgCL (2.46 g, 26 mmol) in 30 mL of MeOH. After the addition, the mixture was stirred at room temperature for 2 h. Additional NaBH4 may be needed till LCMS indicated the imine was consumed completely. 100 mL of water was added to quench the reaction. The resulting mixture was extracted with EtOAc (180 mL X 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-5% MeOH / QLCL) give 2 g of tert-butyl (I. S'.2 / ?.3 / ?.5 / ?)-2-fluoro-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as colorless oil (40% yield), (high polar isomer). LCMS: m / z 273.2 [M+H]+; tR= 1.42 min.

[0259] Synthesis of tert-butyl (liS,27?,37?,57?)-3-((6-chloropyridazin-3-yl)(methyl)amino)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate.

[0260] A mixture of tert-butyl (lS,2A,3A,5A)-2-fluoro-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (2 g, 7.35 mmol), 3,6-dichloropyridazine (2.19 g, 14.7 mmol) and DIPEA (3.8 g, 29.4 mmol) in DMSO (10 ml) was stirred at 120 °C for 12 h. After cooling to room temperature, the mixture wasWSGR Docket No. 51503-780.601quenched with H2O (100 mL) and extracted with EtOAc (150 mL X 3). The combined organic layers were concentrated and purified with silica gel chromatography (0-50% EtOAc / petroleum ether) to give 1.5 g of tert-butyl ( I. S'.2 / ?.3 / ?.5 / ?)-3-((6-chloropyridazin-3-yl)(mcthyl)amino)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate white solid (54% yield). LCMS: m / z 385.2 [M+H]+; tR= 1.93 mm.

[0261] Chiral separation of tert-butyl (liS,27?,37?,57?)-3-((6-chloropyridazin-3-yl)(methyl)amino)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate.P21500 mg of racemic intermediate was separated by below chiral condition to give 630 mg of Pl isomer (1.596 min) and 630 mg of P2 isomer (4.811 min).

[0262] Instrument: SFC-150 (Waters)Column: AD 20*250mm, lOum (Daicel)Column temperature: 35 °CMobile phase: CO2 / MEOH(0.2%Methanol Ammonia) = 65 / 35Flow rate: lOO g / minBack pressure: 100 barDetection wavelength: 214 nmCycle time: 3.5minSample solution: 1500mg dissolved in 100ml MethanolInjection volume: 3ml

[0263] Synthesis of tert-butyl (LS',2 / ?,3 / ?,5 / ?)-2-fluoro-3-((6-(5-(methoxymethoxy)-2-m ethylbenzo [< / ] oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.

[0264] A mixture of tert-butyl ( I. S'.2 / ?.3 / ?.5 / ?)-3-((6-chloropyridazin-3-yl)(mcthyl)amino)-2-fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate (450 mg, 1.17 mmol), 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzo[t / ]oxazole (560 mg, 1.76 mmol), Pd(dppf)C12 (86 mg, 0.117 mmol) and K2CO3 (324 mg, 2.34 mmol) in 1,4-Dioxane (15 mL), water (5 ml) was stirred at 110°C for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to give 550 mg of tert-butyl ( \S.2R. R,5 / ?)-2-fl uoro-3 -((6-(5 -(methoxymethoxy)-2 -methylbenzo [d] oxazol-6-yl)pyridazin-3 -WSGR Docket No. 51503-780.601yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (86% yield). LCMS: m / z 541.9 [M+H]+; tR= 1.98 min.

[0265] Synthesis of 6-(6-(((15, 25,37?, 57?)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[< / ]oxazol-5-ol.Compound A

[0266] To a solution of tert-butyl (15,27?,37?,57?)-2-fluoro-3-((6-(5-(methoxymethoxy)-2-methylbenzo \d\ oxazol-6-yl)pyridazin-3 -yl)(methyl)amino)-9-azabicyclo [3.3.1 ]nonane-9-carboxylate (550 mg, 1.02 mmol) in CH2Q2 (7 mb) was added TFA (3 mL) and the mixture was stirred at room temperature for 2 h, monitored by LCMS. Then the mixture was concentrated and water (10 mL) was added. pH value was adjusted to 8-9 with saturated K2CO3 aqueous solution. The product was collected, concentrated and purified by C18 reversed phase column (0-70% 0.01% NH4HCO3 in H2O / CH3OH) to give 166 mg of 6-(6-(((15,25,37?,57?)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[<7]oxazol-5-ol (41% yield). 'H NMR (400 MHz, MeOD -< A) 58.17 (d, J= 9.9 Hz, 1H), 7.98 (s, 1H), 7.32 (d, J= 9.9Hz, 1H), 7.10 (s, 1H), 6.01 - 5.86 (m, 1H), 5.07 - 4.90 (m, 1H), 3.57-3.47 (m, 2H), 3.11 (s, 3H), 2.71 - 2.64 (m, 1H), 2.62 (s, 3H), 2.15 - 2.02 (m, 3H), 1.97- 1.78 (m, 4H). LCMS: m / z 398.1 [M+H]+; tR= 1.40 min.

[0267] Synthesis of tert-butyl (17?, 25,35, 55’)-2-fluoro-3-((6-(5-(methoxymethoxy)-2-m ethylbenzo [< / ] oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.

[0268] A mixture of tert-butyl (17?, 25,35, 55)-3-((6-chloropyridazin-3-yl)(methyl)amino)-2 -fluoro-9-azabicyclo[3.3.1]nonane-9-carboxylate (450 mg, 1.17 mmol), 5-(methoxymethoxy)-2-methyl-6-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzo[aQoxazole (560 mg, 1.76 mmol), Pd(dppf)C12 (86 mg, 0.117 mmol) and K2CO3 (324 mg, 2.34 mmol) in 1,4-Dioxane (15 mL), water (5 ml) was stirred at 110 °C for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to give 500 mg of tert-butyl (17?, 25,35, 55)-2 -fluoro-3-((6-(5-(methoxymethoxy)-2 -mcthylbcnzo|t / |oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (79% yield). LCMS: m / z 541.9 [M+H]+; tR= 1.98 min.WSGR Docket No. 51503-780.601

[0269] Synthesis of 6-(6-(((17?,27?,3iS,5iS)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[< / ]oxazol-5-ol.

[0270] To a solution of tert-butyl ( l / ?.2. S'.3. S'.5. S)-2-fluoro-3-((6-(5-(mcthoxymcthoxy)-2-methylbenzo \d\ oxazol-6-yl)pyridazin-3 -yl)(methyl)amino)-9-azabicyclo [3.3.1 ]nonane-9-carboxylate (500 mg, 0.92 mmol) in CH2Q2 (7 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 2 h, monitored by LCMS. Then the mixture was concentrated and water (10 mL) was added. pH value was adjusted to 8-9 with saturated K2CO3 aqueous solution. The product was collected, concentrated and purified by C18 reversed phase column (0-70% 0.01% NH4HCO3 in H2O / CH3OH) to give 133 mg of 6-(6-(((lR,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[aQoxazol-5-ol (36% yield). 'H NMR (400 MHz, MeOD -< A) 58.17 (d, J= 9.9 Hz, 1H), 7.98 (s, 1H), 7.32 (d, J= 9.9 Hz, 1H), 7.10 (s, 1H), 6.01 - 5.86 (m, 1H), 5.07 - 4.90 (m, 1H), 3.57 -3.47 (m, 2H), 3.11 (s, 3H), 2.71 - 2.64 (m, 1H), 2.62 (s, 3H), 2.15 - 2.02 (m, 3H), 1.97 - 1.78 (m, 4H). LCMS: m / z 398.1 [M+H]+; fe = 1.40 min.Example 2: Metabolite ID.

[0271] Metabolite identification was performed for both 6-(6-{[(lR,2R,3S,5S)-2-fluoro-8-azabicyclo [3.2.1 ]octan-3 -yl] (methyl)amino } pyridazin-3 -y 1) -2 -methyl- 1,3 -benzoxazol-5 -ol (Compound 117) and Compound B. Human hepatocytes (liverPool™ 10-Doner) from BioIVT (cat. No. X008001) for Compound 117 and (liverPool™ 20-Doner) from BioIVT (cat. No. X008000) for Compound B at 1.0 X 106cells / ml were incubated with test compound (50mM Compound 117, lOmM Compound B) for 240 minutes at 37°C. Incubations were quenched with 2 volumes of acetonitrile (0.1% FA) followed by centrifugation for 15 min at 16,000 g; Supernatant was then analyzed by LC-MS / MS. For UV analysis, 500 mL acetonitrile (0.1% FA) fraction was dried by centrifugal vacuum evaporator and reconstituted with 50 mL water and 50 mL methanol. The following equipment and conditions were used for the analysis:

[0272] Instrumentation: Vanquish UHPLC system (Thermo Fisher Scientific, USA); Vanquish Variable Wavelength (Thermo Fisher Scientific, USA); Thermo Scientific Q Exactive (Thermo Fisher Scientific, USA).

[0273] LC conditions: Column: Waters XSelect HSS T3, 100 x 2.1 mm, 2.5 mm; Solvents: A, water (0.1% formic acid); B, acetonitrile (0.1% formic acid); Flow rate: 500 mL / min; Program for Compound 117: 0-1.5 min, 5%B, 1.5-9 min, 5%-25%B, 9-12 min, 25%-100%B, 12-14 min, 100%B, 14-14.3 min, 100%-5%B, 14.3-15 min, 5%B. Program for Compound B: 0-1.5 min, 5%B, 1.5-9 min, 5%-30%B, 9-12 min, 30%-100%B, 12-14 min, 100%B, 14-14.3 min, 100%-5%B, 14.3-15 min, 5%B.WSGR Docket No. 51503-780.601

[0274] MS conditions: Ionisation mode: Positive mode; Spray Voltage: 3.5 kV; Aux gas flow rate: 15; Aux gas heater temp: 350°C; Scan type: Full MS / ddMS2; Resolution: 70,000; AGC Target: 3 x e6; NCE / stepped NCE (Full Mass) for Compound 117: 25, 35, 45; NCE / stepped NCE (Full Mass) for q Compound B: 30, 35, 40. w g

[0275] Three metabolites were detected for Compound 117 (Table 1), seven metabolit wes were detected qx Zfor Compound B (Table 2).Table 1.Peak R. T. Meas, m / z Mass Mass Biotransformation Normalized Proposed Metabolites No. (min) error Shift peak Area(ppm) @240 minutes1 5.49 280.61090 -1.1 176.03209 Glucorinidation 0.02%(z=2)z«::y %....2 6.97 400.17706 -2.2 15.99491 Oxidation 0.67%. -s.3 8.79 384.18204 -2.6 0.00000 Parent Compound 83.52%4 9.93 400.17719 -1.91 15.99491 Oxidation 15.78%— ft ifit. -A..HOTable 2.Pea R. T. Meas, Mass Mass Biotransformatio Normalize Proposed Metabolites k (min m / z error Shift n d peakNo. ) (PPm Area) @240minutes1 6.14 208.6080 -0.8 18.0105 Oxidation + 1.04%9 (z=2) 6 Hydrogenation / < w •2 6.65 414.1922 -3.1 15.9949 Oxidation 1.40%9 1Y "". A’WSGR Docket No. 51503-780.601Pea R. T. Meas, Mass Mass Biotransformatio Normalize Proposed Metabolites k (min m / z error Shift n d peakNo. ) (PPm Area) @240minutes3 7.48 207.6003 -0.5 15.9949 Oxidation 0.95%4 (z=2) 1 7 / 3-7^'4 8.02 200.5925 -0.5 1.97926 De-methylation + 0.29%1 (z=2) Oxidationi z ««V.... Z5 8.18 398.1980 -1.5 0.00000 Parent Compound 87.68%9u, — i yr w— Ny-r y—pj'" V: HO\ H / H6 8.34 430.1873 -2.8 31.9898 Oxidation 0.75%2 3&Z*7 8.35 428.1715 -3.0 29.9741 Oxidation + De0.99%7 8 hydrogenation>73 < >2 20. -2% z8 8.99 414.1926 -2.2 15.9949 Oxidation 6.90%X £ 6 10Example 3: Protein Binding Assay.

[0276] Protein binding of Compound B was determined in human, rat and mouse plasma using an equilibrium dialysis method (using 96-well Equilibrium Dialysis Plate (HTDialysis LLC, Gales Perry, CT) and HTD 96a / b Dialysis Membrane Strips, MWCO 12-14K). Human mixed gender plasma (pH 7.46) was obtained from BioIVT (batch no. HMN575149), Rat SD strain, mixed gender plasma (pH 7.49) was obtained from BioIVT (batch no. RAT463303) and Mouse CD-I strain, mixed gender plasma (pH 7.23) was obtained from IPHASE (batch no. M21005657.

[0277] A working solution of test compound and control compound (ketoconazole) was prepared in DMSO at a concentration of 1 mM. A basic solution was prepared by dissolving 14.2 g / L Na2HPO4 and 8.77 g / L NaCl in deionized water and the solution could be stored at 4°C for up to 7 days. An acidic solution was prepared by dissolving 12.0 g / L NaH2PO4 and 8.77 g / L NaCl in deionized water and the solution could be stored at 4°C for up to 7 days. The basic solution was titrated with the acidic solution to pH 7.4 and stored at 4°C for up to 7 days. pH was checked on the day of experiment and was adjusted if outside specification of 7.4 ± 0.1. The temperature of a water bath was set to 37°C. Frozen PlasmaWSGR Docket No. 51503-780.601(stored at -80°C) was thawed immediately in a 37°C water bath. The dialysis membranes were soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. Prepared membranes were loaded into the dialysis device and the device was installed following the manufacturer’s guidelines. The air bath was turned on and allow to pre-heat to 37°C. 597 pL of blank plasma solution was added into each vial of a new plastic plate or separate plastic tube by addition of 3 pL of the working solution of test compound, vortex at 1000 rpm for 2 minutes. The final percent volume of organic solvent was 0.5% and the final concentration for test compound was 5 pM. 50 pL of the spiked plasma solution suspension was transferred to a 96-well plate to act as T=0 control sample. All remaining spiked plasma solution is placed in the incubator for the duration of the study. At the same time, the remaining spiked plasma solution sample in the plastic plate or separate plastic tube was incubated for 6 hours at 37°C with 5% CO2 in the CO2 incubator.

[0278] At T=6 hours, 50 pL of the original spiked plasma solution suspension was transferred to the 96-well plate for analysis. The dialysis set up was assembled following the manufacturer’s instructions. Cells were loaded with 120 pL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The unit was covered with a gas permeable lid and incubated for 6 hours at 37°C at 100 rpm with 5% CO2 on an orbital shaker in the CO2 incubator. At the end of incubation, the lid was removed and 50 pL of post-dialysis samples from both buffer and plasma solution chambers were transferred into separated 96-well plate for analysis, respectively. 50 pL of plasma solution was added to the buffer samples, and an equal volume of PBS to the collected plasma solution samples. The plate at was shaken at 1000 rpm for 2 minutes and 400 pL of acetonitrile was added containing an appropriate internal standard (IS) to precipitate protein and release compound. Samples were vortexed at 1000 rpm for 10 minutes and then centrifuged for 30 minutes at 3,220 g. 250 pL of the supernatant was transferred to new 96-well plates and centrifuged again (3,220 g, 30 minutes).100 pL of the supernatant was transferred to new 96-well plates for analysis. 100 pL of distilled water was added to each sample and mixed for analysis by LC-MS / MS. Concentrations of test compound and control compound in the buffer and plasma solution chambers was determined. Percentages of test compound(s) and control compound bound were calculated as follows: % Unbound = (Area ratio buffer chamber / Area ratio plasma solution chamber) x 100; % Bound = 100 - % Unbound; % Recovery = (Area ratio buffer chamber + Area ratio plasma solution chamber) / (Area ratio Total sample) x 100; % Remaining = Area ratio 6hr / Area ratio Ohr x 100. The following chromatography conditions were used:

[0279] UC system: Shimadzu; MS analysis: Triple Quad 5500+ instrument from AB Inc with an ESI interface; Column temperature: 40°C; Injection volume: 1 pE; Column: XSelectHSS T3 2.5pm 2.1x50mm Column; Mobile phase: 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B); Elution rate: 0.8 mL / min; with the following program in Table 3:Table 3.Time (min) 0 0.2 0.5 0.9 0.95 1.2 % B 5 5 95 95 5 5WSGR Docket No. 51503-780.601

[0280] The following MS parameters were used: Ion source: Turbo spray; Ionization model: ESI; Scan type: MRM; Collision gas: 9 L / min; Curtain gas: 40 L / min; Nebulize gas: 55 L / min; Auxiliary gas: 55 L / min; Temperature: 500°C; lonspray voltage: +5500 V. Results for Compound B are in Table 4. Table 4.Species Fraction Unbound (Plasma)Human 0.3255Rat 0.2760Mouse 0.2728

[0281] Compound 117 was subjected to a similar protocol. With some variations. The test concentration was ImM, control compounds were warfarin and quinidine. Incubation time was 5 hours. Results for Compound 117 are in Table 5.Table 5.Species Fraction unbound (Plasma)human 0.165rat 0.213dog 0.29monkey 0.277Example 4: PK Study in nonhuman primates of Compound B.

[0282] Cynomolgus monkeys were administered Compound B at 2 different dose levels. POA was a dose level of 2mg / kg (dosing solution of 0.4mg / ml) and POB was a dose level of lOmg / kg (dosing solution of 2mg / ml). POA was prepared by dissolving 28.8 mg of Compound B in 72.00 m of 0.5%MC, 0. l%Tween80, 30 mM citrate pH3.5-4 followed by vortexing and sonication to obtain a solution with concentration at 0.4 mg / mL of Compound B.

[0283] POB was prepared by dissolving 109.96 mg of Compound B in 54.980 m of 0.5%MC, 0. l%Tween80, 30 mM citrate pH3.5-4 followed by vortexing and sonication to obtain a solution with concentration at 2 mg / mL of Compound B.

[0284] HPLC was performed on the samples using the following equipment and parameters. HPLC: Instrument: Shimadzu (DGU-20A5R, Serial No: L20705826727 IX; LC-30AD Serial No:L20555913986 AE and L20555913987 AE; SIL-30AC, Serial No: L20565906455 AE; Rack Changer II Serial No. L20585901289 SS; CTO-30A: Serial No. L20575801653 CD; CBM-20A: Serial NO. L20235941035 CD). MS: AB API 5500+ LC / MS / MS instrument (Serial No. EX227122104).Column: Agilent Poroshell 120 EC-C18 4 pm (50 x 2.1 mm). Mobile Phase: Solution A: 5% Acetonitrile in Water (0. l%Formic acid); Solution B: 95% Acetonitrile in Water (0. l%Formic acid). Flow rate: 0.6 mL / min, with the following gradient in Table 6.WSGR Docket No. 51503-780.601Table 6.Time (min) A (%) B (%)0.01 95.0 5.000.20 95.0 5.001.50 5.00 95.01.80 5.00 95.01.81 95.0 5.002.00 95.0 5.00

[0285] Injection volume: 3ml.

[0286] The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with DMSO. 5 pL of working solutions (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng / mL) were added to 50 pL of the blank male or female cynomolgus monkeys plasma to achieve calibration standards of 0.5-1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 55 pL. Five quality control samples at 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL and 800 ng / mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards. 55 pL of standards, 55 pL of QC samples and 55 pL of unknown samples (50 pL of male and female plasma with 5 pL of blank solution) were added to 200 pL of acetonitrile containing IS mixture for precipitating protein, respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 degree Celsius, 3900 rpm for 15 min. The supernatant was diluted 3 times with water. 3 pL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0287] Blood samples were taken at the following time points post-does administration: 0.083, 0.17, 0.33, 0.5, 1, 2, 4, 7, 11, 24, and 48 hours.

[0288] Results are shown in Table 7 for the male cynomologous monkeys and in Table 8 for the female cynomologous monkeys.Table 7.Dose Time (h) Concentration (ng / mL)0.083 BLOQ0.17 BLOQ0.33 BLOQ0.5 1.571 13.6POA2 52.64 53.77 47.111 26.124 10.1WSGR Docket No. 51503-780.601Dose Time (h) Concentration (ng / mL)48 2.150.083 BLOQ0.17 BLOQ0.33 10.40.5 44.61 204POB 2 2914 4357 38311 22224 64.348 1.38Table 8.Dose Time (h) Concentration (ng / mL)0.083 BLOQ0.17 BLOQ0.33 BLOQ0.5 BLOQ1 0.601POA 2 8.344 24.37 15.711 10.424 3.6448 0.8980.083 BLOQ0.17 BLOQ0.33 3.560.5 19.21 166POB 2 3934 4517 32011 24724 80.148 26.6WSGR Docket No. 51503-780.601

[0289] BLOQ = Below quantifiable limit of 1 ng / mL for Male; BLOQ = Below quantifiable limit of 0.5 ng / mL for Female. PK Parameters were estimated by non-compartmental model using WinNonlin 6.1. The bioavailability (F%) was calculated as follows: AUClast-PO / AUCINF-PO > 80%: F=(AUCINF-PO* DoseIV) / (mean AUCINF-IV* DosePO)

[0290] AUClast-PO / AUCINF-PO < 80% or AUCINF was not available: F=(AUClast-PO*DoseIV) / (mean AUClast-IV* DosePO). The PK parameters are set forth in Table 9 for the male cynomologous monkeys and Table 10 for the female cynomologous monkeys.Table 9.Dose POA POBPK parameters UnitTl / 2 h 10.3 4.95Tmax h 4.00 4.00Cmax ng / mL 53.7 435AUClast h*ng / mL 823 6128AUCInf h*ng / mL 856 6138 AUC_%Extrap_obs 0 / / o 3.75 0.160 MRTInf obs h 14.1 10.7AUClast / D h*mg / mL 412 613F 0 / / o NA NATable 10.Dose POA POB PK parameters UnitTl / 2 h 10.6 11.9 Tmax h 4.00 4.00 Cmax ng / mL 24.3 451 AUClast h*ng / mL 295 6869 AUCInf h*ng / mL 309 7325 AUC_%Extrap_obs 0 / / o 4.45 6.21 MRTInf obs h 15.0 16.0 AUClast / D h*mg / mL 148 687F 0 / / o NA NAExample 5: PK Study in nonhuman primates of Compound 117.

[0291] Female cynomologous monkeys were administered Compound 117 at 2 different dose levels. POA was a dose level of Img / kg (dosing solution of 0.2mg / ml) and POB was a dose level of 3mg / kg (dosing solution of 0.6mg / ml). POA was prepared by dissolving 15.79 mg of Compound 117 in 78.95 mL of deionized water (0.5%MC, 0.1%Tween80), followed by vortexing and sonication to obtain a solution with concentration at 0.2 mg / mL of Compound 117.WSGR Docket No. 51503-780.601

[0292] POB was prepared by dissolving 48.85 mg of Compound 117 in 81.417 mL of deionized water (0.5%MC, 0.1%Tween80), followed by vortexing and sonication to obtain a solution with concentration at 3 mg / mL of Compound 117.

[0293] HPLC was performed on the samples using the following equipment and parameters. HPLC: Instrument: Shimadzu (DGU-20A5R, Serial No: L20705518888 IX; LC-30AD Serial No:L20555510784 AE and L20555510780AE; SIL-30AC, Serial No: L20565504983AE; Rack Changer II Serial No. L20585501070 SS; CTO-30A: Serial No. L20575501292 CD; CBM-20A: Serial No.L20235533956 CD). MS: AB API 5500 LC / MS / MS instrument (Serial No. EF20381804). Column: HALO C18 90A 2.7pm (50*2.1 mm). Mobile Phase: Solution A: 5% Acetonitrile in Water (0.1%Formic acid); Solution B: 95% Acetonitrile in Water (0.1%Formic acid). Flow rate: 0.6 mL / min, with the following gradient in Table 11:Table 11.Time (min) A (%) B (%)0.01 100 0.000.20 100 0.001.90 10.0 90.02.20 10.0 90.02.21 100 0.002.50 100 0.00

[0294] Injection volume: 1ml.

[0295] The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. 5 pL of working solutions (5, 10, 20, 100, 500, 1000, 5000, 10000 ng / mL) were added to 50 pL of the blank monkey plasma to achieve calibration standards of 0.5-1000 ng / mL (0.5, 1, 2, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 55 pL. Four quality control samples at 1 ng / mL, 2 ng / mL, 50 ng / mL and 800 ng / mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards. 55 pL of standards, 55 pL of QC samples and 55 pL of unknown samples (50 pL of monkey plasma with 5 pL of blank solution) were added to 200 pL of acetonitrile containing IS mixture for precipitating protein, respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 degree Celsius, 3900 rpm for 15 min. The supernatant was diluted 3 times with water. 1 pL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0296] Blood samples were taken at the following time points post-does administration: 0.083, 0.17, 0.33, 0.5, 1, 2, 4, 7, 11, 24, and 48 hours.WSGR Docket No. 51503-780.601

[0297] Results are shown in Table 12.Table 12.Dose Animal Number Time (h) Concentration (ng / ml) POA 1 0.0833 BLOQPOA 1 0.17 BLOQPOA 1 0.33 2.40POA 1 0.5 9.16POA 1 1 23.8POA 1 2 23.1POA 1 4 20.6POA 1 7 11POA 1 11 6POA 1 24 2.8POA 1 48 0.5POA 2 0.083 BLOQPOA 2 0.17 BLOQPOA 2 0.33 BLOQPOA 2 0.5 BLOQPOA 2 1 1.59POA 2 2 3.31POA 2 4 2.1POA 2 7 1.3POA 2 11 0.957POA 2 24 BLOQPOA 2 48 BLOQPOA 3 0.083 BLOQPOA 3 0.17 BLOQPOA 3 0.33 1.1POA 3 0.5 2.88POA 3 1 11.3POA 3 2 15.7POA 3 4 14.2POA 3 7 9.35POA 3 11 5.25POA 3 24 1.68POA 3 48 BLOQPOB 4 0.083 BLOQPOB 4 0.17 BLOQPOB 4 0.33 3.78POB 4 0.5 7.97POB 4 1 22.9POB 4 2 22.7POB 4 4 21.7POB 4 7 15.8POB 4 11 9.49POB 4 24 2.91POB 4 48 BLOQPOB 5 0.083 BLOQPOB 5 0.17 0.601POB 5 0.33 0.742POB 5 0.5 1.9POB 5 1 27.6POB 5 2 36.2WSGR Docket No. 51503-780.601Dose Animal Number Time (h) Concentration (ng / ml) POB 5 4 28.2POB 5 7 17POB 5 11 9.36POB 5 24 3.56POB 5 48 0.756POB 6 0.083 BLOQPOB 6 0.17 BLOQPOB 6 0.33 2.85POB 6 0.5 8.87POB 6 1 56.2POB 6 2 105POB 6 4 92.7POB 6 7 59.1POB 6 11 42.6POB 6 24 14.4POB 6 48 2.42

[0298] BLOQ = Below quantifiable limit of 0.5 ng / mL; PK parameters were estimated by noncompartmental model using WinNonlin 6.1; The bioavailability (F%) was calculated as following: AUClast-PO / AUCINF-PO > 80%: F=(AUCINF-PO*DoseIV) / (mean AUCINF-IV*DosePO) AUClast-PO / AUCINF-PO < 80% or AUCINF was not available: F=(AUClast-PO*DoseIV) / (mean AUClast-IV*DosePO); NA = Not available. The PK parameters are set forth in Table 13 as a mean for all the animals given a particular dose.Table 13.Dose POA POBPK parameters UnitTl / 2 h 8.1 8.8 Tmax h 1.67 1.67 Cmax ng / mL 14.3 55 AUClast h*ng / mL 143 641 AUCInf h*ng / mL 154 665 AUC_%Extrap_obs 0 / / o 15.0 5.2 MRTInf obs h 10.7 11.5 AUClast / D h*mg / mL 143 214F 0 / / o 19.3 28.3Example 6. RAT PK following IV administration of Compound B

[0299] Female Sprauge Dawley rats were administered Compound B by IV at a dose level of Img / kg (dosing solution of 0.2mg / ml). The IV dose was prepared by dissolving 1.06 mg of Compound B in 5.3 mL of 30%HP-β-CD followed by vortexing and sonication to obtain a solution with concentration at 0.2 mg / mL of Compound B.WSGR Docket No. 51503-780.601

[0300] HPLC was performed on the samples using the following equipment and parameters. HPLC: Instrument: Shimadzu (DGU-20A5R, Serial No: L20705826739 IX; LC-30AD Serial No:L20555913985 AE and L20555913969 AE; SIL-30AC, Serial No: L20565806434 AE; Rack Changer II Serial No. L20585801286 SS; CTO-30A: Serial No. L20575801652 CD; CBM-20A: Serial NO. L20235941033 CD). MS: AB API 5500 LC / MS / MS instrument (Serial No. EX227152104). Column: Agilent Poroshell 120 EC-C8 4 pm (50 * 2.1 mm). Mobile Phase: Solution A: 5% Acetonitrile in Water (0.1%Formic acid); Solution B: 95% Acetonitrile in Water (0.1%Formic acid). Flow rate: 0.6 mL / min, with the following gradient in Table 14:Table 14.Time (min) A (%) B (%)0.01 95.0 5.000.20 95.0 5.001.50 5.00 95.01.80 5.00 95.01.81 95.0 5.002.00 95.0 5.00

[0301] Injection volume: 5ml.

[0302] The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. 5 pL of working solutions (1, 2, 4, 10, 20, 100, 200, 1000, 2000 ng / mL) were added to 50 pL of the blank SD Rat plasma to achieve calibration standards of 0.5-1000 ng / mL ( 0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 55 pL. Five quality control samples at 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL and 800 ng / mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards. 50 pL standards, 50 pL QC samples and 50 pL unknown samples (50 pL plasma with 5 pL blank solution) were added to 200 pL of acetonitrile containing IS mixture for precipitating protein respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 degree Celsius, 3900 rpm for 15 min, the supernatant was diluted 3 times with water. 5 pL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0303] Blood samples were taken at the following time points post-dose administration: 0.083, 0.17, 0.33, 0.5, 1, 2, 4, 7, 11 and 24 hours.WSGR Docket No. 51503-780.601

[0304] Results are shown in Table 15.Table 15.Animal Number Time (h) Concentration (ng / ml)1 0.083 1961 0.17 1411 0.33 1091 0.5 99.51 1 69.41 2 50.01 4 35.71 7 25.61 11 15.91 24 3.292 0.083 1882 0.17 1232 0.33 1032 0.5 99.12 1 54.22 2 39.23 4 44.83 7 19.62 11 13.62 24 2.773 0.083 1853 0.17 1373 0.33 1293 0.5 94.73 1 55.43 2 55.33 4 38.43 7 31.63 11 13.23 24 2.701 0.083 1961 0.17 1411 0.33 1091 0.5 99.51 1 69.41 2 50.01 4 35.71 7 25.61 11 15.91 24 3.292 0.083 1882 0.17 1232 0.33 1032 0.5 99.12 1 54.22 2 39.23 4 44.83 7 19.62 11 13.6WSGR Docket No. 51503-780.601Animal Number Time (h) Concentration (ng / ml) 2 24 2.77 3 0.083 185 3 0.17 137 3 0.33 129 3 0.5 94.7 3 1 55.4 3 2 55.3 3 4 38.4 3 7 31.6 3 11 13.23 24 2.70

[0305] BLOQ = Below quantifiable limit of 0.5 ng / mL; PK parameters were estimated by noncompartmental model using WinNonlin 6.1; The bioavailability (F%) was calculated as following: AUClast-PO / AUCINF-PO > 80%: F=(AUCINF-PO*DoseIV) / (mean AUCINF-IV*DosePO) AUClast-PO / AUCINF-PO < 80% or AUCINF was not available: F=(AUClast-PO*DoseIV) / (mean AUClast-IV*DosePO); NA = Not available. The PK parameters are set forth in Table 16.Table 16.PK parameters Unit Rat 1 Rat 2 Rat 3 Mean SD CV(%) Cl obs mL / min / kg 28.4 31.4 28.9 29.6 1.6 5.43 Tl / 2 h 5.74 5.93 4.98 5.55 0.50 9.02 Co ng / mL 268 282 246 266 18 6.73 AUClast h*ng / mL 559 507 557 541 30 5.47 AUClnf h*ng / mL 586 530 576 564 30 5.28 AU C_%Extrap_ob S 0 / / o 4.64 4.47 3.37 4.16 0.69 16.6 MRTinf_obs h 6.98 6.76 6.34 6.69 0.32 4.85 AUClast / D h*mg / mL 559 507 557 541 30 5.47 Vss_obs L / kg 11.9 12.8 11.0 11.9 0.9 7.34Example 7 Rat PK for Compound 117.

[0306] Male Sprauge Dawley rats were administered Compound 117 by IV at a dose level of Img / kg (dosing solution of 0.5mg / ml). The IV dose was prepared by dissolving 1.17 mg of Compound 117 in 0.117 mL of DMSO followed by vortexing for 2 minutes and sonication for 3 minutes, then 0.117 mL of Solutol HS15 was added and vortexed for 3 minutes and finally 2.106mL of saline was added and vortexed for 3 minutes to obtain a solution with concentration at 0.5 mg / mL of Compound 117.

[0307] Analysis was carried out on samples using the following equipment and parameters: LCMSMS-39 (Triple Quad 6500+); Positive ion, ESI; MRM detection. HPLC was performed with a Waters X-Bridge BEH C18 (2.1x50 mm, 1.7 pm) column at 50°C, using solution A: H2O-0.025% FA-1mM NH4OAc; solution B: ACN-0.025% FA-1mM NH4OAc, a flow rate of 0.6 mL / min, with the following gradient set forth in Table 17:WSGR Docket No. 51503-780.601Table 17.Time (min) Mobile Phase B (%)0.300 2.001.00 90.01.50 90.01.51 2.002.00 Stop

[0308] 1 pL of supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0309] Blood samples were taken at the following time points post-dose administration: 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration.

[0310] Results are shown in Table 18.Table 18.Animal Number Time (h) Concentration (ng / ml)1 0.083 85.9 1 0.25 77.8 1 0.5 67.7 1 1 45.9 1 2 37.2 1 4 26.5 1 8 14.0 1 24 1.46 2 0.083 91.2 2 0.25 72.6 2 0.5 67.4 2 1 49.6 2 2 37.0 2 4 26.8 2 8 10.5 2 24 1.14 3 0.083 82.0 3 0.25 75.2 3 0.5 74.8 3 1 49.2 3 2 37.7 3 4 22.4 3 8 13.43 24 1.09

[0311] PK parameters were estimated by non-compartmental model using WinNonlin 8.2; NA = Not available. The PK parameters are set forth in Table 19.WSGR Docket No. 51503-780.601Table 19.PK parameters Unit Rat 1 Rat 2 Rat 3 Mean SD CV(%) CL L / hr / kg 2.58 2.85 2.72 2.72 0.136 5.02 Vss L / kg 14.6 14.4 14.3 14.4 0.163 1.13 Tl / 2 hr 4.82 4.43 4.54 4.59 0.200 4.36 AUClast hr*ng / mL 377 343 361 361 17.1 4.75 AUCINF hr*ng / mL 388 351 368 369 18.6 5.03 MRTlast hr 4.99 4.50 4.76 4.75 0.241 5.07 MRTINF hr 5.67 5.04 5.26 5.32 0.316 5.94 CL mL / min / kg 43.0 47.5 45.3 45.3 2.27 5.02Example 8: Solid Dispersion Formulation Screening.

[0312] Spray Dried Dispersion Manufacturing.

[0313] Eight Compound B:polymer spray dry intermediate (SDI) formulations were manufactured for feasibility screening. These formulations were spray dried from 80:20 dichloromethane methanol (DCM: MeOH) or neat methanol, then secondary dried in a tray dryer to remove residual solvent remaining after spray drying. In this operation, the “wet” SDI was held at 40°C in a convection tray oven for approximately 24 hours. Gas chromatography - Headspace Sampling (GC-HS) was used to measure the residual solvent in Compound B SDIs as described below.

[0314] Residual Solvent by Gas Chromatography - Headspace Sampling (GC-HS)

[0315] The residual solvent content of SDIs was measured by GC-HS after secondary drying.Measurements were made using an HP 6890 series GC equipped with an Agilent 7697A headspace sampler. GC samples were prepared by dissolving approximately 100 mg sample in 4 mL dimethyl sulfoxide (DMSO). The method was used without verification activities for the drug intermediate, but later verified for analysis of the cGMP drug intermediate. The GC method parameters are summarized in Table 20, Table 21, and Table 23.Table 20. Headspace Autosampler Parameters.Parameter ValueMethod Method 2Sample Temperature 105 °CSample Loop Temperature 110 °CTransfer Line Temperature 115 °CGC Cycle Time 45 minVial Equilibration Time 30 minInjection Time 1.00 minInjection Loop Size 1 mL100 mL / min; 1 minPost Injection PurgeDefaultCarrier Gas N2, >99.999%Carrier Gas Flow 1.6 mL / minVial Pressure 15.0 psiWSGR Docket No. 51503-780.601Parameter ValueMethod Method 2LOQ 80 ppmTable 21. Gas Chromatograph Operating Parameters.Parameter ValueInjector Temperature 180 °CDetector Temperature 300 °CDetector Type FID30 m x 0.32 mm x 1.80 pm capillary column with 6% Column cyanopropylphenyl 94% dimethylpolysiloxane Agilent GC column DB- 624 PN: 123-1334Carrier Gas N2Flow Rate (Flow Control1.6 mL / min (Constant Flow)Mode)Split Ratio 30:1Split Flow 40Inlet Type S / SL EPCInlet Mode SplitInjection Port Liner Appropriate headspace injection port linerTable 23. Oven Temperature GradientRate Temperature Hold Time Total Time Oven(°C / min) (°C) (min) (min) Initial NA 40 5 5 Ramp 1 2 90 0 30Ramp 2 30 225 2 36.5

[0316] Spray Dried Dispersion Manufacturing Results.

[0317] A summary of spray drying parameters, yields, residual solvent, and appearance are shown in Table 24.Table 24. Summary of Spray Drying Parameters for Compound B Feasibility SDIs.20:80 20:80 20:80 20:80 20:80 20:80 20:80 20:80Compound Compound Compound Compound Compound Compound Compound CompoundFormulation B: B: B: B:B: PVP B: B: B:HPMC HPMCP- Eudragit Eudragit K30 PVP-VA64 HPMCAS-H SoluplusE3LV HP55 L100 L100-55 Batch Size (g)20.007 20.010 20.007 20.005 20.006 20.005 20.001 20.001 Total Solids80:20 80:20 80:20 80:20 80:20Heated 80:20 80:20 Spray Solvent DCM: MeO DCM: MeO DCM: MeO DCM: MeO DCM: MeO Methanol DCM: MeOH DCM: MeOH H H H H HTotal Solids8 8 8 8 8 8 4 4 (wt%)Drying GasBiichi B-290 with B-295 Condenser (recycle mode)ModeCondenserTemperature -18 to -20 -18 to -20 -19 to -20 -19 to -20 -18 to -19 -18 to -20 -18 to -20 -18 to -20 (°C)Cyclone Used StandardSolution Flow20.8 - 22.2 23.8 - 26.2 14.8 - 15.0 18.9 - 22.5 20.2 - 22.8 19.5 -22.7 19.6 -22.3 19.1 -21.3Rate (g / min)WSGR Docket No. 51503-780.60120:80 20:80 20:80 20:80 20:80 20:80 20:80 20:80Compound Compound Compound Compound Compound Compound Compound CompoundFormulation B: B: B: B:B: PVP B: B: B:HPMC HPMCP- Eudragit Eudragit K30 PVP-VA64 HPMCAS-H SoluplusE3LV HP55 L100 L100-55 Atomization28 26 26 28 28 28 28 28 Pressure (psi)InletTemperature 98-102 98-100 104-126 87-91 87-88 87-89 74-80 80-82 (°C)OutletTemperature 44-45 45 54-56 44-45 45 44-45 39-41 40-41 (°C)Wet SDD79 66 85 81 90 86 84 Yield (wt%) 491Dry SDD72 55 66 73 81 76 76 58 Yield (wt%)Secondary 24 hours 24 hours 24 hours 24 hours 24 hours 24 hours 24 hours24 hours 40°C Drying 40°C 40°C 40°C 40°C 40°C 40°C 40°CDCM:Residual DCM: DCM: ND DCM: 6970< LOQ MeOH: DCM: ND DCM: ND DCM: ND Solvent2< LOQ MeOH: MeOH:MeOH: < LOQ MeOH: ND MeOH: ND MeOH: ND (PPm) MeOH: ND < LOQ < LOQ< LOQ'Gross weight for wet collection was incorrectly captured and led to an incorrect net wt. Upon drying material was verified and the dry yield is correct2LOQ = limit of quantitation = 200 ppm; ND = not detected

[0318] Feasibility SDI Characterization.

[0319] Initial SDI formulations were characterized by modulated differential scanning calorimetry (MDSC), X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), and non-sink dissolution in biorelevant media, each of which was performed as described below.

[0320] Differential Scanning Calorimetry (DSC).

[0321] DSC was performed using a TA Instruments Discovery DSC2500 or X3 differential scanning calorimeter equipped with a TA instruments Refrigerated Cooling System (RCS) 90 operating in either modulated or ramp mode. DSC was used to measure thermodynamic properties of Compound B SDIs, including the following: glass transition temperature (Tg), the temperature at which amorphous materials transition from a low mobility glassy state to a high mobility rubbery state; cold crystallization temperature (Tc), a crystallization event at a temperature lower than the melt temperature; and melting temperature (Tm). The system was purged by nitrogen flow at 50 mL / min to ensure inert atmosphere through the course of measurement.

[0322] Dispersions were evaluated for the effect of water on glass transition by analyzing samples at relative humidity levels of 32%, 50%, and 75%. SDI was added to hermetic DSC pans without lids and equilibrated to selected relative humidities (RH), then crimped inside a humidity-controlled glove box to capture the excess moisture within the pan. Water can act like a plasticizer and suppresses the glass transition temperature. This Tgvs. %RH experiment evaluated physical stability of the dispersion. These data can be used to select appropriate conditions for accelerated stability studies. Experimental parameters were set to capture Tgonly. Crystallization and melting events were not used in this analysis.WSGR Docket No. 51503-780.601

[0323] DSC parameters are summarized in Table 25 and Table 26.Table 25. Modulated DSC (MDSC) Parameters.Parameter ValueTA Discovery DSC2500 or X3 with RCS90 InstrumentchillerSample Pans Tzero Al, non-hermetic Temperature Range 0°C - 200 °CHeating Rate 2 °C / minScanning Mode ModulatedModulation Frequency 60 sModulation Amplitude 1 °CTable 26. MDSC Tgversus %RH ParametersParameters ValueTA Discovery DSC2500 or X3 with RCS90 InstrumentchillerSample Pans Tzero Al, hermetic Temperature Range -20 - 150 °CHeating Rate 2 °C / minScanning mode ModulatedModulation Frequency 60 sModulation Amplitude 1 °C

[0324] X-Ray Powder Diffraction (XRPD)

[0325] XRPD was performed using a Rigaku Miniflex 6G X-ray diffractometer to evaluate the crystallinity of bulk Compound B and SDIs. Amorphous materials provided an “amorphous halo” diffraction pattern, absent of discrete peaks that are found in crystalline material. Samples were irradiated with monochromatized Cu Ka radiation and analyzed from 5° and 40° with a continuous scanning mode. Samples were rotated during analysis to minimize preferred orientation effects. XRPD parameters are shown in Table 27.Table 27. XRPD Analysis Parameters.Parameter ValueInstrument Rigaku Miniflex 6G Radiation Source Cu-Ka (1.5406 A), Line Focus 0.4mm x 12mm Scan Type Coupled 20 / 0 Scan Range 5 °C-40°CStep Increment 0.005 °CRamp Rate 2.0 °C / min (SDI); 20.0°C / min Voltage 40kVCurrent 15mARotation 30rpmHolder Zero-Background CupReceiving Slit Width 13.0mm (open)Divergent Slit Width 0.625mmKnife Edge Width 1.0mmWSGR Docket No. 51503-780.601

[0326] Particle Morphology by Scanning Electron Microscopy (SEM)

[0327] SEM samples were prepared by dispersing powder onto an adhesive carbon-coated sample stub and coating with a thin conductive layer of gold-palladium using a Cressington 108 Auto. Samples were analyzed using a Phenom XL fitted with an Everhart-Thornley (secondary electron) detector or backscatter detector operating in high vacuum mode. Micrographs at various magnifications were captured for qualitative particle morphology analysis. Experimental parameters were varied from sample to sample to obtain the best imaging conditions.

[0328] Non-Sink Dissolution Performance in Biorelevant Media

[0329] Dissolution performance for bulk Compound B, SDIs, and tablets was evaluated by a two-stage non-sink dissolution in biorelevant media test which simulates pH and bile salt concentrations of the stomach and upper intestine. Pre-weighed powder was briefly suspended in media (e.g. by 10 seconds vortexing with 4.0 mL media) and transferred to a pre-heated (37 °C) volume of 50 mL of 0.0 IN HC1 (aq) pH ~ 2.0, without pepsin or bile salts), in a USP Type 2 mini-vessel (100 mL total vessel volume) while stirring at 100 rpm. After 30 minutes of gastric exposure, an equal volume of 2x concentrated fasted-state simulated intestinal fluid (FaSSIF) was added to the vessel, resulting in a final pH of 6.8 in FaSSIF (lOOmM PBS containing 2.24 mg / mL FaSSIF / fed state simulated intestinal fluid (FeSSIF) / fasted state simulated gastric fluid (FaSSGF) powder (Biorelevant Inc.)) in a total volume of 100 mL. At each timepoint 1.0 mL aliquots were taken, centrifuged for 3 minutes at 13000 rpm, then diluted in an appropriate diluent for HPLC analysis to determine total solubilized drug concentration (e.g. free drug, drug in micelles, and drug in drug-polymer colloids). The first two timepoints were taken from the simulated gastric medium and the remaining from the intestinal medium. Dissolution parameters are summarized in Table 28. Compound concentration was determined using the high-performance liquid chromatography (HPLC) method described in Table 29.Table 28. Non-sink dissolution in biorelevant media Test Parameters.Parameter ValueApparatus USP Type 2 (100 mL)Gastric Media 0.01 N HC1 (aq) Intestinal Media FaSSIF (pH 6.8) Temperature 37 ± 0.5 °CPaddle Speed 100 rpmDose 1.0 — > 0.5 mgA / mLWSGR Docket No. 51503-780.601Table 29. HPLC Parameters for Non-sink dissolution in biorelevant media analysis.Parameter ValueColumn Thermo Hypersil GOLD, 3 pm, 4.6 x 50 mm, PN: 25003-054630 Mobile Phase A 0.1% FA in WaterMobile Phase B 0.1% FA in ACNDiluent 1:1 MeOH: WaterTime% MPB(min)Program 0 183.5 18Flow Rate 1.0 mL / minColumn Temperature 30°CSample Temperature Room temperatureInjection Volume 3 pLNeedle Wash DiluentDetection Method 3 pLDetection Wavelength UVDetection Bandwidth 294 nmSlit Width 4 nmReference Wavelength 8 nmCollect Spectra OffRun Time 3.5 minCompound B Approximate2.5 minRT

[0330] Feasibility SDI Characterization Results.

[0331] Thermal analysis by MDSC showed all dispersions had a single Tgindicating a homogeneous amorphous solid dispersion. The non-reversing heat flow did not show crystallization or other events and has been omitted. Soluplus SDI formulation (SDI 6) had the lowest Tgat 72 °C. All other SDIs had high glass transition temperatures. To ensure long-term physical stability, an SDI should be stored at least 10°C below the Tgat a given condition so that mobility of the drug in the dispersion is low. MDSC data are summarized in Table 30. XRPD analysis indicated that the SDIs were amorphous dispersions with no crystalline peaks observed.WSGR Docket No. 51503-780.601Table 30. MDSC Data of Compound B Feasibility SDIs.Composition Formulations TgonsetTgHalf-Height (°C) Identification (weight ratio) (°C)SDI 1 20:80 Compound B: PVP K30 SDI 140 149±1 SDI 2 20:80 Compound B: PVP-VA64 SDI 100 105±0SDI 3 20:80 Compound B: HPMC E3LV SDI 104 113±0SDI 4 20:80 Compound B: HPMCAS-H SDI 108 114±0SDI 5 20:80 Compound B: HPMCP HP55 SDI 144 148±0SDI 6 20:80 Compound B: Soluplus 62 72±0SDI 7 20:80 Compound B: Eudragit L100 SDI 189 192±0SDI 8 20:80 Compound B: Eudragit L10055 SDI 133 144±1

[0332] Surface morphology of the SDI particles was characterized using scanning electron microscopy. Typical SDI morphology was observed consisting of collapsed and un-collapsed spheres with smooth surfaces. No crystalline material was observed in any sample.

[0333] The dissolution performance of the feasibility SDIs and bulk Compound B was tested in a nonsink dissolution in biorelevant media experiment. All SDIs provided similar or higher solubilized Compound B concentrations with good sustainment throughout the test. Eudragit LI 00-55 (SDI 7) provided the highest level, but also had slower dissolution. Eudragit SDIs (SDI 7 and SDI 8) and HPMCP HP55 (SDI 5) continued to dissolve after transfer to intestinal medium. Gastric solubility varied among the SDIs, but SDIs made with acidic polymers generally had a lower gastric drug concentration. Dissolution results are shown in FIG. 1 and Table 31.Table 31. Non-sink dissolution in biorelevant media data for Compound B Feasibility SDIs Compared to Bulk Compound BCmaxGB CmaxIBFormulation AUC35-210 IB C210(μgA / mL) (μgA / mL) (min*pgA / mL) (μgA / mL) 20:80 Compound B: PVP K30 SDI 724 319 54500 311 20:80 Compound B: PVP-VA64 SDI 767 377 65800 377 20:80 Compound B: HPMC E3LV SDI 607 345 59500 345 20:80 Compound B: HPMCAS-H SDI 554 280 48300 275 20:80 Compound B: HPMCP HP55 SDI 140 372 64300 372 20:80 Compound B: Soluplus SDI 577 293 50600 289 20:80 Compound B: Eudragit LI 00 SDI 249 393 68100 392 20:80 Compound B: Eudragit L100-55 SDI 268 421 68500 421Compound B 570 339 58900 336

[0334] PVP-VA64 (SDI 2), HPMC E3LV (SDI 3), HPMCP-HP55 (SDI 5), and Eudragit L100-55 (SDI 8) SDI formulations were selected for further study. PVP-VA64 and HPMC E3LV are neutral polymers whereas HPMCP-HP55 and Eudragit LI 00-55 are acidic polymers. Selected formulations wereWSGR Docket No. 51503-780.601additionally characterized for Tgas a function of relative humidity to evaluate relative physical stability and placed in stability chambers to evaluate accelerated chemical and physical stability.

[0335] Effect of Relative Humidity on Suppression of Glass Transition Temperature

[0336] The physical stability of the selected SDIs was evaluated by equilibrating SDI to selected relative humidities: 32.8%, 50%, and 75.3% RH and measuring the Tgby MDSC. Results are reported in Table 32. SDIs with neutral polymers have Tgs that were low at high humidity conditions. HPMCP HP55 and Eudragit L100-55 SDI Tgs remained high at high humidities. SDI can be stored at least 10°C below the Tgto increase long-term physical stability.Table 32. Tgas a Function of %RH for Compound B FormulationsSample Composition Relative Humidity Tg(°C)0.0%a105±020:80 Compound 32.8% 69±0SDI 2B: PVP-VA64 SDI 50.0% 44±075.3% 17±00.0% 113±020:80 Compound 32.8% 81±2SDI 3B: HPMC E3LV SDI 50.0% 62±475.3% 35±10.0% 148±020:80 Compound 32.8% 120±2SDI 5B: HPMCP HP55 SDI 50.0% 94±075.3% 65±40.0% 144±120:80 Compound 32.8% 101±5B: Eudragit LI 0055 SDI 8SDI 50.0% 86±175.3% 58±2aSDI in non-hermetic pan, H2O is driven off during heating, therefore does not suppress Tg.

[0337] Feasibility SDI Accelerated Stability.

[0338] SDI formulations 20:80 Compound B: PVP-VA64, 20:80 Compound B: HPMC E3LV, 20:80 Compound B: HPMCP HP55, and 20:80 Compound B: Eudragit L100 55 were aged for 2 months at 25°C / 60%RH in open packaging, and 40°C / 75%RH in open and closed packaging by the stability protocol as described in Table 33 to rapidly assess the physical and chemical stability. The aged SDIs were evaluated by appearance, amorphous character by XRPD assay, and impurities by HPLC.Table 33. Experimental Setup for Stability ProtocolOpen Container: powder directly in open HDPE bottle without cap. Cotton batting in neck of bottlePackaging Configuration Closed Container: Powder placed in amber scintillation vial and inserted into a foil-foil pouch and heat induction sealed. 0.5 g silica desiccant gel added in between vial and foil bag.Amount per Container ~0.5 g SDIOrientation in Chamber UprightWSGR Docket No. 51503-780.601

[0339] Appearance testing showed SDI stored at open conditions were powder, except PVP-VA64 which had fused into a brown solid. Visual observations are described in Table 34. Prior to additional analysis, fused samples were lightly ground with a mortar and pestle to enable testing.Table 34. Visual Appearance of Compound B SDIs after 1- and 2-Month StabilitySample Storage StorageComposition Appearance Description Condition TimeNA t = 0 Yellow tinted powder 1 month Yellow tinted powder with 25 °C / 60%RH some clumping / Open Yellow tinted powder with 2 months20:80 some clumping Compound Light brown solid sticking SDI 2 1 month40°C / 75%RHB: PVP-VA64 to container sides / Open Brown fused solid sticking SDI 2 monthsto container sides 1 month Yellow tinted powder with 40°C / 75%RH some clumping / Closed2 months Yellow tinted powder with some clumping NA t = 0 Yellow tinted powder 1 month Yellow tinted powder with 25 °C / 60%RH some clumping 20:80 / Open Yellow tinted powder with 2 monthssome clumping CompoundSDI 3 Yellow tinted powder with B: HPMC E3LV 1 month40°C / 75%RH some clumping SDI / Open2 months Yellow tinted powder with some clumping 40°C / 75%RH 1 month Yellow tinted powder / Closed 2 months Yellow tinted powder NA t = 0 Yellow tinted powder 1 month Yellow tinted powder with 25 °C / 60%RH some clumping 20:80 / Open2 months Yellow tinted powder with some clumping CompoundSDI 5 Yellow tinted powder with B: HPMCP 1 month40°C / 75%RH some clumping HP55 SDI / Open2 months Dark Yellow tinted powder with some clumping 40°C / 75%RH 1 month Yellow tinted powder / Closed 2 months Yellow tinted powder NA20:80 t = 0 Yellow tinted powder SDI 28Compound 1 month Yellow tinted powder withsome clumpingWSGR Docket No. 51503-780.601Sample Storage StorageComposition Appearance Description Condition TimeB: Eudragit 25 °C / 60%RH2 months Yellow tinted powder with L10055 SDI / Open some clumping Yellow tinted powder with 40°C / 75%RH 1 monthsome clumping / Open 2 months Yellow tinted powder with some clumping 40°C / 75%RH 1 month Yellow tinted powder / Closed 2 months Yellow tinted powder

[0340] XRPD analysis of the aged SDI samples showed most SDIs remained amorphous with no detectable crystalline material after 2 months of aging. PVP-VA64 SDI formulation showed signs of crystallization at 40°C / 75%RH open after 1 month. Degree of crystallization did not appear to change significantly between the 1 -month and 2-month samples. Diffractograms are shown in FIG. 2A, FIG.2B, FIG. 2C, and FIG. 2D

[0341] Assay and impurities analysis of the aged SDI samples showed significant impurity increases in the HPMCP HP55 and Eudragit L100-55 SDIs over the course at all conditions. The HPMC E3LV SDI showed some impurity growth in the open conditions after 2 months. The PVP-VA64 formulation was the only one that showed no impurity increase when compared to t=0 SDI. Assay values varied between SDI formulations and samples. Data are summarized in Table 35, Table 36, Table 37, and Table 38. Table 35. Assay and Impurities Results for Compound B PVP-VA64 SDIs after 1- and 2-Months Stability.Formulation 20:80 Compound B: PVP-VA64 SDISDI 2Compound BStability to 25°C / 6 0%RH 40°C / 7 5%RH 40°C / 7 5%RH RRT 1 month 2 months 1 month 2 months 1 month 2 months 0.73 - <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% 0.83 - - - - - - <0.05% - 0.88 - - - - - - - <0.05% 0.97 0.11% <0.05% <0.05% 0.09% <0.05% 0.10% <0.05% 0.08% 1.04 - - <0.05% - - - - 1.08 <0.05% - - - - - - 1.14 <0.05% - - - - - <0.05% 1.19 <0.05% - - - - <0.05% - - 1.21 0.14% 0.09% 0.13% 0.15% 0.16% 0.14% 0.16% 0.13% 1.31 <0.05% - - <0.05% - <0.05% <0.05% 0.00% Total 0.25% 0.09% 0.13% 0.23% 0.16% 0.24% 0.16% 0.21%Assay (wt%) - 22.1% ± 25.2% ± 24.4% ± 27.5% ± 25.8% ± 24.4% ± 24.6% ±WSGR Docket No. 51503-780.601Table 36. Assay and Impurities Results for Compound HPMC E3LV SDIs after 1- and 2-Months Stability20:80 Compound B: HPMC E3LV SDI FormulationSDI 3Compound BStability 25°C / 6 0%RH 40°C / 7 5%RH 40°C / ' 75%RH toRRT 1 month 2 months 1 month 2 months 1 month 2 months 0.83 - - - - - - <0.05% - 0.87 - - - - - - - <0.05% 0.88 - - - - - - - <0.05% 0.97 0.11% 0.07% 0.08% 0.12% 0.08% 0.12% 0.08% 0.13% 0.98 - - - - - - <0.05% 1.02 - - - - - 0.06% - 1.05 <0.05% - 0.06% <0.05% <0.05% <0.05% 0.16% 1.06 - 0.06% 0.06% 0.05% <0.05% 0.12% 0.26% 1.07 - <0.05% 0.08% <0.05% 0.07% 0.17% 0.39% 1.08 <0.05% 0.06% <0.05% 0.06% <0.05% 0.26% 0.07% 1.09 - <0.05% - - - <0.05% - 1.12 - - - - <0.05% - 0.10% 1.13 - - - - - - <0.05% 1.14 <0.05% - - - - - <0.05% 1.16 - - - - - - <0.05% 1.18 - - - - - - <0.05% 1.19 <0.05% - 0.05% - <0.05% - <0.05% 1.21 0.14% 0.11% 0.06% 0.12% 0.16% 0.13% 0.13% 0.13% 1.23 - - - - <0.05% - - - 1.28 - - - <0.05% - <0.05% - <0.05% 1.3 - - <0.05% - <0.05% - - - 1.31 <0.05% - <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% 1.38 - - - - - - - <0.05% Total 0.25% 0.19% 0.25% 0.48% 0.35% 0.31% 0.83% 1.24%Assay (wt%) - 20.6% ± 24.3% ± 23.0% ± 25.6% ± 23.9% ± 23.9% ± 22.2% ±Table 37. Assay and Impurities Results for Compound B HPMCP HP55 SDIs after 1- and 2- Months Stability20:80 Compound B: HPMCP HP55 SDI FormulationSDI 5Stability Compound B 25°C / 6 0%RH 40°C / 7 5%RH 40°C / 75%RH Condition to OP EN CLC )SED O] PEN RRT 1 month 2 months 1 month 2 months 1 month 2 months 0.65 - - - - - - - <0.05% 0.69 - - <0.05% - - - - 0.06% 0.73 - - <0.05% - <0.05% - 0.30% 1.13% 0.75 - - - - - - - 0.07% 0.77 - - - <0.05% - - - 0.07% 0.78 - - 0.27% <0.05% 0.10% - 0.11% 0.07% 0.8 - - - - - - - <0.05%WSGR Docket No. 51503-780.6010.81 - - 0.52% 0.86% 0.07% - <0.05% 0.14% 0.82 - - - - - - - <0.05% 0.84 - - 7.61% 12.37% 1.46% 2.14% 45.31% 61.48% 0.85 - - 0.12% 0.23% 0.09% <0.05% 1.47% 3.08% 0.85 - - - - - <0.05% - - 0.86 - - - 0.57% 0.06% 0.15% 0.12% 9.86% 0.87 - - 0.69% - 0.07% <0.05% 4.05% - 0.88 - - 0.09% 2.08% 1.22% <0.05% 1.10% 2.27% 0.9 - - - - - - - <0.05% 0.91 - - 4.39% 1.16% 1.02% 2.19% 1.34% 0.05% 0.93 - - - 0.58% 0.32% 3.92% 0.11% 0.91% 0.94 - - 1.44% - - - - <0.05% 0.95 - - 0.10% 0.45% 0.68% 7.37% 2.28% 0.62% 0.95 - - - 4.04% - - - 1.51% 0.96 - 2.55% 5.13% 5.17% 7.16% 9.21% 4.11% 1.97% 0.96 - - - - - - - 0.40% 0.97 0.11% 3.74% 6.32% 0.20% 9.40% 0.33% 5.66% 0.30% 0.99 - 0.06% - - - - - 0.07% 1.04 - - - - - - <0.05% 0.14% 1.05 <0.05% - <0.05% <0.05% <0.05% <0.05% 0.08% <0.05% 1.07 - - - - - <0.05% - - 1.08 <0.05% - - - <0.05% <0.05% <0.05% - 1.11 - - - - - <0.05% - - 1.14 <0.05% - - <0.05% - <0.05% <0.05% - 1.19 <0.05% - - - - <0.05% - - 1.21 0.14% 0.11% 0.17% 0.11% 0.13% 0.11% 0.05% 0.14% 1.23 - - <0.05% - <0.05% - - - 1.26 - - - - - 0.07% - 0.09% 1.28 - - - <0.05% - <0.05% - <0.05% 1.31 <0.05% - <0.05% <0.05% - <0.05% <0.05% - Total0.25% 6.46% 27.72% 27.83% 21.78% 25.50% 66.08% 84.43% Impurities13.9% ± 19.6% ± 17.3% ± 21.7% ± 20.2% ± 8.2% ± Assay (wt%) - 1.7% ± 0.01.9 0.0 0.1 0.1 0.0 0.0WSGR Docket No. 51503-780.601Table 38. Assay and Impurities Results for Compound B Eudragit L100-55 SDIs after 1- and 2- Months StabilityFormulation 20:80 Compound B: Eudragit L100-55 SDISDI 8Stability Compound B to 25°C / 6( )%RH 40°C / 7 5%RH 40°C / 7 5%RH RRT 1 month 2 months 1 month 2 months 1 month 2 months 0.73 - - <0.05% - - 0.06% 0.20% 0.77 - <0.05% <0.05% - - 0.07% 0.14% 0.82 - - - - - - <0.05% 0.84 0.43% 3.22% 4.55% 1.23% 1.89% 15.53% 24.87% 0.88 0.24% 0.86% 0.09% 0.18% 0.78% 1.37% 0.89 <0.05% - - - - - 0.92 <0.05% <0.05% - 0.05% - <0.05% 0.94 <0.05% - - - <0.05% - 0.95 0.07% <0.05% - <0.05% <0.05% <0.05% 0.96 0.06% 0.08% - <0.05% - - 0.97 0.11% 0.07% 0.09% 0.17% 0.07% 0.13% 0.07% 0.10% 0.98 - - <0.05% - <0.05% - - 1.05 <0.05% <0.05% <0.05% - <0.05% - <0.05% 1.06 - <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% 1.06 - - - <0.05% - <0.05% - 1.07 - <0.05% 0.06% 0.06% 0.05% 0.07% <0.05% 1.08 <0.05% <0.05% - <0.05% - 0.18% - 1.14 <0.05% - 0.08% - 0.06% - 0.07% 1.19 <0.05% - 0.06% - 0.05% - <0.05% 1.21 0.14% 0.11% 0.18% 0.15% 0.06% 0.14% - 0.14% 1.26 - - - 0.10% - - - - 1.28 - - - <0.05% - <0.05% - <0.05% 1.3 - - <0.05% - - - 0.06% - 1.31 <0.05% - 0.06% <0.05% 0.06% <0.05% - - Total 0.25% 0.61% 3.91% 6.12% 1.57% 2.54% 16.82% 26.90%Assay (wt%) - 20.4% ± 23.6% ± 22.0% ± 25.1% ± 23.6% ± 20.0% ± 16.9% ±Example 9: SDI Manufacture for Pharmacokinetic (PK) Study.

[0342] PK SDI Manufacturing.

[0343] PVP-VA64 (PK SDI 1), HPMC E3LV (PK SDI 2), HPMCP HP55 (PD SDI 3), and Eudragit L100-55 (PK SDI 4) SDIs at 20:80 Compound B:polymer were tested for manufacturability, physical properties, and stability. Table 39 summarizes the spray drying parameters, yields, and residual solvent levels. The residual solvents in all SDIs tested were below ICH limits after secondary drying.Table 39. Summary of Spray Drying Parameters for PK SDIs20:80 20:80 20:80 20:80 Formulation Compound B: Compound B: Compound B: Compound B:PVP-VA64 HPMC E3LV HPMCP-HP55 Eudragit L100-55 Batch Size (g) 36.25 (7.25) 36.25 (7.25) 36.25 (7.25) 36.25 (7.25) Total Solids (active)Composition PK SDI 1 PK SDI 2 PK SDI 3 PK SDI 4IdentificationWSGR Docket No. 51503-780.601Spray Solvent 80:20 DCM: MeOH Heated Methanol 80:20 DCM: MeOH 80:20 DCM: MeOH Total Solids 8 8 8 4 (Active) (wt%)Drying Gas Mode Büchi B-290 with B-295 Condenser (recycle mode) Condenser -18 to -20 -18 to -20 -18 to -20 -18 to -20 Temperature (°C)Cyclone Used StandardSolution Flow Rate 19.2-21.3 13.5 - 15.5 19.6 - 23.6 19.0 - 21.2 (g / min)Atomization 28 26 28 28 Pressure (psi)Inlet Temperature 93-96 129 - 134 91 - 99 89 - 91 (°C)Outlet Temperature 43-45 54 - 56 44 - 46 40 - 41 (°C)Wet SDD Yield 63 69 85 54 (wt%)Dry SDD Yield 55 (69 with 46 (78 with 68 73(wt%) chamber) chamber) Secondary Drying 24 h at 40 °C 24 h at 40 °C 24 h at 40 °C 24 h at 40 °C Residual Solvent DCM: < LOQMethanol: 210 N / A2N / A2(PPm) Methanol: ND1API is Compound B2GC was not performed on PK SDI 3 and PK SDI 4LOQ: limit of quantitation (200 ppm); ND: not detected; ICH limits: 600 ppm DCM, 3000 ppmMeOH

[0344] PK SDI Characterization.

[0345] HPMC E3LV and PVP-VA64 SDIs were characterized by visual appearance XRPD, SEM, MDSC, non-sink dissolution, and assay and impurities.

[0346] Thermal analysis done by MDSC showed that both dispersions have a single Tgindicating a homogeneous amorphous solid dispersions (Table 40). MDSC was performed as described in Example 8. The Tgs are similar to the Tgs the same formulations in Example 8 (see e.g., Table 30).Table 40. MDSC Data for Compound B PK SDIsFormulations Composition Identification Tg(°C) 20:80 Compound B: HPMC E3LV SDI PK SDI 2 115±120:80 Compound B: PVP-VA64 SDI PK SDI 1 106±1

[0347] Characterization by XRPD indicated that the PK SDIs are amorphous dispersions with no crystalline peaks observed in the SDI diffractograms. XRPD was performed as described in Example 8. Diffractograms are shown in FIG. 3.WSGR Docket No. 51503-780.601

[0348] Surface morphology of the PK SDI particles was characterized using scanning electron microscopy (SEM). SEM was performed as described in Example 8. Typical SDI morphology was observed consisting of collapsed and un-collapsed spheres with smooth surfaces. No crystalline material was observed in any sample.

[0349] The particle size distribution (PSD) of SDI samples was determined by light diffraction using a Mastersizer 3000 with an Aero S unit (Malvern Instruments). The parameters are listed in Table 41. Dv10, Dv50 and Dv90 diameters were used to describe the particle size distribution.Table 41. PSD Parameters.Parameter ValueInstrument Malvern Mastersizer 3000 Dispersion Unit Aero S (Dry) Dispersion Gas Nitrogen Gas Pressure 1.0 bar Feed Rate 50% Obscuration Limits 0.1%-10% Refractive Index Name Drug and Polymer Dispersion Refractive Index 1.68Density 0.5 g / mL Measurement Duration 5 sMeasurement Replicates n=3

[0350] Particle size data showed both SDIs had a monomodal distribution. These data is summarized in Table 42.Table 42. Particle Size Distribution Data for Compound B PK SDIs.Dv10 Dv50 Dv90 D [4,3] D [3,2] Sample Description Composition(pm) (pm) (pm) (pm) (pm) 20:80 Compound B:PK SDI 2 3 7 17 10 5 HPMC E3LV SDI20:80 Compound B:PK SDI 1 2 5 11 6 3PVP-VA64 SDI

[0351] The performance of the PK SDIs was evaluated by non-sink dissolution in biorelevant media. PK SDIs showed similar dissolution performance compared to feasibility SDIs. Results are shown in FIG. 4 and Table 43.WSGR Docket No. 51503-780.601Table 43. Non-sink dissolution in biorelevant media data for Compound B PK SDIs Compared to Bulk Compound BCmax AUC35.Composition CmaxGB C210 Formulation FaSSIF 2ioFaSSIF Identification (pgA / mL) (pgA / mL)(pgA / mL) (min*pgA / mL)20:80 Compound B:PK SDI 2 606 344 59800 342 HPMC E3LV (PK SDI)20:80 Compound B:PK SDI 1 668 326 56700 322 PVP-VA64 (PK SDI)20:80 Compound B:HPMC E3LV SDI 3 607 345 59500 345 (Feasibility SDI)20:80 Compound B:PVP-VA64 (Feasibility SDI 2 767 377 65800 377SDI)

[0352] Assay and impurities results for the PK SDIs showed the purity profiles were similar to the ingoing Compound B indicating no degradation during manufacture. Purity data is summarized in Table 44.Table 44. Assay and Impurities of Compound B PK SDIs Compared with Ingoing Compound B 20:80 20:80 Compound B Compound BRRT Compound B: HPMC Compound B: PVP- (New Lot) (Old Lot)E3LV, PK SDI 2 VA64, PK SDI 1 0.74 - - - <0.05% 0.84 0.67% - - - 0.88 0.50% - - <0.05% 0.89 0.13% - - - 0.92 <0.05% - - - 0.97 0.10% 0.11% 0.09% <0.05% 1.04 0.27% - <0.05% - 1.06 0.05% - 0.06% <0.05% 1.08 <0.05% <0.05% <0.05% - 1.12 <0.05% - - - 1.14 - <0.05% - - 1.19 - <0.05% - - 1.21 - 0.14% - - 1.30 <0.05% <0.05% - - 1.35 - - <0.05% <0.05% 1.39 0.16% - - - Total1.88% 0.25% 0.15% 0.00% ImpuritiesAssay (wt%) - - 21.2% ± 0.6 20.3% ± 0.2Example 10: Prototype Tablet Development

[0353] 5 mg Tablet Manufacturing Feasibility - Direct Compression

[0354] Two dispersions, 20:80 Compound B: HPMC E3LV and 20:80 Compound: PVP-VA64 were selected for tablet development and evaluation in pharmacokinetic (PK) studies. Acryl-EZE coating wasWSGR Docket No. 51503-780.601selected to provide an enteric release profile. Tablets were seal coated with Opadry Clear first as a protective layer. Tablet formulations are summarized in Table 45 and Table 46. Each tablet contains 5 mg of Compound B.Table 45. HPMC SDI Tablet Formulations.Formulation 1A Formulation 2A Formulation 3A Component w / w % mg / tablet w / w % mg / tablet w / w % mg / tablet 20:80 Compound20.00 25.00 20.00 25.00 20.00 25.00 B: HPMC E3LVEmcompress 75.00 93.75 — — — — Parteck M200— — 73.00 91.25 71.00 88.75 (mannitol)Kollidon CL3.00 3.75 5.00 6.25 7.00 8.75 (crospovidone)Cab-O-Sil (fumed1.00 1.25 1.00 1.25 1.00 1.25 silicon dioxide)Pruv (sodium1.00 1.25 1.00 1.25 1.00 1.25 stearyl fumarate)Total 100.00 125.00 100.00 125.00 100.00 125.00 Opadry Clear1.5011.88 1.5011.88 1.5011.88 03K19229Acryl-EZE White3.0013.81 3.0013.81 3.0013.81 93018359Coating Total 4.50 5.69 4.50 5.69 4.50 5.69Overall Total 104.50 130.69 104.50 130.69 104.50 130.69 1. Target weight gain for seal coat of uncoated tablet core is 1.5%. Target weight gain for enteric coat is 3.0% of the seal coated tablet. Actual weight gain, w / w% of the overall tablet weight is 1.44% Opadry 03K19299 Clear and 2.92% Acryl-EZE 93018359Table 46. PVP-VA64 SDI Tablet Formulations.Formulation IB Formulation 2B Formulation 3B Component w / w % mg / tablet w / w % mg / tablet w / w % mg / tablet 20:80 Compound20.00 25.00 20.00 25.00 20.00 25.00 B: PVP-VA64Emcompress 75.00 93.75 — — — — Parteck M200— — 73.00 91.25 75.00 93.75 (mannitol)Kollidon CL3.00 3.75 5.00 6.25 3.00 3.75 (crospovidone)Cab-O-Sil (silicon1.00 1.25 1.00 1.25 1.00 1.25 dioxide)Pruv (sodium1.00 1.25 1.00 1.25 1.00 1.25 stearyl fumarate)Tablet Core Total 100.00 125.00 100.00 125.00 100.00 125.00 Opadry Clear1.5011.88 1.5011.88 1.5011.88 03K19229Acryl-EZE White3.0013.81 3.0013.81 3.0013.81 93018359Coating Total 4.50 5.69 4.50 5.69 4.50 5.69Overall Total 104.50 130.69 104.50 130.69 104.50 130.69WSGR Docket No. 51503-780.6011. Target weight gain for seal coat of uncoated tablet core is 1.5%. Target weight gain for enteric coat is 3.0% of the seal coated tablet. Actual weight gain, w / w% of the overall tablet weight is 1.44% Opadry 03K19299 Clear and 2.92% Acryl-EZE 93018359

[0355] All materials were blended in aturbula blender, passed through a 20 mesh (841 micron) screen, and turbula blended for an additional 5 minutes. Total batch size was approximately 5 g per formulation.

[0356] 5 mg Prototype Tablet Manufacturing - Direct Compression

[0357] Formulations 3A and 3B were selected to manufacture the Compound B 5 mg tablets. Each tablet contains 5 mg of Compound B. Both formulations had disintegration times in the range of target tablet tensile strengths. A summary of the formulations is shown in Table 47.Table 47. Formulations of Compound B 5 mg TabletsFormulation 3A Formulation 3B Polymer: HPMC E3LV Polymer: PVP-VA64 Component w / w % mg / tablet w / w % mg / tablet 20:80 Compound20.00 25.00 20.00 25.00 B: PolymerParteck M200 (mannitol) 71.00 88.75 75.00 93.75 Kollidon CL7.00 8.75 3.00 3.75 (crospovidone)Cab-O-Sil (silicon dioxide) 1.00 1.25 1.00 1.25 Pruv (sodium stearyl1.00 1.25 1.00 1.25 fumarate)Tablet Core Total 100.00 125.00 100.00 125.00 Opadry Clear 03K19229 1.511.88 1.511.88 Acryl-EZE White3.013.81 3.013.81 93018359Acryl-EZE WhiteN / A N / A 3.013.92 93018359Coating Total 4.5 5.69 7.5 9.61Overall Total 104.5 130.69 107.5 134.61 1. Target weight gain for seal coat of uncoated tablet core is 1.5%. Target weight gain for enteric coat is 3.0% of the seal coated tablet. Target weight gain for the additional round of coating is 3.0% of the previously coated tablet. Actual weight gain, w / w% of the overall tablet weight is 1.44% Opadry 03K 19299 Clear, 2.92% Acryl-EZE 93018359 (1stcoat) and, 2.92% Acryl-EZE 93018359 (2ndcoat).

[0358] All materials were blended in aturbula blender, passed through a 20 mesh (841 micron) screen, and turbula blended for an additional 5 minutes.

[0359] Characterization of 5 mg Prototype Tablet

[0360] The two PK tablet formulations were characterized by water content by Coulometric Karl Fischer (KF) titration, non-sink dissolution in biorelevant media, and assay and impurities by HPLC.

[0361] Samples were analyzed for water content by a Metrohm 831 Karl Fischer (KF) Coulometric Titrator with a Metrohm 874 oven processor. About 100 mg samples were sealed in 6 mL crimp vials followed by measurement of water content with the following parameters: Reagent Hydranal Coulomat AG-Oven, Oven temperature 130 °C and sample extraction time 300 seconds.WSGR Docket No. 51503-780.601

[0362] Water content values were typical for tablets manufactured from HPMC E3LV and PVP-VA64 SDIs. Water content was low despite the hygroscopic polymers in the SDIs due to the enteric coating. Results are summarized in Table 48.Table 48. Water Content Data for Compound B PK TabletsFormulation Water Content (wt%) Compound B Tablet (HPMC E3LV SDI), 5 mg, Formulation 3A 1.4Compound B Tablet (PVP-VA64 SDI), 5 mg, Formulation 3B 1.4

[0363] The dissolution performance of the PK tablets was tested by non-sink dissolution in biorelevant media. Non-sink dissolution assays were performed as described in Example 8. Final concentrations of tablet formulations in FaSSIF media were greater than their parent SDIs, possibly drug entering the FaSSIF. Neither tablet had any detected drug release in gastric media indicating the enteric coating provided gastric protection. The HPMC E3-LV tablet had a slower dissolution rate than the PVP-VA64 tablet formulation. Dissolution results are summarized in FIG. 5 and Table 49.Table 49. Non-sink dissolution in biorelevant media Data for Compound B PK TabletsCmaxGB Cmax IB AUC35-210 IB C210 Formulation Composition(pgA / mL) (pgA / mL) (min*pgA / mL) (pgA / mL) 20:80 CompoundPK SDI 2 606 344 59800 342 B: HPMC E3LV20:80 CompoundPK SDI 1 668 326 56700 322 B: PVP-VA64Compound B Tablets, Formulation0 548 82100 548 5 mg (HPMC E3LV) 3ACompound B Tablets, Formulation0 516 87400 5135 mg (PVP-VA64) 3B

[0364] 5 mg HPMC E3LV SDI tablet had a label claim of higher than expected label claim at 106%. This could be due to the HPLC method as there is some interference near the API peak. An increase in impurities was also detected when compared to the ingoing SDI, but no new impurities were detected. Impurities with an RRT of 1.04 and 1.08 were detected above the LOQ in the tablet but were below LOQ in the SDI. These two impurities contributed to a higher total impurity count for the tablets. Results are shown in Table 50. A large peak was also detected at RRT 1.77 which was confirmed to be Pruv and thus was omitted from the total impurity count.WSGR Docket No. 51503-780.601Table 50. Assay / Impurities of Compound B: HPMC E3LV SDI PK Tablets Compared with Bulk Compound B and Ingoing SDI20:80 Compound B RRT Compound B Compound B: HPMC E3LV Tablet 1, (containing 5 mg of SDI Compound B) 0.86 - - <0.05%0.97 0.11% 0.09% 0.07%1.04 - <0.05% 0.10%1.06 - 0.06% 0.06%1.07 - - <0.05%1.08 <0.05% <0.05% 0.05%1.14 <0.05% - - 1.19 <0.05% - - 1.21 0.14% - 0.13%1.30 <0.05% - <0.05%1.35 - <0.05% <0.05%Total0.25% 0.15% 0.41% ImpuritiesAssay (wt%) - 21.2% ± 0.6 NA106.0% ± 0.0

[0365] 5 mg PVP-VA64 SDI tablets had a label claim of 88%. This could be due to the extraction method and or the HPLC method which had significant interference around the API peak. Impurities analysis showed similar total related substances compared with the parent SDIs and bulk Compound B, indicating that no chemical degradation occurred during the spray drying or tablet manufacturing processes. Results are summarized in Table 51.Table 51. Assay / Impurities of Compound B: PVP- VA64 SDI PK Tablets Compared with Bulk API Compound B and Ingoing SDICompound B20:80 Compound B: PVP- RRT Compound B Tablet 2, (containing 5 mg of VA64 SDICompound B)0.74 - <0.05% <0.05%0.86 - - <0.05%0.88 - <0.05% <0.05%0.97 0.11% <0.05% <0.05%1.06 - <0.05% - 1.08 <0.05% - - 1.14 <0.05% - - 1.19 <0.05% - - 1.21 0.14% 0.12%1.30 <0.05% - - 1.35 - <0.05% <0.05%Total Impurities 0.25% 0.00% 0.12%Assay (wt%) - 20.3% ± 0.2 NA% Label Claim - NA 88.8% ± 0.1WSGR Docket No. 51503-780.601

[0366] 8 mg Prototype Tablet Manufacturing - Dry Granulation

[0367] Tablets comprising a dose of 8 mg Compound B per tablet were manufactured. Previousbl C Ci Tttaeoreoangsdevelopment work was performed using a direct compression process flow. Here this process was changed to dry granulation. Tablet formulations are summarized in Table 52 and Table 53.Table 52. HPMC E3LV SDI Tablet Formulations.Formulation 4A Formulation 5A Componentwt.% (mg / tablet) wt.% (mg / tablet) 20:80 Compound20.00 40.00 20.00 40.00 B: HPMC E3LVMannitol Ml 00 60.50 121.00 45.00 90.00 Starch 1500 - - 15.00 30.00 Kollidon CL4.00 8.00 4.00 8.00 (crospovidone)Cab-O-Sil (silicon1.00 2.00 1.00 2.00 dioxide)Pruv (sodium stearyl0.50 1.00 0.50 1.00 fumarate)Intragranular Total 86.00 172.00 85.50 171.00 Mannitol M200 10.00 20.00 10.00 20.00 Kollidon CL3.50 7.00 4.0 8.00 (crospovidone)Pruv (sodium stearyl0.50 1.00 0.5 1.00 fumarate)Extragr anular Total 14.00 28.00 14.50 29.00 Tablet Core Total 100.00 200.00 100.00 200.00 Opadry Clear 03K19229 2.014.0 2.014.0 Acryl-EZE White7.0114.28 7.0114.28 93018359Coating Total 9.0118.28 9.0118.28Overall Total 109.0 218.00 109.0 218.001. Target weight gain for seal coat of uncoated tablet core is 2.0%. Target weight gain for enteric coat is 7.0% of the seal coated tablet. Actual weight gain, w / w% of the overall tablet weight is 1.83% Opadry 03K19299 Clear and 6.54% Acryl-EZE 93018359WSGR Docket No. 51503-780.601Table 53. PVP-VA64 SDI Tablet Formulations.Formulation 4B Formulation 5Bbl C Ci Tttaeoreoangs Componentwt.% (mg / tablet) wt.% (mg / tablet) 20:80 Compound20.00 40.00 20.00 40.00 B: PVP-VA64Mannitol Ml 00 64.50 129.00 48.00 96.00 Starch 1500 - - 16.00 32.00 Kollidon CL2.00 4.00 2.00 4.00 (crospovidone)Cab-O-Sil (silicon1.00 2.00 1.00 2.00 dioxide)Pruv (sodium stearyl0.50 1.00 0.50 1.00 fumarate)Intragranular Total 88.00 176.00 87.50 175.00 Mannitol M200 10.00 20.00 10.00 20.00 Kollidon CL1.5 3.00 2.00 4.00 (crospovidone)Pruv (sodium stearyl0.5 1.00 0.5 1.00 fumarate)Extragr anular Total 12.00 24.00 12.50 25.00 Tablet Core Total 100.00 200.00 100.00 200.00 Opadry Clear2.014.0 2.014.0 03K19229Acryl-EZE White7.0114.28 7.0114.28 93018359Coating Total 9.0118.28 9.0118.28OverallOverall Total 218.00 109.0 218.00Total1. Target weight gain for seal coat of uncoated tablet core is 2.0%. Target weight gain for enteric coat is 7.0% of the seal coated tablet. Actual weight gain, w / w% of the overall tablet weight is 1.83% Opadry 03K19299 Clear and 6.54% Acryl-EZE 93018359

[0368] All intragranular materials were blended in aturbula blender, passed through a 20 mesh (841 micron) screen, and turbula blended for an additional 5 minutes. Process flow chart of Compound B tableting can be found in FIG. 6. Total batch size was approximately 50 g per formulation.

[0369] Characterization of 8 mg Prototype Tablets.

[0370] The four 8 mg PK tablet formulations were characterized by water content by KF, non-sink dissolution in biorelevant media, and assay and impurities by HPLC. All assays were performed as previously described.

[0371] Water content values were typical for tablets manufactured from HPMC E3LV and PVP-VA64 SDIs. Tablet formulations 5A and 5B had a higher water content than formulations 4A and 4B (Table 54).Table 54. Water Content Data for Compound B PK Tablets.Formulation Water Content (wt%)Compound B Tablet, Formulation 4A 2.2Compound B Tablet, Formulation 4B 1.9Compound B Tablet, Formulation 5A 3.3Compound B Tablet, Formulation 5B 3.6WSGR Docket No. 51503-780.601

[0372] The performance of the tablets was assessed in a non-sink dissolution in biorelevant media. All tablets performed similarly. No release of drug was detected in the gastric media due to the enteric coating. Tablet formulation 4A had a slower dissolution rate compared to the other tablet formulations but reached a comparable total drug concentration. All tablets had a final total drug concentration above the theoretical limit of 500 μg / mL. This was also observed previously with the direct compression prototype tablets. Dissolution results are summarized in FIG. 7 and Table 55.Table 55. Non-sink dissolution in biorelevant media Data for Compound B PK Tablets.CmaxGB Cmax IB AUC35-210 IB C210 Formulation(μgA / mL) (μgA / mL) (min*pgA / mL) (μgA / mL) Compound B Tablet, Formulation 4A0 542 85500 542 (HPMC E3 LV)Compound B Tablet, Formulation 4B0 571 94400 571 (PVP-VA64)Compound B Tablet, Formulation 5A0 534 89000 534 (HPMC E3 LV)Compound B Tablet, Formulation 5B0 553 92000 553(PVP-VA64)

[0373] 8 mg HPMC E3LV SDI tablets had a label claim of 87.4% for formulation 4A and 89.7% for formulation 5A. An increase in impurities was also detected when compared to the ingoing Compound B, with a single new impurity detected at an RRT of 1.19. The impurity at an RRT 1.39 was detected at significantly higher levels than detected in the ingoing Compound. Results are shown in Table 56. A large peak was also detected at RRT 1.77 which was confirmed to be Pruv and thus was omitted from the total impurity count.Table 56. Assay / Impurities of Compound B PK Tablets made with HPMC E3LV SDI Compared with Bulk Compound B and Ingoing SDICompound Compound B Tablet, Compound B Tablet, RRT B Formulation 4A Formulation 5A 0.73 - <0.05% <0.05%0.79 - 0.05% <0.05%0.84 0.67% 0.72% 0.69%0.85 - <0.05% <0.05%0.88 0.50% 0.32% 0.36%0.89 0.13% - - 0.92 <0.05% - - 0.97 0.10% <0.05% <0.05%1.04 0.27% 0.36% 0.18%1.04 - - 0.21%1.05 - 0.07% 0.07%1.06 0.05% <0.05% 0.08%1.07 - 0.18% 0.25%1.08 <0.05% <0.05% <0.05%- <0.05% 0.05%1.11WSGR Docket No. 51503-780.601Compound Compound B Tablet, Compound B Tablet, RRT B Formulation 4A Formulation 5A1.12 <0.05% <0.05% - 1.14 - <0.05% <0.05%1.19 - 0.22% 0.64%1.21 - <0.05% - 1.22 - <0.05% - 1.30 <0.05% - - 1.33 - <0.05%1.35 - - - 1.39 0.16% 0.40% 0.42%1.49 - <0.05% - Total1.88% 2.31% 2.94% ImpuritiesAssay (wt%) - 87.4% ± 0.4 89.7% ± 1.0

[0374] 8 mg PVP-VA64 SDI tablets had a label claim of 91.3% for formulations 4B and 91.5% for formulation 5B. An increase in impurities was also detected when compared to the ingoing Compound B, with a single new impurity detected at an RRT of 1.19. The impurity at an RRT 1.39 was detected at significantly higher levels than detected in the ingoing Compound B. Results are shown in Table 57. A large peak was also detected at RRT 1.77 which was confirmed to be Pruv and thus was omitted from the total impurity count.Table 57. Assay / Impurities of Compound B PK Tablets made with PVP-VA64 SDI Compared with Bulk Compound B and Ingoing SDICompound Compound B Tablet, Compound B Tablet, RRT B Formulation 4B Formulation 5B 0.73 - <0.05% <0.05%0.82 - <0.05% <0.05%0.84 0.67% 0.50% 0.39%0.85 - <0.05% <0.05%0.88 0.50% 0.54% 0.63%0.89 0.13% 0.09% 0.10%0.92 <0.05% <0.05% <0.05%0.97 0.10% <0.05% <0.05%1.04 0.27% - - 1.06 0.05% - - 1.08 <0.05% - - 1.12 <0.05% - - 1.19 - 0.15% 0.24%1.30 <0.05% - - -1.33 <0.05% <0.05%WSGR Docket No. 51503-780.601Compound Compound B Tablet, Compound B Tablet, RRT B Formulation 4B Formulation 5B 1.39 0.16% 0.41% 0.44%1.49 - <0.05% - 1.51 - <0.05% - Total1.88% 1.69% 1.79% ImpuritiesAssay (wt%) - 91.3%* 91.5% ± 1.0* Single replicate runExample 11: Demonstration SDI Manufacture

[0375] Spray Solution and Wet SDI Stability

[0376] Spray solution from 20:80 Compound B: HPMC E3LV and 20:80 and Compound B: PVP-VA64 SDIs was sampled and held in stainless steel containers to establish a maximum hold time for future manufactures. Chemical stability was assessed by diluting an aliquot with diluent to a concentration appropriate for the assay and impurities method. Solution was monitored for impurity growth over time compared to the ingoing Compound B. The Compound B: HPMC E3LV spray solution was found to be stable for 8 days held heated at 40°C. No degradation was observed out to 8 days; however, impurity loss was noted. During this stage in the method development, it was hypothesized the change in impurities were caused by poor analytical solution stability. Additional testing determined sample solutions protected from light and chilled have different impurity profiles than solutions without heat / light protection. Results are summarized in Table 58. Samples were analyzed per draft analytical method, AM-0509.

[0377] The Compound B: PVP-VA64 spray solution was found to be stable for 4 days at room temperature. After three days, impurity growth was observed at RRT 0.75, 0.82. A loss of impurities (RRT 1.03 and 1.18) was also observed for Compound B: PVP-VA64. Results are summarized in Table 59. Impurities were reported at two detection wavelengths, 220 nm and 310 nm, due to significant baseline interference at 220 nm from the polymer. A single impurity was reported at 220 nm.Table 58. 20:80 Compound B: HPMC E3LV spray solution stabilityRRT 0.75 0.8110.8620.89720.904 0.97 1.0131.03 1.05 1.06 1.07 1.08 1.10 1.11 1.21 1.36 IngoingCompound <0.05 ND 0.37 0.61 0.16 0.10 0.18 0.22 ND ND ND ND ND ND 0.05 0.46 BT= 0 day 0.07 0.48 0.17 0.30 0.16 0.11 0.21 0.23 ND ND ND ND <0.05 <0.05 0.06 0.46 T= 1 day 0.21 ND ND ND 0.15 0.10 ND 0.16 ND ND ND ND 0.18 0.05 0.05 0.39 T= 2 days 0.17 ND ND ND 0.13 0.10 ND 0.14 0.10 0.06 0.15 0.05 0.10 0.05 0.05 0.35 T= 3 days 0.16 ND ND ND 0.12 0.10 ND 0.12 0.10 0.06 0.18 0.06 0.06 0.05 <0.05 0.33 T= 8 days 0.18 ND ND ND 0.07 0.10 ND <0.05 0.06 0.07 0.23 0.08 0.06 <0.05 0.27WSGR Docket No. 51503-780.6011RRT 0.81 not detected in Compound B or 20:80 Compound B: HPMC E3LV SDI samples. RRT 0.81 may be due to contamination.2RRT 0.86 and RRT 0.897 are both detected in Compound B and (heated) spray solution at t=0, however, were not detected in later timepoints. The impurity may be insoluble in spray solution over time.3RRT 1.01 is tailing peak of Compound B and may not be detected based on chromatography.Table 59. 20:80 Compound B: PVP-VA64 spray solution stabilityRRT 0.75 0.82 0.8620.89720.904 0.97 1.0131.03 1.05 1.06 1.07 1.18 IngoingCompound 0.05 ND 0.26 0.13 0.14 0.10 0.11 0.15 0.06 <0.05 0.05 0.07 BT= 1 day <0.05 <0.05 0.20 0.15 0.14 0.09 ND 0.14 0.15 ND 0.06 0.12 T= 2 days <0.05 0.06 0.15 0.14 0.13 0.10 ND 0.10 0.12 0.07 0.09 0.16 T= 3 days 0.05 0.07 0.15 0.10 0.12 0.10 0.11 0.06 0.11 0.05 0.07 <0.05 T= 4 days 0.07 0.10 0.13 0.10 0.12 0.10 ND <0.05 0.11 0.05 0.09 ND T= 8 days 0.21 0.17 0.05 0.05 <0.05 0.10 ND ND 0.18 0.18 <0.05 ND2RRT 0.86 and RRT 0.897 are both detected in Compound B and (heated) spray solution at t=0, however, were not detected in later timepoints. The impurity may be insoluble in spray solution over time.3RRT 1.01 is tailing peak of Compound B and may not be detected based on chromatography.

[0378] SDI prior to tray drying (wet SDI) was evaluated for physical and chemical stability by holding in stainless steel containers at 2-8°C for t = 1, 2, 3, and 8 days. At each timepoint an aliquot of SDI was dried in the lab oven to mimic tray drying after holding wet for the noted number of days. Samples were evaluated for assay and impurities, XRPD, appearance, MDSC and SEM following previously described methods. Wet 20:80 Compound B: HPMC E3LV SDI was determined to be chemically stable for 8 days, with no degradation observed. RRT 1.19 growth was observed at 8-days wet, however, impurity growth at RRT 1.19 has been studied and increases with sonication time (thermal degradant). Data is summarized in Table 60.

[0379] Wet 20:80 Compound B: PVP-VA64 SDI was determined to be chemically stable for 4 days, with degradation observed at 9 days. Data is summarized in Table 61.Table 60. Wet SDI chemical stability of 20:80 Compound B: HPMC E3LVRRT 0.76 0.81 0.85 0.895 0.904 0.97 1.01 1.03 1.06 1.07 1.14 1.19 1.36 Ingoing ND ND 0.76 0.54 0.16 0.09 ND 0.25 0.11 <0.05 ND ND 0.46 Compound BT= 1 day <0.05 0.06 0.20 0.66 0.13 0.12 0.22 0.21 0.14 0.07 ND ND 0.44 T= 2 days 0.07 0.05 0.08 0.44 0.14 0.14 0.45 0.11 0.11 <0.05 0.07 ND 0.44 T= 3 days 0.05 0.05 0.17 0.60 0.13 0.11 0.24 0.15 0.15 0.08 0.10 ND 0.44 T= 8 daysND 0.10 0.16 0.76 0.15 0.08 ND 0.27 0.10 ND ND 0.30 0.43 WetT=8 days 0.05 0.06 0.20 0.65 0.13 0.08 ND 0.22 0.06 0.19 ND ND 0.44 Dry SDI 0.06 0.05 0.16 0.57 0.12 0.12 0.29 0.12 0.18 0.10 0.13 ND 0.44WSGR Docket No. 51503-780.601Table 61. Wet SDI chemical stability of 20:80 Compound B: PVP-VA64RRT 0.85 0.86 0.88 0.895 0.904 0.97 1.01 1.05 1.06 1.07 1.11 1.19 IngoingCompound 0.56 ND <0.05 0.10 0.14 0.09 ND 0.20 0.09 <0.05 0.05 0.05 BT= 1 day 0.06 0.05 0.06 0.12 0.14 0.12 0.14 <0.05 0.12 <0.05 0.06 <0.05 T= 2 days 0.21 0.05 0.15 0.14 0.10 0.18 <0.05 ND 0.07 0.17 T= 3 days ND 0.11 <0.05 0.11 0.13 0.10 0.08 0.08 0.13 0.07 0.05 T= 4 days 0.11 0.07 0.11 0.14 0.13 0.20 0.05 0.13 <0.05 0.08 <0.05 T=9 days ND 0.19 0.06 0.20 0.15 0.09 0.16 0.14 0.08 <0.05 0.16Dry SDI 0.11 ND 0.05 0.08 0.13 0.13 0.21 <0.05 0.13 ND <0.05 <0.05

[0380] XRPD showed the wet HPMC E3LV SDI (Wet SDI 2) remained amorphous through 8 days and the PVP-VA64 SDI (Wet SDI 1) remained amorphous through 9 days. Representative diffractograms are shown in FIG. 8A and FIG. 8B, respectively.

[0381] SEM images showed typical SDI morphology of collapsed spheres that were consistent with feasibility batches for both SDIs. No crystallinity was detected and no changes to particle morphology were observed during drying.

[0382] Thermal analysis by MDSC showed that both wet SDIs had a single Tgat all timepoints indicating they SDIs remained a homogeneous amorphous solid dispersion. The non-reversing heat flow did not show crystallization or other events. MDSC data is summarized in Table 62.Table 62. MDSC Data of Wet SDIsSample Description Composition Tgonset (°C) TgHalf-Height (°C) 20:80 Compound B:HPMC E3LV SDI, Wet, Wet SDI 2 104 115±1 Dried on t=l day20:80 Compound B:HPMC E3LV SDI, Wet, Wet SDI 2 103 115±2 Dried on t=2 day20:80 Compound B:HPMC E3LV SDI, Wet, Wet SDI 2 105 117±3 Dried on t=4 day20:80 Compound B:HPMC E3LV SDI, Wet, Wet SDI 2 110 119±6 Dried on t=8 day20:80 Compound B:PVP-VA64 SDI, Wet, Wet SDI 1 100 105±0 Dried on t=l day20:80 Compound B:PVP-VA64 SDI, Wet, Wet SDI 1 100 105±0 Dried on t=2 day20:80 Compound B:PVP-VA64 SDI, Wet, Wet SDI 1 100 105±l Dried on t=3 day20:80 Compound B:PVP-VA64 SDI, Wet, Wet SDI 1 100 105±l Dried on t=4 day20:80 Compound B:PVP-VA64 SDI, Wet, Wet SDI 1 102 106±1Dried on t=9 dayWSGR Docket No. 51503-780.601

[0383] Demonstration Batch SDI Characterization

[0384] Appearance of the 20:80 Compound B: HPMC E3LV SDI demonstration batch SDI showed the SDI is a light tan powder and the SDI contains 1.43% water. Appearance of the 20: 80 Compound B: PVP-VA64 SDI demonstration batch SDI showed the SDI is a light tan powder and the SDI contains 2.13% water. These data are summarized in Table 63.Table 63. Visual Appearance and Water Content of Compound B Demonstration SDIs Formulation Appearance Water Content (wt%) 20:80 Compound B: HPMCLight Tan Powder 1.43E3LV SDI20:80 Compound B: PVP-VA64 Light Tan Powder 2.13Example 12: Tablet Scale-Up and Demonstration Batches

[0385] 20:80 Compound B: HPMC E3LV SDI granulation formulation 4A was nominated for scale-up and granulation development on the pilot scale Gerteis MINI-PACTOR with a slight modification. An additional 0.5% sodium stearyl fumarate was added to the extragranular component of the scale-up blend to quicken disintegration times. A summary of the scale-up tablet formulation is shown in Table 65. Each tablet of Table 65 has 8 mg of Compound B.Table 65. 20:80 Compound B: HPMC E3LV SDI Scale-up Tablet Formulation Summary Scale-up Formulation Demonstration Formulation Component Compound B Compound B Common Blend Common BlendTablets Tablets (wt.%) (wt.%)(mg / tablet) (mg / tablet) 20:80 Compound B:20.00 40.00 20.00 40.00 HPMC E3LV SDIParteck Ml 0060.00 120.00 60.00 120.00 (mannitol)Kollidon CL-F14.00 8.00 4.00 8.00 (crospovidone)Cab-O-Sil1.00 2.00 1.00 2.00 (silicon dioxide)Pruv(sodium stearyl 0.50 1.00 0.50 1.00 fumarate)Intragranular Total 85.50 171.00 85.50 171.00 Parteck M20010.00 20.00 9.50 19.00 (mannitol)Kollidon CL-F14.00 8.00 4.00 8.00 (crospovidone)Pruv(sodium stearyl 0.50 1.00 1.00 2.00 fumarate)Extragranular Total 14.50 29.00 14.50 29.00 Tablet Core Total 100.00 200.00 100.00 200.00 Opadry Clear2.0024.00 2.0024.00 03K19229Acryl-EZE White7.00214.28 7.00214.28 93018359Coated Tablet Total 109.00 218.28 109.00 218.28WSGR Docket No. 51503-780.6011Kollidon CL-F was used in place of Kollidon Cl for scale up and demonstration batch manufacture.2Target weight gain for seal coat of uncoated tablet core is 2.0%. Target weight gain for enteric coat is 7.0% of the seal coated tablet. Actual weight gain, w / w% of the overall tablet weight is 1.83% Opadry 03K19299 Clear and 6.54% Acryl-EZE 93018359.

[0386] The scale-up blend (Demonstration Formulation) was evaluated at multiple processing conditions on the Gerteis MINI-PACTOR for bulk powder properties and compressibility. The primary processing parameter investigated was press force, ranging from 5.0 to 5.5 kN / cm, and two granulator screen sizes, 0.8 mm / square and 1.0 mm / square. A summary of the pilot scale granulation conditions can be found in Table 66.Table 66. Scale-up Roller Compaction Processing Parameter Summary.Parameter Condition A Condition B Condition C Roll Type Knurled Knurled Knurled Press Force (kN / cm) 5.5 5.0 5.0Gap (mm) 2.5 2.5 2.5 Roll Speed (rpm) 2.5 2.5 2.5 Granulator Screen 0.8 mm / Square 0.8 mm / Square 1.0 mm / Square Granulator Type Star Rotor Star Rotor Star Rotor Granulator Speed, CW60 60 60 (rpm)Granulator Speed, CCW60 60 60(rpm)

[0387] All scale-up processing conditions resulted in hard / brittle ribbons that easily passed through the granulator screen. There were no major visual differences between any of the conditions assessed.

[0388] Scale-up granulations were evaluated for particle size distribution. Granulation particle size distribution can be found in FIG. 9 and scale-up tablet characterization is provided in Table 67.Table 67. Scale-up Compound B Tablet, 8 mg, Physical Characterization.Disintegration Time in Water [First, Last]ID(min:sec)02:15, 02:40Compound B Tablets, 8 mg03:40, 05:50Condition A07:41, 08:4801:47, 02:20Compound B Tablets, 8 mg 04:48, 06:01Condition B 08:45, 09:2010:07, 12:0202:09, 03:30Compound B Tablets, 8 mg04:25, 06:22Condition C08:54, 16:30

[0389] Condition B was nominated for demonstration batch manufacture based on material characterization, tablet physical properties, and visual observations.WSGR Docket No. 51503-780.601

[0390] Demonstration Batch Common Granulation

[0391] During scale-up tablet physical characterization it was found that the tablet ejection force was slightly high and that hazing was observed on the die table. The extragranular sodium stearyl fumarate (Pruv) concentration was increased from 0.5 to 1.0 % and the extragranular mannitol (Parteck M200) was decreased from 10.0 to 9.5 % to reduce tablet ejection force, as described above.

[0392] The Compound B demonstration batch common granulation, 40 mg / g, was manufactured using condition B from the scale-up development with a press force of 5.0 kN / cm. A granuleparticle size distribution can be found in FIG. 10.

[0393] Demonstration Batch Tablet Compression

[0394] The Compound B granulation, 40 mg / g, was used to manufacture 8 mg tablets. A total batch size of approximately 8,500 tablets was manufactured. Table 69 provides a summary of the tablet disintegration time.Table 69. Compound B Demonstration Batch Tablet Disintegration Time.Disintegration TimeID Dose Strength (mg) in Water [First, Last](mm:ss)05:50, 06:33Demonstration Tablets 8 07:45, 08:5008:54, 10:29

[0395] A seal coating was applied to demonstration batch of Compound B tablets using a Vector LDCS Hi-Coater with 1.5 L pan (RD-101). A summary of tablet coating parameters can be found in Table 70.The Opadry clear film coating system was reconstituted with purified water in a 2L vessel and stirred for a minimum of 45 minutes using an overhead mixer. Coating suspensions were gently stirred throughout coating process.Table 70. Seal Coating Parameters for Demonstration Batch of Compound B Tablets, 8 mg.Compound B Tablets, 8 mg Compound B Tablets, 8 mg Tablet Coating ParametersCondition 1 Condition 2 Coating Excipient Opadry Clear 03K19229Solids Content (% wt.) 10Coating Solvent Purified waterBatch Size (g) 845.1 845.2Target Weight Gain 2.0% ± 0.5%Pan Size 1.5 LSpray Gun Schlick, 0.8 mmGun to Bed Distance (inches) 2.5Atomizing Air Pressure (psi) 18Pattern Air Pressure (psi) 15Pan Speed (rpm) 20Coater Airflow (cfm) 95Inlet Temperature (°C) 43.9 - 66.7 53.3 - 55.9 Exhaust Air Temperature (°C) 43.9 - 46.7 43.3 - 47.2Spray Rate (g / min) 6.92 - 11.41 6.64 - 8.34WSGR Docket No. 51503-780.601

[0396] No major defects were observed in tablet coating. However, there was a slight texture observed on the coated tablets from each coating condition. The tablets coated following condition 2, with a lower solution flow rate and increased air temperature, appeared smoother than the tablets coated under condition 1.

[0397] In-process testing for the Compound B 8 mg, seal coated tablets included weight and appearance, results provided in Table 71. No major defects were observed in tablet coating. However, there was a slight texture observed on the coated tablets from each coating condition. The tablets were coated following Condition 2, with a lower solution flow rate and increased air temperature, appeared smoother than the tablets coated under Condition 1 (Table 71).Table 71. In-Process Testing of Demonstration Batch of Compound B Tablets, 8 mg, Seal Coated.Compound B Tablets, 8 mg Compound B Tablets, 8 mg In-Process TestCondition 1 Condition 2 Average Core Tablet Weight 199 mgAverage Coated Tablet Weight 203.8 mg 203.0 mg Actual Weight Gain 2.4% 2.0%White and tan mottled round White and tan mottled roundAppearance tablets, very slightly textured tablets, slightly textured surfacesurface

[0398] In-process testing for the coated tablets included weight, appearance, and disintegration time, results provided in Table 71. No major defects were observed in coated tablets; however, a minor defect was noted. A slight orange peel texture was observed on the tablet surface of tablets in both manufacturing conditions but was more apparent for Condition 1. Tablets manufactured under Condition 2 were selected to be used in method development and stability studies.

[0399] An enteric coating was applied to demonstration batch of Compound B tablets using a Vector LDCS Hi-Coater with 1.5 L pan (RD-101). A summary of tablet coating parameters is provided in Table 72.Table 72. In-Process Testing of Demonstration Batch of Compound B Tablets, 8 mg, Enteric Coated.Compound B Tablets, 8 Compound B Tablets, 8 mgIn-Process TestCondition 1 mg Condition 2 Average Seal Coated Tablet Weight 203.8 mg 203.0 mg Average Coated Tablet Weight 217.3 mg 216.6 mg Actual Weight Gain 6.6% 6.7% White round tablets, slight White round tablets, very Appearanceorange peel texture slight orange peel texture Slight change in surface texture,Slight change in surface no damage or color change inObservations after 1 hour in 0.1 N HC1 texture, no damage or tablets, the 0.1 N HC1 bathcolor change turned yellowDisintegration Time (mm:ss) First: 03:05 First: 03:20(Phosphate Buffer pH 6.8) Last: 07: 15 Last: 07: 10WSGR Docket No. 51503-780.601

[0400] Demonstration batch tablets were analyzed for appearance, identification by HPLC (retention time and spectral comparison), assay and impurities, content uniformity, water content by KF, and biorelevant two-stage and sink dissolution. All assays were performed as previously described. These results are provided in Table 73.Table 73. Testing of Physical Characteristics of Demonstration Batch of Compound B Tablets, 8 mg, Enteric Coated.Test ResultAppearance (Visual) White Round TabletsAssay HPLC 92.4%LCTotal Impurities and Related3.09% LCSubstances (HPLC)Individual Impurities and RRT %AreaRelated Substances (HPLC) 0.815 0.060.842 <0.050.854 0.890.897 0.540.929 <0.050.973 0.131.031 0.451.044 0.081.050 <0.051.054 <0.051.061 0.241.069 <0.051.094 <0.051.106 0.061.114 <0.051.177 0.091.195 <0.051.353 0.541.523 <0.05Uniformity of Dosage (HPLC) Average: 92%LC%RSD: 0.8%Meets USP <905> criteria(AV=7.8)Water Content (KF) 1.19 wt%Delayed Release (2-Stage) AverageBath: Time (min) %RSD Dissolution %DissolvedBath 1:120 0 0Bath 2: 10 44 19Bath 2:20 77 11Bath 2:30 87 5Bath 2:45 90 2Bath 2:60 90 1Bath 2:75 91 1Example 13: 9 mg and 16 mg Compound B formulations

[0401] 9 mg and 16 mg Compound B formulations are shown in Table 74 - Table 86. All materials, including intragranular materials, can be blended in a turbula blender, passed through a 20 mesh (841 micron) screen, and turbula blended for an additional 5 minutes. Tablets can be characterized by waterWSGR Docket No. 51503-780.601content by Coulometric Karl Fischer (KF) titration, non-sink dissolution in biorelevant media, and assay and impurities by HPLC. All assays can be performed as described in in Examples 10.Table 74. HPMC SDI Tablet Formulations (9 mg Compound B)Formulation 1A’ - 9 Formulation 2A’ - 9 Formulation 3A’ - 9 mg mg mgComponent w / w % mg / tablet w / w % mg / tablet w / w % mg / tablet 20:80 Compound20.00 45.00 20.00 45.00 20.00 45.00 B: HPMC E3LVEmcompress 75.00 168.75 — — — — Parteck M200— — 73.00 164.25 71.00 159.75 (mannitol)Kollidon CL3.00 6.75 5.00 11.25 7.00 15.75 (crospovidone)Cab-O-Sil (fumed1.00 2.25 1.00 2.25 1.00 2.25 silicon dioxide)Pruv (sodium stearyl1.00 2.25 1.00 2.25 1.00 2.25 fu...

Claims

1. WSGR Docket No. 51503-780.601CLAIMSWhat is claimed is:

1. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier,wherein the compound is 6-(6-((2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin- 3 -yl) -2 -methylbenzo [d] oxazol -5 -ol,wherein the pharmaceutical composition is in a solid dosage form.

2. The pharmaceutical composition of claim 1, wherein the compound has a structure ofH(Compound B).

3. The pharmaceutical composition of claim 1, wherein the compound is 6-(6-(((lR,2R,3S,5S)-2- Fluoro-9-azabicyclo[3.

3. l]nonan-3-yl)(methyl)amino)pyridazine-3-yl)-2-methylbenzo[d]oxazol-5- ol.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable excipient or carrier comprises a polymer.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises the Compound B and a polymer.

6. The pharmaceutical composition of claim 1, wherein the ASD is a Spray Dry Intermediate (SDI).

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutical composition comprises a Spray Dry Intermediate (SDI), and wherein the SDI comprises the Compound B and a polymer.

8. The pharmaceutical composition of any one of claims 4 to 7, wherein the polymer is a copolymer.

9. The pharmaceutical composition of any one of claims 4 to 8, wherein the polymer is an anionic polymer.

10. The pharmaceutical composition of any one of claims 4 to 8, wherein the polymer is a cationic polymer.

11. The pharmaceutical composition of any one of claims 4 to 8, wherein the polymer is an acidic polymer.

12. The pharmaceutical composition of any one of claims 4 to 8, wherein the polymer is a neutral polymer.

13. The pharmaceutical composition of any one of claims 4 to 12, wherein the polymer comprises polyvinylpyrrolidone (PVP K30), polyvinylpyrrolidone-co-vinyl acetate (PVP-VA64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl caprolactam-polyvinylWSGR Docket No. 51503-780.601acetate -polyethylene glycol graft copolymer (e.g., sold under the trade name Soluplus), methacrylic acid-methyl methacrylate copolymer (e.g., sold under the trade name Eudragit L100), methacrylic acid-ethyl acrylate copolymer (e.g., sold under the trade name Eudragit L100-55), or a combination thereof.

14. The pharmaceutical composition of claim 13, wherein the polymer is selected from the group consisting of PVP-VA64, HPMC, HPMCP, and methacrylic acid-ethyl acrylate copolymer.

15. The pharmaceutical composition of claim 14, wherein the polymer is selected from the group consisting of PVP-VA64 and HPMC.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 1:99 to about 50:50.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 10:90 to about 30:70.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer at a weight ratio of about 20:80.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the ASD or SDI comprises the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and the polymer in an amorphous state.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the ASD or SDI is present in the pharmaceutical composition in an amount of about 5% to 50% by weight.

21. The pharmaceutical composition of any one of claims 1 to 20, wherein the ASD or SDI is present in the pharmaceutical composition in an amount of about 10% to 30% by weight.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the ASD or SDI is present in the pharmaceutical composition in an amount of about 15% to 25% by weight.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the composition comprises a core-shell structure.

24. The pharmaceutical composition of claim 23, wherein the core comprises the ADS or SDI.

25. The pharmaceutical composition of claim 24, wherein the ASD or SDI is present in the core in an amount of about 5% to 40% by weight.

26. The pharmaceutical composition of claim 24, wherein the ASD or SDI is present in the core in an amount of about 5% to 35% by weight.

27. The pharmaceutical composition of claim 24, wherein the ASD or SDI is present in the core in an amount of about 10% to 30% by weight.

28. The pharmaceutical composition of claim 24, wherein the ASD or SDI is present in the core in an amount of about 15% to 25% by weight.WSGR Docket No. 51503-780.60129. The pharmaceutical composition of claim 24, wherein the ASD or SDI is present in the core in an amount of about 20% by weight.

30. The pharmaceutical composition of any one of claims 24 to 29, wherein the core further comprises a binder, a filler, a glidant, a lubricant, or a combination thereof.

31. The pharmaceutical composition of claim 30, wherein the binder comprises a polymer.

32. The pharmaceutical composition of claim 30 or 31, wherein the binder comprises crospovidone (e.g., Kollidon CL).

33. The pharmaceutical composition of any one of claims 30 to 32, wherein the binder is present in the pharmaceutical composition in an amount of about 1% to 15% by weight.

34. The pharmaceutical composition of any one of claims 30 to 32, wherein the binder is present in the pharmaceutical composition in an amount of about 2% to 10% by weight.

35. The pharmaceutical composition of any one of claims 30 to 34, wherein the binder is present in the core in an amount of about 1% to 15% by weight.

36. The pharmaceutical composition of any one of claims 30 to 34, wherein the binder is present in the core in an amount of about 2% to 8% by weight.

37. The pharmaceutical composition of any one of claims 30 to 36, wherein the filler comprises lactose, cellulose, sucrose, mannitol, starch, or a combination thereof.

38. The pharmaceutical composition of any one of claims 30 to 36, wherein the filler comprises mannitol (e.g., mannitol M200 grade or mannitol M100 grade).

39. The pharmaceutical composition of any one of claims 30 to 36, wherein the filler comprises calcium phosphate.

40. The pharmaceutical composition of any one of claims 30 to 39, wherein the filler is present in the pharmaceutical composition in an amount of about 30% to about 90%, about 40 wt% to about 90 wt%, about 50 wt% to about 80 wt%, or about 60 wt% to about 75 wt% by weight.

41. The pharmaceutical composition of any one of claims 30 to 39, wherein the filler is present in the pharmaceutical composition in an amount of about 40% to 70% by weight.

42. The pharmaceutical composition of any one of claims 30 to 41, wherein the filler is present in the core in an amount of about 30% to 90% by weight.

43. The pharmaceutical composition of any one of claims 30 to 41, wherein the filler is present in the core in an amount of about 40 wt% to about 90 wt%, about 50 wt% to about 80 wt%, or about 60 wt% to about 75 wt% by weight.

44. The pharmaceutical composition of any one of claims 30 to 41, wherein the filler is present in the core in an amount of about 50% to 75% by weight.

45. The pharmaceutical composition of any one of claims 30 to 41, wherein the filler is present in the core in an amount of about 65% to 75% by weight.

46. The pharmaceutical composition of any one of claims 30 to 45, wherein the glidant comprises silicon dioxide (e.g., fumed silica).WSGR Docket No. 51503-780.60147. The pharmaceutical composition of any one of claims 30 to 46, wherein the glidant is present in the pharmaceutical composition in an amount of about 0.1% to 5% by weight.

48. The pharmaceutical composition of any one of claims 30 to 46, wherein the glidant is present in the pharmaceutical composition in an amount of about 0.5% to 2% by weight.

49. The pharmaceutical composition of any one of claims 30 to 48, wherein the glidant is present in the core in an amount of about 0.1% to 5% by weight.

50. The pharmaceutical composition of any one of claims 30 to 48, wherein the glidant is present in the core in an amount of about 0.5% to 1.5% by weight.

51. The pharmaceutical composition of any one of claims 30 to 50, wherein the lubricant comprises talc, magnesium stearate, sodium stearyl fumarate, or a combination thereof.

52. The pharmaceutical composition of any one of claims 30 to 50, wherein the lubricant comprises sodium stearyl fumarate.

53. The pharmaceutical composition of any one of claims 30 to 52, wherein the lubricant is present in the pharmaceutical composition in an amount of about 0.1% to 2% by weight.

54. The pharmaceutical composition of any one of claims 30 to 52, wherein the lubricant is present in the pharmaceutical composition in an amount of about 0.5% to 1.5% by weight.

55. The pharmaceutical composition of any one of claims 30 to 54, wherein the lubricant is present in the core in an amount of about 0.1% to 2% by weight.

56. The pharmaceutical composition of any one of claims 30 to 54, wherein the lubricant is present in the core in an amount of about 0.5% to 1.5% by weight.

57. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises the ASD or SDI, mannitol, crospovidone, silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and sodium stearyl fumarate.

58. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate.

59. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80.

60. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises about 20 wt% of the ASD or SDI, about 70 wt% mannitol, about 8 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP-VA64, HPMC (e.g., HPMC E3LV) or a combination thereof.WSGR Docket No. 51503-780.60161. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises about 20 wt% of the ASD or SDI, about 71 wt% mannitol (e.g., mannitol M200), about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate.

62. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises about 20 wt% of the ASD or SDI, about 71 wt% mannitol, about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80.

63. The pharmaceutical composition of any one of claims 30 to 56, wherein the core comprises about 20 wt% of the ASD or SDI, about 71 wt% mannitol, about 7 wt% crospovidone, about 1 wt% silicon dioxide (e.g., untreated fumed colloidal silicon dioxide), and about 1 wt% sodium stearyl fumarate, and wherein the ASD or SDI comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer is selected from the group consisting of PVP-VA64 and HPMC (e.g., HPMC E3LV).

64. The pharmaceutical composition of any one of claims 23 to 63, wherein the core comprises over 85% by weight of the pharmaceutical composition.

65. The pharmaceutical composition of any one of claims 23 to 64, wherein the core comprises about 90-97% by weight of the pharmaceutical composition.

66. The pharmaceutical composition of any one of claims 30 to 65, wherein the shell comprises a protective layer and enteric coating.

67. The pharmaceutical composition of any one of claims 30 to 65, wherein the shell comprises less than 15% by weight of the pharmaceutical composition.

68. The pharmaceutical composition of any one of claims 30 to 65, wherein the shell comprises about 5- 10% by weight of the pharmaceutical composition.

69. The pharmaceutical composition of any one of claims 30 to 68, wherein the core comprises an intragranular component and an extragranular component.

70. The pharmaceutical composition of claim 69, wherein the core comprises the intragranular component in an amount of at least 50% by weight (wt%).

71. The pharmaceutical composition of claim 69, wherein the core comprises the intragranular component in an amount of about 10 wt% to about 99 wt%.

72. The pharmaceutical composition of claim 69, wherein the core comprises the intragranular component in an amount of about 55 wt% to about 95 wt%.

73. The pharmaceutical composition of claim 69, wherein the core comprises the intragranular component in an amount of about 86 wt%.

74. The pharmaceutical composition of any one of claims 69 to 73, wherein the core comprises the extragranular component in an amount of about 1 wt% to about 50 wt%.WSGR Docket No. 51503-780.60175. The pharmaceutical composition of any one of claims 69 to 73, wherein the core comprises the extragranular component in an amount of about 5 wt% to about 25 wt%.

76. The pharmaceutical composition of any one of claims 69 to 73, wherein the core comprises the extragranular component in an amount of about 10 wt% to about 20 wt%.

77. The pharmaceutical composition of any one of claims 69 to 73, wherein the core comprises the extragranular component in an amount of about 14 wt%.

78. The pharmaceutical composition of any one of claims 69 to 77, wherein the intragranular component comprises the ASD, a filler, a binder, a glidant, and a lubricant.

79. The pharmaceutical composition of claim 78, wherein the intragranular component comprises the ASD, mannitol, crospovidone, silico dioxide (e.g., untreated firmed colloidal silicon dioxide), and sodium stearyl fumarate.

80. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 60 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core.

81. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 60 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:

80.

82. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 60 wt% mannitol, about 4 wt% crospovidone, about 1 wt% silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV).

83. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 60.5 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core.

84. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 60.5 wt% mannitol (e.g., mannitol M100), about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80.

85. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 60.5 wt% mannitol, about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV).WSGR Docket No. 51503-780.60186. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 23.3 wt% of the ASD, about 70.4 mannitol, about 4.7 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6% wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV).

87. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 64.5 wt% mannitol (e.g., mannitol M100), about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core.

88. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 64.5 wt% mannitol, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:

80.

89. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 20 wt% of the ASD, about 64.5 wt% mannitol about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP VA64.

90. The pharmaceutical composition of claim 79, wherein the intragranular component comprises about 22.7 wt% of the ASD, about 73.3 wt% mannitol, about 2.3 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6 wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP VA 64.

91. The pharmaceutical composition of claim 78, wherein the intragranular component comprises the ASD, mannitol, starch, crospovidone, silico dioxide (e.g., untreated fumed colloidal silicon dioxide), and sodium stearyl fumarate.

92. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 20 wt% of the ASD, about 45 wt% mannitol (e.g., mannitol M100), about 15 wt% starch (e.g., starch 1500), about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core.

93. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 20 wt% of the ASD, about 45 wt% mannitol, about 15 wt% starch, about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80.

94. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 20 wt% of the ASD, about 45 wt% mannitol, about 15 wt% starch, about 4 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarateWSGR Docket No. 51503-780.601relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC (e.g., HPMC E3LV).

95. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 23.4 wt% of the ASD, about 52.7 wt% mannitol, about 17.6 wt% starch, about 4.7 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6 wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises HPMC.

96. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 20 wt% of the ASD, about 48 wt% mannitol, about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core.

97. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 20 wt% of the ASD, about 48 wt% mannitol, about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80.

98. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 20 wt% of the ASD, about 48 wt% mannitol, about 16 wt% starch, about 2 wt% crospovidone, about 1 wt% untreated fumed colloidal silicon dioxide, and about 0.5 wt% sodium stearyl fumarate relative to the core, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of about 20:80, wherein the polymer comprises PVP VA64.

99. The pharmaceutical composition of claim 91, wherein the intragranular component comprises about 22.9 wt% of the ASD, about 54.9 wt% mannitol M100, about 18.3 wt% starch 1500, about 2.3 wt% crospovidone, about 1.2 wt% untreated fumed colloidal silicon dioxide, and about 0.6 wt% sodium stearyl fumarate relative to the intragranular component, and wherein the ASD comprises the Compound B and the polymer in a weight ratio of 20:80, wherein the polymer comprises PVP VA64.

100. The pharmaceutical composition of any one of claims 69 to 99, wherein the extragranular component comprises at least a portion of the filler, at least a portion of the binder, at least portion of the glidant, at least a portion of the lubricant, or a combination thereof.

101. The pharmaceutical composition of any one of claims 69 to 100, wherein the extragranular component comprises a filler, a binder, and a lubricant.

102. The pharmaceutical composition of claim 100 or 101, wherein the extragranular component comprises mannitol, crospovidone, and sodium stearyl fumarate.

103. The pharmaceutical composition of claim 102, wherein the extragranular component comprises about 10 wt% mannitol (e.g., mannitol M200), about 3.5 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core.WSGR Docket No. 51503-780.601104. The pharmaceutical composition of claim 102, wherein the extragranular component comprises about 10 wt% mannitol, about 4 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core.

105. The pharmaceutical composition of claim 102, wherein the extragranular component comprises about 9.5 wt% mannitol, about 4 wt% crospovidone, and about 1 wt% sodium stearyl fumarate relative to the core.

106. The pharmaceutical composition of claim 102, wherein the extragranular component comprises about 10 wt% mannitol, about 1.5 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core.

107. The pharmaceutical composition of claim 102, wherein the extragranular component comprises about 10 wt% mannitol, about 2 wt% crospovidone, and about 0.5 wt% sodium stearyl fumarate relative to the core.

108. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises an amorphous solid dispersion (ASD), and wherein the ASD comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises polyvinylpyrrolidone-co- vinyl acetate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), a methacrylate copolymer (such as methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl acrylate copolymer), or a combination thereof.

109. The pharmaceutical composition of 108, wherein the ASD is a Spray Dry Intermediate (SDI).

110. The pharmaceutical composition of claim 108 or 109, wherein the ASD or SDI comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 50%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises polyvinylpyrrolidone-co- vinyl acetate.

111. The pharmaceutical composition of claim 108 or 109, wherein the ADS or SDI comprises about 20% wt of the Compound B and 80% wt of polyvinylpyrrolidone-co-vinyl acetate.

112. The pharmaceutical composition of claim 108 or 109, wherein the ASD or SDI comprises about 10% to 30% wt (e.g., about 10%, 15%, 20%, 25%, or 30%) of the Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and 70% to 90% wt (e.g., about 70%, 75%, 80%, 85%, or 90%) of a polymer, and wherein the polymer comprises HPMC.

113. The pharmaceutical composition of claim 108 or 109, wherein the ASD or SDI comprises about 20% wt of the Compound B and about 80% wt of HPMC.

114. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and optionally a shell, wherein:(a) the core comprises, by weight,WSGR Docket No. 51503-780.601about 10-40% of an ASD, wherein the ASD comprises about 10-40% of Compound B or the pharmaceutically acceptable salt or stereoisomer thereof and about 60-90% of a polymer (such as HPMC);about 50-90% of a filler (such as mannitol),about 1-15% of a binder (such as crospovidone),about 0.1-5% of a glidant, andabout 0.1-5% of a lubricant; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises over 80% wt of the pharmaceutical composition.

115. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and optionally a shell, wherein:(a) the core comprises, by weight,about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC;about 60-80% of mannitol,about 4-12% of crospovidone,about 0.5-2% of silicon dioxide, andabout 0.5-2% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 85% wt of the pharmaceutical composition.

116. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC;about 71% of mannitol,about 7% of crospovidone,about 1% of silicon dioxide, andabout 1% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 95% wt of the pharmaceutical composition.

117. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and optionally a shell, wherein:(a) the core comprises, by weight,about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate;about 65-85% of mannitol,about 1-5% of crospovidone,WSGR Docket No. 51503-780.601about 0.5-2% of silicon dioxide, andabout 0.5-2% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 85% wt of the pharmaceutical composition.

118. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate;about 75% of mannitol,about 3% of crospovidone,about 1% of silicon dioxide, andabout 1% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt of the pharmaceutical composition.

119. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% ofHPMC;about 70-71% (e.g., 70.5%) of mannitol,about 7-8% (e.g., 7.5%) of crospovidone,about 1% of silicon dioxide, andabout 1% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt of the pharmaceutical composition.

120. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and optionally a shell, wherein:(a) the core comprises, by weight,about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% ofHPMC;about 45-65% of mannitol,about 5-25% of starch,about 4-12% of crospovidone,about 0.5-2% of silicon dioxide, andabout 0.5-2% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 85% wt of the pharmaceutical composition.WSGR Docket No. 51503-780.601121. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% ofHPMC;about 55% of mannitol,about 15% of starch,about 8% of crospovidone,about 1% of silicon dioxide, andabout 1% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt of the pharmaceutical composition.

122. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and optionally a shell, wherein:(a) the core comprises, by weight,about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate;about 65-85% of mannitol,about 1-7% of crospovidone,about 0.5-2% of silicon dioxide, andabout 0.5-2% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 85% wt of the pharmaceutical composition.

123. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate;about 74-75% (e.g., 74.5%) of mannitol,about 3-4% (e.g., 3.5%) of crospovidone,about 1% of silicon dioxide, andabout 1% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt of the pharmaceutical composition.

124. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,WSGR Docket No. 51503-780.601about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate;about 50-70% of mannitol,about 5-25% of starch,about 1-7% of crospovidone,about 0.5-2% of silicon dioxide, andabout 0.5-2% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 85% wt of the pharmaceutical composition.

125. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of polyvinylpyrrolidone-co-vinyl acetate;about 58% of mannitol,about 16% of starch,about 4% of crospovidone,about 1% of silicon dioxide, andabout 1% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt of the pharmaceutical composition.

126. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 15-25% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC;about 60-80% of mannitol,about 4-12% of crospovidone,about 0.5-2% of silicon dioxide, andabout 0.5-3% of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 85% wt of the pharmaceutical composition.

127. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of a SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC;about 69-70% (e.g., 69.5%) of mannitol,WSGR Docket No. 51503-780.601about 8% of crospovidone,about 1% of silicon dioxide, andabout 0.5 -1.5 % (e.g., 0.5 % or 1.5%) of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt of the pharmaceutical composition.

128. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core and a shell, wherein:(a) the core comprises, by weight,about 20% of an SDI, wherein the SDI comprises about 20% of Compound B and about 80% of HPMC;about 69.5% of mannitol,about 8% of crospovidone,about 1% of silicon dioxide, andabout 1.5 % of sodium stearyl fumarate; and(b) the shell comprises a film coating, optionally an enteric coating;wherein the core comprises about over 90% wt (e.g., about 91% or about 92%) of the pharmaceutical composition.

129. The pharmaceutical composition of any one of claims 1 to 107 wherein the pharmaceutical composition comprises a core and a shell,wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the core):about 20 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and wherein the ASD is optionally an SDI;about 60 wt% mannitol (e.g., M100);about 4 wt% crospovidone;about 1 wt% untreated fumed colloidal silicon dioxide; and about 0.5 wt% sodium stearyl fumarate; andwherein the extragranular component comprises (relative to the core):about 9.5 wt% mannitol M200;about 4 wt% crospovidone;about 1 wt% sodium stearyl fumarate.

130. The pharmaceutical composition of Claim 129, wherein the shell comprises, relative to the pharmaceutical composition,about 2 wt% of a protective layer (e.g., a seal coat), optionally comprising polyvinyl alcohol (PVA), HPMC, or a combination thereof; andabout 7 wt% of an enteric coating, optionally comprising polymethacrylate (e.g., L100-55 grade).WSGR Docket No. 51503-780.601131. The pharmaceutical composition of claim 130, wherein the protective layer (e.g., seal coat) comprises polyvinyl alcohol (PVA), HPMC, or a combination thereof, and wherein the enteric coating comprises a polymethacrylate copolymer (e.g., a copolymer of methacrylic acid).

132. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core comprising about 92% wt of the composition and a shell comprising about 8% wt of the pharmaceutical composition,wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the pharmaceutical composition):about 18 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and wherein in the ASD is an SDI; about 55 wt% mannitol (e.g., M100);about 3-4 wt% crospovidone;about 0.5-1 wt% untreated fumed colloidal silicon dioxide; andabout 0.1-0.5 wt% sodium stearyl fumarate; andwherein the extragranular component comprises (relative to the pharmaceutical composition):about 9 wt% mannitol (e.g., M200);about 3-4 wt% crospovidone;about 0.5-1 wt% sodium stearyl fumarate; andwherein the shell comprises (relative to the pharmaceutical composition):about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6-7 wt% of an enteric coating comprising polymethacrylate (e.g., L100-55 grade).

133. The pharmaceutical composition of any one of claims 1 to 107, wherein the pharmaceutical composition comprises a core comprising about 91-92% wt of the pharmaceutical composition and a shell comprising about 8-9% wt of the pharmaceutical composition,wherein the core comprises an intragranular component and an extragranular component, wherein the intragranular component comprises (relative to the core):about 20 wt% of the ASD, wherein the ASD comprises the Compound B and HPMC in a weight ratio of about 20:80, and optionally wherein in the ASD is an SDI;about 60 wt% mannitol (e.g., M100);about 4 wt% crospovidone;about 1 wt% silicon dioxide; andabout 0.5 wt% sodium stearyl fumarate; andwherein the extragranular component comprises (relative to the core):WSGR Docket No. 51503-780.601about 9.5 wt% mannitol (e.g., M200);about 4 wt% crospovidone;about 1 wt% sodium stearyl fumarate; andwherein the shell comprises (relative to the pharmaceutical composition):about 2 wt% of a protective layer (e.g., a seal coat) comprising a polymer selected from the group consisting of polyvinyl alcohol (PVA) and HPMC; and about 6-7 wt% of an enteric coating comprising polymethacrylate (e.g., L100-55 grade).

134. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 0.1 to about 20 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

135. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 0.5 to about 15 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

136. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 1 to about 10 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

137. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 4 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

138. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 5 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

139. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 6 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

140. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 8 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

141. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 9 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

142. The pharmaceutical composition of any one of claims 1 to 133, wherein the pharmaceutical composition comprises about 16 mg of the Compound B or a pharmaceutically acceptable salt or a stereoisomer thereof.

143. The pharmaceutical composition of any one of claims 1 to 142, wherein the ASD or SDI has a glass transition temperature (Tg) of about 50 °C or greater at 0.0% relative humidity.WSGR Docket No. 51503-780.601144. The pharmaceutical composition of any one of claims 1 to 142, wherein the ASD or SDI has Tgof about 75 °C or greater, of about 90 °C or greater, or of about 100 °C or greater at 0.0% relative humidity.

145. The pharmaceutical composition of any one of claims 1 to 144, wherein the ASD or SDI has Tgof 105 °C at 0.0% relative humidity.

146. The pharmaceutical composition of any one of claims 1 to 145, wherein the ASD or SDI has Tgof about 113 °C at 0.0% relative humidity.

147. The pharmaceutical composition of any one of claims 1 to 146, wherein the ASD or SDI provides a maximum concentration of solubilized Compound B after the gastric phase of a non-sink dissolution assay (CmaxGB) of greater than about 100 μg Compound B / mL.

148. The pharmaceutical composition of any one of claims 1 to 147, wherein the ASD or SDI provides a CmaxGB of greater than about 200 pg Compound B / mL.

149. The pharmaceutical composition of any one of claims 1 to 148, wherein the ASD or SDI provides a CmaxGB of greater than about 500 pg Compound B / mL.

150. The pharmaceutical composition of any one of claims 1 to 149, wherein the ASD or SDI provides a CmaxGB of greater than about 600 pg Compound B / mL.

151. The pharmaceutical composition of any one of claims 1 to 150 wherein the ASD or SDI provides a CmaxGB of greater than about 767 pg Compound B / mL.

152. The pharmaceutical composition of any one of claims 1 to 151, wherein the ASD or SDI provides a maximum concentration of solubilized Compound B after the intestinal phase of a non-sink dissolution assay (CmaxIB) of greater than about 100 μg Compound B / mL.

153. The pharmaceutical composition of any one of claims 1 to 152, wherein the ASD or SDI provides a CmaxIB of greater than about 200 pg Compound B / mL.

154. The pharmaceutical composition of any one of claims 1 to 153, wherein the ASD or SDI provides a CmaxIB of greater than about 300 pg Compound B / mL.

155. The pharmaceutical composition of any one of claims 1 to 154, wherein the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±30% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDL156. The pharmaceutical composition of any one of claims 1 to 154, wherein the ASD or SDI provides an AUC35-210 FaSSIF of Compound B that is within ±20% of the AUC35-210 FaSSIF provided by a corresponding composition of Compound B without the ASD or SDL157. The pharmaceutical composition of any one of claims 1 to 156, wherein the ASD or SDI comprises less than 10% total impurities as measured by high-performance liquid chromatography (HPLC) after being stored for 2 months at about 40°C / 75%RH (e.g., in closed packaging).

158. The pharmaceutical composition of any one of claims 1 to 157, wherein the ASD or SDI comprises less than 5% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH.

159. The pharmaceutical composition of any one of claims 1 to 158, wherein the ASD or SDI comprises less than 3% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH.WSGR Docket No. 51503-780.601160. The pharmaceutical composition of any one of claims 1 to 159, wherein the ASD or SDI comprises less than 2% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH.

161. The pharmaceutical composition of any one of claims 1 to 160, wherein the ASD or SDI comprises at most about 1% total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH.

162. The pharmaceutical composition of any one of claims 1 to 161, wherein the ASD or SDI comprises at most 0.5% about total impurities as measured by HPLC after being stored for 2 months at 40°C / 75%RH.

163. The pharmaceutical composition of any one of claims 1 to 161, wherein, after being stored for 2 months at 40°C / 75%RH, the ASD or SDI has an assay value of Compound B that is within ±20%, ±15%, ±10%, or ±5% of the initial assay value.

164. The pharmaceutical composition of any one of claims 1 to 163, wherein the ASD or SDI has a Dv50 of about 0.1 μm to about 20 μm.

165. The pharmaceutical composition of any one of claims 1 to 164, wherein the ASD or SDI has a Dv50 of about 0.5 μm to about 10 μm.

166. The pharmaceutical composition of any one of claims 1 to 165, wherein the ASD or SDI has a Dv50 of about 1 μm to about 5 μm.

167. The pharmaceutical composition of any one of claims 1 to 166, wherein the ASD or SDI has a Dv50 of about 3 μm.

168. The pharmaceutical composition of any one of claims 1 to 167, wherein the ASD or SDI has a Dv50 of about 2 μm.

169. The pharmaceutical composition of any one of claims 1 to 168, wherein the ASD or SDI remained amorphous for at least a month when stored at 25°C / 60%RH condition, as determined by X-ray powder diffraction (XRPD).

170. The pharmaceutical composition of any one of claims 1 to 168, wherein the ASD or SDI remained amorphous for at least two months when stored at 25°C / 60%RH condition, as determined by X-ray powder diffraction (XRPD).

171. The pharmaceutical composition of any one of claims 1 to 168, wherein the ASD or SDI remained amorphous for at least a month when stored at 40°C / 75%RH condition, as determined by X-ray powder diffraction (XRPD).

172. The pharmaceutical composition of any one of claims 1 to 168, wherein the ASD or SDI remained amorphous for at least two months when stored at 40°C / 75%RH condition, as determined by X-ray powder diffraction (XRPD).

173. The pharmaceutical composition of any one of claims 1 to 172, wherein the ASD or SDI is chemically stable for at least 1 day when stored at 2-8 °C when the ASD or SDI is wet.

174. The pharmaceutical composition of any one of claims 1 to 173, wherein the ASD or SDI is chemically stable for at least 2 days when stored at 2-8 °C when the ASD or SDI is wet.WSGR Docket No. 51503-780.601175. The pharmaceutical composition of any one of claims 1 to 174, wherein the ASD or SDI is chemically stable for at least 3 days when stored at 2-8 °C when the ASD or SDI is wet.

176. The pharmaceutical composition of any one of claims 1 to 175, wherein the ASD or SDI is chemically stable for at least 4 days when stored at 2-8 °C when the ASD or SDI is wet.

177. The pharmaceutical composition of any one of claims 1 to 176, wherein the ASD or SDI is chemically stable for at least 5 days when stored at 2-8 °C when the ASD or SDI is wet.

178. The pharmaceutical composition of any one of claims 1 to 177, wherein the ASD or SDI is chemically stable for at least 7 days when stored at 2-8 °C when the ASD or SDI is wet.

179. The pharmaceutical composition of any one of claims 1 to 178, wherein the ASD or SDI is chemically stable for at least 8 days when stored at 2-8 °C when the ASD or SDI is wet.

180. The pharmaceutical composition of any one of claims 173 to 179, wherein a chemically stable, wet ASD or SDI does not exhibit any degradation peak of Compound B as determined by HPLC.

181. The pharmaceutical composition of any one of claims 173 to 180, wherein the wet ASD or SDI has a total solid of about 1-10 wt%.

182. The pharmaceutical composition of any one of claims 1 to 181, wherein the pharmaceutical composition provides a CmaxGB of less than about 20 pg Compound B / mL.

183. The pharmaceutical composition of any one of claims 1 to 182, wherein the pharmaceutical composition provides a CmaxGB of less than about 10 pg Compound B / mL.

184. The pharmaceutical composition of any one of claims 1 to 183, wherein the pharmaceutical composition provides a CmaxGB of less than about 1 pg Compound B / mL.

185. The pharmaceutical composition of any one of claims 1 to 184, wherein the pharmaceutical composition provides a CmaxGB of less than about 0.1 pg Compound B / mL.

186. The pharmaceutical composition of any one of claims 1 to 185, wherein the pharmaceutical composition provides a CmaxGB of about 0 pg Compound B / mL.

187. The pharmaceutical composition of any one of claims 1 to 186, wherein the pharmaceutical composition provides a CmaxIB of greater than about 200 pg Compound B / mL.

188. The pharmaceutical composition of any one of claims 1 to 187, wherein the pharmaceutical composition provides a CmaxIB of greater than about 300 pg Compound B / mL.

189. The pharmaceutical composition of any one of claims 1 to 188, wherein the pharmaceutical composition provides a CmaxIB of greater than about 500 pg Compound B / mL.

190. The pharmaceutical composition of any one of claims 1 to 189, wherein the pharmaceutical composition provides a CmaxIB of about 520 pg Compound B / mL.

191. The pharmaceutical composition of any one of claims 1 to 190, wherein the pharmaceutical composition provides a CmaxIB of about 550 pg Compound B / mL.

192. The pharmaceutical composition of any one of claims 1 to 191, wherein the pharmaceutical composition comprises granules.

193. The pharmaceutical composition of any one of claims 1 to 192, wherein the pharmaceutical composition comprises a granule size Dv90 of about 1250 μm to about 100 μm.WSGR Docket No. 51503-780.601194. The pharmaceutical composition of any one of claims 1 to 193, wherein the pharmaceutical composition comprises a granule size Dv90 of about 200 μm to about 1000 μm.

195. The pharmaceutical composition of any one of claims 1 to 194, wherein the pharmaceutical composition comprises a granule size Dv90 about 300 μm to about 750 μm.

196. The pharmaceutical composition of any one of claims 1 to 195, wherein the pharmaceutical composition comprises a granule size Dv90 of less than about 700 μm.

197. The pharmaceutical composition of any one of claims 1 to 195, wherein the pharmaceutical composition comprises a granule size Dv90 of about 500 μm to about 700 μm.

198. The pharmaceutical composition of any one of claims 1 to 197, wherein the pharmaceutical composition comprises a granule size Dv90 of less than about 600 μm.

199. The pharmaceutical composition of any one of claims 1 to 198, wherein the pharmaceutical composition is a tablet.

200. The pharmaceutical composition of any one of claims 1 to 198, wherein the pharmaceutical composition is a capsule.

201. A pharmaceutical composition selected from Formulations 1A-5A, 1A’-5A’, 1A”-5A”, 1B-5B, 1B’- 5B’, 1B”-5B”, 4A(1)’, 4A(1)”, 4A(2)’, 4A(2)”, SDI 1 to SDI 8, and Formulations of Tables 30-32, 45-47, 52-53, 65, and 74-86.

202. A pharmaceutical composition comprising the Formulation of Table 86.

203. A method of modulating splicing comprising administering to cells the pharmaceutical composition of any one of claims 1 to 202, wherein the pharmaceutical composition modulates splicing at a splice site sequence of a pre-mRNA that encodes an mRNA, wherein the mRNA encodes a target protein or a functional RNA.

204. A method of treating a disease or condition comprising administering the pharmaceutical composition of any one of claims 1 to 202, to a subject in need thereof.

205. Use of the pharmaceutical composition of any one of claims 1 to 202, in the manufacture of a medicament for the treatment of a condition or disease.

206. The method or use of claim 204 or 205, wherein the disease or condition is Huntington’s Disease.

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