LIPID-BASED FORMULATIONS OF SCY-078 SALTS

[0001] This application claims priority to U.S. Provisional Application No. 62/932,851 filed November 8, 2019, which application is incorporated by reference herein in its entirety.

[0002] Compositions comprising pharmaceutically acceptable salts of SCY-078 (or “compound 1”), a glucan synthase inhibitor, and methods comprising the same for treating and/or preventing, among other things, Invasive Candidiasis and Invasive Aspergillosis are disclosed herein. Methods for preparing pharmaceutical compositions comprising pharmaceutically acceptable salts of SCY-078 are also disclosed.

[0003] SCY-078 is a first-in-class triterpenoid antifungal with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus. Other microbial utilities of SCY-078 are disclosed, for example, in U.S. Patent No. 8,188,085, the relevant portions of which are incorporated herein by reference.

[0004] Pharmaceutically acceptable salts of SCY-078, including for example the phosphate, citrate, hippurate, mesylate, and fumarate salts, and polymorphs thereof are disclosed in U.S. Patent No. 10,174,074, which is incorporated in its entirety by reference herein. The citrate salt of SCY-078 is being developed by Scynexis, Inc. as an oral and intravenous (IV) drug for the treatment of multiple serious fungal infections, including vulvovaginal candidiasis, invasive candidiasis, invasive aspergillosis, and refractory invasive fungal infections. [0005] The U.S. Food and Drug Administration (“FDA”) has granted both Qualified Infectious Disease Product and Fast Track designations for the oral formulation of SCY-078. These designations highlight the significant unmet needs for effective new oral therapies against serious fungal infections. Additionally, a common challenge for oral formulations is the lack of drug bioavailability for subjects in need thereof, especially where solubility of the drug is low or the drug load is high. Gastrointestinal related adverse events may also occur, for example, when oral bioavailability is low.

[0006] Accordingly, there is a need in the art for pharmaceutical compositions, including solid oral dosage forms, comprising pharmaceutically acceptable salts of SCY-078 which may provide upon oral administration to a subject in need thereof increased bioavailability and/or result in a lower incidence of one or more adverse events compared to conventional formulations. The present disclosure may fulfill one or more of these needs and/or may provide other advantages.

[0007] Disclosed are pharmaceutical compositions comprising: a. a pharmaceutically acceptable salt of compound 1 ; b. a lipophilic component; optionally at least one surfactant; d. optionally at least one nucleation inhibitor; optionally at least one disintegrant; f. optionally at least one lubricant; g· optionally at least one glidant; h. optionally at least one binder; and

1. optionally at least one filler.

[0008] Also disclosed are methods of preparing pharmaceutical compositions comprising a pharmaceutically acceptable salt of compound 1 and methods of treating and/or preventing fungal infections by administering pharmaceutical compositions comprising the same. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGURES la-c provide the composition of melt granulation (MG) formulations.

[0010] FIGURE 2 provides the process flow diagram for melt granulation of MG2-13.

[0011] FIGURE 3 provides the active dispersion preparation and process parameters for melt granulation for MG1-13.

[0012] FIGURE 4 provides the composition of fluid bed granulation formulations.

[0013] FIGURE 5 provides the process flow diagram for fluid bed granulation of FB 1.

[0014] FIGURE 6 provides the process flow diagram for fluid bed granulation of FB2-5.

[0015] FIGURES 7a and 7b provide the active dispersion preparation and process parameters for fluid bed granulation of FB 1-5.

[0016] FIGURE 8 provides the composition of pellet mounting formulations.

[0017] FIGURE 9 provides the process flow diagram for pellet mounting of PM3 and

PM4.

[0018] FIGURES 10a and 10b provide the active dispersion/solution preparation and process parameters for pellet mounting of PM1-4.

[0019] FIGURE 11 provides the composition of high shear granulation formulations.

[0020] FIGURE 12 provides the process flow diagram for pellet mounting of HSG1-4.

[0021] FIGURES 13a and 13b provide the solution/dispersion preparation and process parameters for HSG bottom-driven process of HSG1-4.

[0022] FIGURE 14 provides the fluid bed drying parameters for HSG bottom-driven process of HSG1-4.

[0023] FIGURE 15 provides the internal phase granules sieving parameters for HSG bottom-driven process of HSG1-4. [0024] FIGURE 16 provides the compressibility index (Cl) and Hausner ratio (H) value interpretation.

[0025] FIGURE 17 provides the bulk/tapped density values and flow characteristics of final lubricated granules and interpretation thereof.

[0026] FIGURE 18 is an overlay of X-ray diffractograms of lipid-based formulations MG8, MG13, FBI, HSG2, and HSG4, and SCY-078 citrate.

[0027] FIGURE 19 is an overlay of DSC thermograms of lipid-based formulations MG8, MG13, FBI, HSG2, and HSG4, and SCY-078 citrate.

[0028] FIGURES 20a-c are tables of in process testing results for tablets, 100 mg.

[0029] FIGURE 21 provides the composition of the coating suspension.

[0030] FIGURE 22 provides the coating process parameters.

[0031] FIGURE 23 provides the weight gain of film coated tablets.

[0032] FIGURE 24 provides the test article administration in PK study in beagle dogs.

[0033] FIGURE 25 provides the composition of immediate release control formulation A.

[0034] FIGURE 26 provides the manufacturing flow chart for immediate release control formulation A.

[0035] FIGURES 27a and 27b provide data from comparative oral PK study in dogs.

[0036] Disclosed herein are compositions comprising pharmaceutically acceptable salts of SCY-078 and methods for preparing the same. The compositions of the present disclosure may be useful for treating and/or preventing at least one disorder and/or condition that is treatable by inhibiting glucan synthase, such as Invasive Candidiasis and Invasive Aspergillosis.

[0037] In some embodiments, disclosed is a pharmaceutical composition comprising: a. a pharmaceutically acceptable salt of compound 1 ; and b. a lipophilic component;

[0038] In some embodiments, the subject is a human subject. In some embodiments, the subject is a non-human subject. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a dog. In some embodiments, the dog is a beagle. In some embodiments, the subject is a cow. In some embodiments, the subject is a horse. In some embodiments, the subject is a pig. In some embodiments, the subject is a sheep. In some embodiments, the subject is a goat. In some embodiments, the subject is a cat. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rabbit. In some embodiments, the subject is a rat.

[0039] In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, 0-48 h, by dose for compound 1 of at least 50 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, 0-48 h, by dose for compound 1 of at least 60 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, 0-48 h, by dose for compound 1 of at least 70 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, 0-48 h, by dose for compound 1 of at least 80 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, 0-48 h, by dose for compound 1 of at least 90 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, 0-48 h, by dose for compound 1 of at least 100 hr*ng/mL/mg.

[0040] In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, inf, by dose for compound 1 of at least 60 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, inf, by dose for compound 1 of at least 70 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, inf, by dose for compound 1 of at least 80 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, inf, by dose for compound 1 of at least 90 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, inf, by dose for compound 1 of at least 100 hr*ng/mL/mg. In some embodiments, the composition provides, upon oral administration to a beagle dog, a plasma area under the curve, inf, by dose for compound 1 of at least 110 hr* ng/mL/mg.

[0041] In some embodiments, the plasma area under the curve, 0-48 h, by dose for compound 1 provided by a composition dosed to a subject in the fed state divided by the plasma area under the curve, 0-48 h, by dose for compound 1 provided in the same composition dosed to a subject in the fasted state is between 0.8 to 1.25, 0.8 to 1.15, 0.8 to 1.05, 0.8 to 0.95, 0.9 to 1.25, 0.9 to 1.15, 0.9 to 1.05, 1 to 1.25, or 1 to 1.15.

[0042] In some embodiments, the plasma area under the curve, inf, by dose for compound 1 provided by a composition dosed to a subject in the fed state divided by the plasma area under the curve, inf, by dose for compound 1 provided in the same composition dosed to a subject in the fasted state is between 0.8 to 1.25, 0.8 to 1.15, 0.8 to 1.05, 0.8 to 0.95, 0.9 to 1.25, 0.9 to 1.15, 0.9 to 1.05, 1 to 1.25, or 1 to 1.15.

[0043] In some embodiments, the composition is an immediate-release oral solid dosage form and oral administration of the dosage form in a beagle dog provides a maximum plasma concentration by dose for compound 1 of at least 3.4 ng/mL/mg. In some embodiments, the composition is an immediate-release oral solid dosage form and oral administration of the dosage form in a beagle dog provides a maximum plasma concentration by dose for compound 1 of at least 4.0 ng/mL/mg. In some embodiments, the composition is an immediate-release oral solid dosage form and oral administration of the dosage form in a beagle dog provides a maximum plasma concentration by dose for compound 1 of at least 4.6 ng/mL/mg. In some embodiments, the composition is an immediate-release oral solid dosage form and oral administration of the dosage form in a beagle dog provides a maximum plasma concentration by dose for compound 1 of at least 5.2 ng/mL/mg. In some embodiments, the composition is an immediate-release oral solid dosage form and oral administration of the dosage form in a beagle dog provides a maximum plasma concentration by dose for compound 1 of at least 5.8 ng/mL/mg.

[0044] In some embodiments, the maximum plasma concentration by dose for compound 1 provided by a composition dosed to a subject in the fed state divided by the maximum plasma concentration by dose for compound 1 provided in the same composition dosed to a subject in the fasted state is between 0.8 to 1.25, 0.8 to 1.15, 0.8 to 1.05, 0.8 to 0.95, 0.9 to 1.25, 0.9 to 1.15, 0.9 to 1.05, 1 to 1.25, or 1 to 1.15.

[0045] In some embodiments, the composition provides, upon oral administration to a subject, an absolute bioavailability for compound 1 of more than 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, or 80%.

[0046] In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to from 50 mg to 300 mg of compound 1. In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to 50 mg of compound 1. In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to 100 mg of compound 1. In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to 150 mg of compound 1. In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to 200 mg of compound 1. In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to 250 mg of compound 1. In some embodiments, the pharmaceutical composition comprises an amount by weight of the pharmaceutically acceptable salt of compound 1 equivalent to 300 mg of compound 1.

[0047] In some embodiments, the pharmaceutically acceptable salt of compound 1 has a chemical purity of at least 90%. In some embodiments, the pharmaceutically acceptable salt of compound 1 has a chemical purity of at least 95%. In some embodiments, the pharmaceutically acceptable salt of compound 1 has a chemical purity of at least 98%. In some embodiments, the pharmaceutically acceptable salt of compound 1 has a chemical purity of at least 99%.

[0048] In some embodiments, the amount of the pharmaceutically acceptable salt of compound 1 in crystalline form is less than 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% as determined by Power X-Ray Powder Diffraction (XRPD). The XRPD can be determined, for example, using a Bruker X-ray diffractometer model D2 Phaser, with Cu Ka radiation (l=1.54184 A) at an increment of 0.01 2Q with a 0.2 second step time (scan rate of 3° 2Q / min) over a range of 3-56° 2Q, a 0.6 mm opening slit, 1.0 mm scatter plate and 3.0 mm detector windows. The crystallinity is calculated by dividing the total area of crystalline peaks by the total area under the diffraction curve (crystalline plus amorphous peaks).

[0049] In some embodiments, the pharmaceutical composition has a shelf-life of at least 6, 12, 24, or 36 months. In some embodiments, the pharmaceutical composition has a shelf- life of at least 12 months. In some embodiments, the pharmaceutical composition has a shelf- life of at least 24 months. In some embodiments, the pharmaceutical composition has a shelf- life of at least 36 months. In some embodiments, the pharmaceutical composition has a shelf life of between 12 and 24 months. In some embodiments, the pharmaceutical composition has a shelf life of between 12 and 36 months. In some embodiments, the pharmaceutical composition is stored at room temperature and has a shelf life of at least 6, 12, 24, or 36 months. In some embodiments, the pharmaceutical composition is stored at room temperature and has a shelf life of between 12 and 24 months. In some embodiments, the pharmaceutical composition is stored at room temperature and has a shelf life of between 12 and 36 months. In some embodiments, the pharmaceutical composition is stored below room temperature and has a shelf life of at least 6, 12, 24, or 36 months. In some embodiments, the pharmaceutical composition is stored below room temperature and has a shelf life of between 12 and 24 months. In some embodiments, the pharmaceutical composition is stored below room temperature and has a shelf life of between 12 and 36 months.

[0050] In some embodiments, the pharmaceutically acceptable salt of compound 1 is chosen from phosphate, citrate, hippurate, mesylate, and fumarate salts. In some embodiments, the pharmaceutically acceptable salt of compound 1 is chosen from phosphate salts. In some embodiments, the pharmaceutically acceptable salt of compound 1 is chosen from citrate salts. In some embodiments, the pharmaceutically acceptable salt of compound 1 is chosen from hippurate salts. In some embodiments, the pharmaceutically acceptable salt of compound 1 is chosen from mesylate salts. In some embodiments, the pharmaceutically acceptable salt of compound 1 is chosen from fumarate salts. [0051] In some embodiments, the pharmaceutical composition is in the form of a solid preparation suitable for oral administration (e.g., powders, capsules, tablets, films). In some embodiments, the pharmaceutical composition is in the form of a powder. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a film.

[0052] In some embodiments, the pharmaceutical composition is in the form of a solid preparation suitable for oral administration, wherein the composition comprises a powder blend or granules comprising the pharmaceutically acceptable salt of compound 1, the lipid component, and optionally at least one additional pharmaceutically acceptable excipient, for example, a surfactant, a nucleation inhibitor, a disintegrant, a lubricant, a glidant, a binder, and a filler and any combination thereof.

[0053] In some embodiments, the granules are prepared by a method comprising wet granulation, high shear granulation, melt granulation, and/or fluid bed granulation. In some embodiments, the granules are prepared by a method comprising wet granulation. In some embodiments, the granules are prepared by a method comprising high shear granulation. In some embodiments, the granules are prepared by a method comprising melt granulation. In some embodiments, the granules are prepared by a method comprising fluid bed granulation.

[0054] In some embodiments, the pharmaceutical composition is in the form of a solid preparation suitable for oral administration, wherein the composition was prepared by a method comprising pellet mounting.

[0055] In some embodiments, the weight ratio of the pharmaceutically acceptable salt of compound 1 to the lipophilic component is within the range of 1:1 to 1:4. In some embodiments, the weight ratio of the pharmaceutically acceptable salt of compound 1 to the lipophilic component is within the range of 1:1 to 1:3. In some embodiments, the weight ratio of the pharmaceutically acceptable salt of compound 1 to the lipophilic component is within the range of 1:1 to 1:2. In some embodiments, the weight ratio of the pharmaceutically acceptable salt of compound 1 to the lipophilic component is within the range of 1:1 to 1:1.5. [0056] In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1 at 10-30 weight percent and the lipophilic component at 10-45 weight percent. In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1 at 10-30 weight percent and the lipophilic component at 10-30 weight percent. In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1 at 15-30 weight percent and the lipophilic component at 15-45 weight percent. In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1 at 15-30 weight percent and the lipophilic component at 15-30 weight percent. In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1 at 15-25 weight percent and the lipophilic component at 15-40 weight percent. In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1 at 15-25 weight percent and the lipophilic component at 15-25 weight percent.

[0057] In some embodiments, the pharmaceutical composition further comprises at least one additional pharmaceutically acceptable excipient, for example, a surfactant, a nucleation inhibitor, a disintegrant, a lubricant, a glidant, a binder, and a filler and any combination thereof.

[0058] In some embodiments, the lipophilic component comprises esters of alcohols with medium and/or long chain fatty acids. In some embodiments, the lipophilic component comprises glyceryl monocaprylocaprate, glyceryl monostearate, glyceryl behenate, caprylocaproyl polyoxyl-8 glyceride, and/or hydrogenated phosphatidylcholine. In some embodiments, the lipophilic component comprises glyceryl monocaprylocaprate and glyceryl monostearate. In some embodiments, the lipophilic component comprises caprylocaproyl polyoxyl-8 glyceride.

[0059] In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the surfactant comprises at least one of polyethylene glycol fatty acid esters, alcohol-oil transesterification products, polyethylene glycol glycerol fatty acid esters, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, polyethylene glycol alkyl phenols, poloxamers, mono- and diglycerides, polyglycerized fatty acids, sorbitan fatty acid esters, propylene glycol fatty acid esters, lower alcohol fatty acid esters, sterol and sterol derivatives, sugar esters, and ionic surfactants. In some embodiments, the surfactant comprises polyethylene glycol sorbitan fatty acid esters.

[0060] In some embodiments, the pharmaceutical composition further comprises a nucleation inhibitor. In some embodiments, the nucleation inhibitor comprises at least one of synthetic polymers, inorganic and mineral products, modified natural polymers, natural polymers, and non-polymeric substances. In some embodiments, the nucleation inhibitor comprises at least one of polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, hydroxyalkyl celluloses, hydroxyalkyl alkyl celluloses, cellulose phthalates, polyalkylene glycols, (meth)acrylic resins. In some embodiments, the nucleation inhibitor comprises polyvinyl lactams. In some embodiments, the nucleation inhibitor comprises polyvinyl pyrrolidone.

[0061] In some embodiments, the pharmaceutical composition further comprises a disintegrant. In some embodiments, the disintegrant comprises at least one of croscarmellose sodium and sodium starch glycolate.

[0062] In some embodiments, the pharmaceutical composition further comprises a lubricant. In some embodiments, the lubricant comprises at least one of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, and hydrogenated vegetable oil.

[0063] In some embodiments, the pharmaceutical composition further comprises a glidant. In some embodiments, the glidant comprises at least one of colloidal silicon dioxide and talc.

[0064] In some embodiments, the pharmaceutical composition further comprises a binder. In some embodiments, the binder comprises at least one of polyvinyl pyrrolidone, dibasic calcium phosphate, sucrose, corn starch, and modified cellulose.

[0065] In some embodiments, the pharmaceutical composition further comprises a filler. In some embodiments, the filler comprises at least one of sugars, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, modified cellulose, talc, calcium phosphate, and starch. [0066] In some embodiments, the pharmaceutical composition comprises the citrate salt of compound 1, glyceryl monocaprylocaprate, optionally glyceryl monostearate, and optionally polyvinyl pyrrolidone. In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose, optionally croscarmellose sodium, and optionally magnesium stearate.

[0067] In some embodiments, the pharmaceutical composition is in the form of a solid preparation suitable for oral administration, where at least the citrate salt of compound 1, is present as a homogenous dispersion in the lipid matrix.

[0068] In some embodiments, the pharmaceutical composition is in the form of a solid preparation suitable for oral administration, where at least the citrate salt of compound 1, glyceryl monocaprylocaprate, glyceryl monostearate (where applicable), and polyvinyl pyrrolidone (where applicable) are present as a homogenous dispersion.

[0069] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 10-30 weight percent; b. glyceryl monocaprylocaprate at 10-30 weight percent; glyceryl monostearate at 0-30 weight percent; d. polyvinyl pyrrolidone at 0-20 weight percent; e. microcrystalline cellulose at 30-70 weight percent; f. croscarmellose sodium at 0-15 weight percent; and g· magnesium stearate at 0-5 weight percent.

[0070] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 10-30 weight percent; b. glyceryl monocaprylocaprate at 10-30 weight percent; c. glyceryl monostearate at 0-20 weight percent; d. polyvinyl pyrrolidone at 0-10 weight percent; e. microcrystalline cellulose at 40-60 weight percent; f. croscarmellose sodium at 0-10 weight percent; and g. magnesium stearate at 0-3 weight percent.

[0071] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 10-30 weight percent; b. glyceryl monocaprylocaprate at 10-30 weight percent; c. glyceryl monostearate at 5-15 weight percent; d. polyvinyl pyrrolidone at 0-10 weight percent; e. microcrystalline cellulose at 40-60 weight percent; f. croscarmellose sodium at 0-10 weight percent; and g. magnesium stearate at 0-2 weight percent.

[0072] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 15-30 weight percent; b. glyceryl monocaprylocaprate at 15-30 weight percent; c. glyceryl monostearate at 0-30 weight percent; d. polyvinyl pyrrolidone at 0-20 weight percent; e. microcrystalline cellulose at 30-70 weight percent; f. croscarmellose sodium at 0-15 weight percent; and g. magnesium stearate at 0-5 weight percent.

[0073] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 15-30 weight percent; b. glyceryl monocaprylocaprate at 15-30 weight percent; c. glyceryl monostearate at 0-20 weight percent; d. polyvinyl pyrrolidone at 0-10 weight percent; e. microcrystalline cellulose at 40-60 weight percent; f. croscarmellose sodium at 0-10 weight percent; and g. magnesium stearate at 0-3 weight percent.

[0074] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 15-30 weight percent; b. glyceryl monocaprylocaprate at 15-30 weight percent; c. glyceryl monostearate at 5-15 weight percent; d. polyvinyl pyrrolidone at 0-10 weight percent; microcrystalline cellulose at 40-60 weight percent; f. croscarmellose sodium at 0-10 weight percent; and g· magnesium stearate at 0-2 weight percent.

[0075] In some embodiments, the pharmaceutical composition comprises: a. a citrate salt of compound 1 at 15-25 weight percent; b. glyceryl monocaprylocaprate at 15-25 weight percent; glyceryl monostearate at 0-30 weight percent; d. polyvinyl pyrrolidone at 0-20 weight percent; e. microcrystalline cellulose at 30-70 weight percent; f. croscarmellose sodium at 0-15 weight percent; and g· magnesium stearate at 0-5 weight percent.

[0076] In some embodiments, the pharmaceutical composition comprises: h. a citrate salt of compound 1 at 15-25 weight percent; i. glyceryl monocaprylocaprate at 15-25 weight percent; j· glyceryl monostearate at 0-20 weight percent; k. polyvinyl pyrrolidone at 0-10 weight percent; l. microcrystalline cellulose at 40-60 weight percent; m. croscarmellose sodium at 0-10 weight percent; and n. magnesium stearate at 0-3 weight percent.

[0077] In some embodiments, the pharmaceutical composition comprises: o. a citrate salt of compound 1 at 15-25 weight percent;

P· glyceryl monocaprylocaprate at 15-25 weight percent; q· glyceryl monostearate at 5-15 weight percent; r. polyvinyl pyrrolidone at 0-10 weight percent; s. microcrystalline cellulose at 40-60 weight percent; t. croscarmellose sodium at 0-10 weight percent; and u. magnesium stearate at 0-2 weight percent.

[0078] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 26.8 hydrogenated phosphatidylcholine 33 glycerol monocaprylocaprate 11.3 glyceryl mono stearate 10.3 microcrystalline cellulose 15.5 croscarmellose sodium 3.1

Tablet Composition

Melt Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0079] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 20.5 hydrogenated phosphatidylcholine 25.2 glycerol monocaprylocaprate 8.7 glyceryl mono stearate 7.9 microcrystalline cellulose 35.4 croscarmellose sodium 2.4

Tablet Composition

Melt Granule Blend 97.7 croscarmellose sodium 1.5 magnesium stearate 0.8 [0080] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 22.7 hydrogenated phosphatidylcholine 16.5 glycerol monocaprylocaprate 5.7 glyceryl mono stearate 5.2 microcrystalline cellulose 46.9 croscarmellose sodium 3.1

Tablet Composition

Melt Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0081] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 20.2 glycerol monocaprylocaprate 12.8 glyceryl mono stearate 11.5 microcrystalline cellulose 52.7 croscarmellose sodium 2.8

Tablet Composition

Melt Granule Blend 97.3 croscarmellose sodium 1.8 magnesium stearate 0.9

[0082] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 18.1 hydrogenated phosphatidylcholine 22.4 glycerol monocaprylocaprate 7.6 glyceryl mono stearate 7 microcry stalline cellulo se 41.8 croscarmellose sodium 3.1

Tablet Composition

Melt Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0083] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 21.8 glycerol behenate 10.9 glycerol monocaprylocaprate 10.9 glyceryl mono stearate 9.9 microcrystalline cellulose 43.5 croscarmellose sodium 3

Tablet Composition

Melt Granule Blend 97.1 croscarmellose sodium 1.9 magnesium stearate 1

[0084] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 22.9 glycerol monocaprylocaprate 9.7 glyceryl mono stearate 8.8 microcry stalline cellulo se 47.1 croscarmellose sodium 2.6 Tablet Composition

Melt Granule Blend 91.1 glycerol behenate 6.2 croscarmellose sodium 1.8 magnesium stearate 0.9

[0085] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 20.3 glycerol monocaprylocaprate 12.9 glyceryl mono stearate 11.5 microcrystalline cellulose 52.2 croscarmellose sodium 3.1

Tablet Composition

Melt Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0086] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 20.3 glycerol monocaprylocaprate 16.2 glyceryl mono stearate 8.2 microcrystalline cellulose 52.2 croscarmellose sodium 3.1

Tablet Composition

Melt Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1 [0087] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 21 glycerol monocaprylocaprate 13.3 glyceryl mono stearate 11.9 microcrystalline cellulose 53.8

Tablet Composition

Melt Granule Blend 94 croscarmellose sodium 5 magnesium stearate 1

[0088] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 19.1 glycerol monocaprylocaprate 12.1 glyceryl mono stearate 10.9 polyvinyl pyrrolidone 7.3 microcrystalline cellulose 47.6 croscarmellose sodium 2.9

Tablet Composition

Melt Granule Blend 97.3 croscarmellose sodium 1.9 magnesium stearate 0.9

[0089] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 19.1 glycerol monocaprylocaprate 12.2 glyceryl mono stearate 10.9 polyvinyl pyrrolidone 7.2 microcrystalline cellulose 47.6 croscarmellose sodium 3

Tablet Composition

Melt Granule Blend 84.6 microcrystalline cellulose 13 croscarmellose sodium 1.6 magnesium stearate 0.8

[0090] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Melt Granule Blend a citrate salt of compound 1 19.9 glycerol monocaprylocaprate 16.4 glyceryl mono stearate 7.7 polyvinyl pyrrolidone 5.2 microcrystalline cellulose 47.7 croscarmellose sodium 3.1

Tablet Composition

Melt Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0091] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Fluid Bed Granule Blend a citrate salt of compound 1 20.3 glycerol monocaprylocaprate 12.9 glyceryl mono stearate 11.5 microcry stalline cellulo se 52.1 croscarmellose sodium 3.1 Tablet Composition

Fluid Bed Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0092] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Fluid Bed Granule Blend a citrate salt of compound 1 19.9 glycerol monocaprylocaprate 16.4 glyceryl mono stearate 7.2 polyvinyl pyrrolidone 5.2 microcrystalline cellulose 47.7 croscarmellose sodium 3.1

Tablet Composition

Fluid Bed Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0093] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Fluid Bed Granule Blend a citrate salt of compound 1 19.9 glycerol monocaprylocaprate 19 glyceryl mono stearate 5.2 polyvinyl pyrrolidone 5.2 microcrystalline cellulose 47.3 croscarmellose sodium 3.1

Tablet Composition

Fluid Bed Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1 [0094] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Fluid Bed Granule Blend a citrate salt of compound 1 15.5 glycerol monocaprylocaprate 12.8 glyceryl mono stearate 6 polyvinyl pyrrolidone 5.2 microcrystalline cellulose 57.5 croscarmellose sodium 3.1

Tablet Composition

Fluid Bed Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0095] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Fluid Bed Granule Blend a citrate salt of compound 1 13.8 glycerol monocaprylocaprate 11.4 glyceryl mono stearate 5.4 polyvinyl pyrrolidone 2.1 plasacryl T20TM 2.1 microcrystalline cellulose 62.2 croscarmellose sodium 3.1

Tablet Composition

Fluid Bed Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[0096] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w) Pellet Mounting Formulation a citrate salt of compound 1 15.0 glycerol monocaprylocaprate 12.4 glyceryl mono stearate 5.8 polyvinyl pyrrolidone 5 celphere CP-305 (core Pellets) 61.8

[0097] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Pellet Mounting Formulation a citrate salt of compound 1 15.0 glycerol monocaprylocaprate 12.4 glyceryl mono stearate 5.8 polyvinyl pyrrolidone 5 plasacryl T20TM 1 celphere CP-708 (core Pellets) 60.8

[0098] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Pellet Mounting Formulation a citrate salt of compound 1 13.4 glycerol monocaprylocaprate 11.1 glyceryl mono stearate 5.2 polyvinyl pyrrolidone 4 plasacryl T20TM 2 celphere CP-708 (core Pellets) 64.3

[0099] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

Pellet Mounting Formulation a citrate salt of compound 1 13.4 glycerol monocaprylocaprate 11.1 glyceryl mono stearate 5.2 polyvinyl pyrrolidone 2 plasacryl T20TM 2 celphere CP-708 (core Pellets) 65.8

[00100] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

High Shear Granule Blend a citrate salt of compound 1 19.9 glycerol monocaprylocaprate 16.4 glyceryl mono stearate 7.7 polyvinyl pyrrolidone 5.2 microcrystalline cellulose 47.7 croscarmellose sodium 3.1

Tablet Composition

High Shear Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[00101] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

High Shear Granule Blend a citrate salt of compound 1 17.4 glycerol monocaprylocaprate 14.3 glyceryl mono stearate 6.8 polyvinyl pyrrolidone 4.5 microcrystalline cellulose 53.8 croscarmellose sodium 3.1

Tablet Composition

High Shear Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1 [00102] In some embodiments, the pharmaceutical composition comprises the following components:

(% w/w)

High Shear Granule Blend a citrate salt of compound 1 19.8 glycerol monocaprylocaprate 16.3 glyceryl mono stearate 7.6 polyvinyl pyrrolidone 5.2 microcrystalline cellulose 48 croscarmellose sodium 3.1

Tablet Composition

High Shear Granule Blend 97 croscarmellose sodium 2 magnesium stearate 1

[00103] In some embodiments, the pharmaceutical composition is in the form of a tablet and the tablets are coated with a coating. In some embodiments, the coating comprises a colorant. In some embodiments, the colorant is water based. In some embodiments, the colorant is solvent based. In some embodiments, the colorant comprises Opadry II. In some embodiments, the Opadry II is HPMC based. In some embodiments, the Opadry II is PVA based.

[00104] In some embodiments, disclosed is a method of treating a fungal infection in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises: a. an effective amount of a pharmaceutically acceptable salt of compound 1 ; and b. a lipophilic component.

[00105] In some embodiments, the method results in a lower incidence of one or more adverse events, as compared to subjects receiving the same total daily dose of immediate release control formulation A.

[00106] In some embodiments, the method results in a lower incidence of one or more adverse events chosen from nausea, vomiting, diarrhea, and/or abdominal pain. In some embodiments, the method results in a lower incidence of nausea. In some embodiments, the method results in a lower incidence of vomiting. In some embodiments, the method results in a lower incidence of diarrhea. In some embodiments, the method results in a lower incidence of abdominal pain.

[00107] The terms “at least one” and “one or more” are intended to be synonymous and to refer to no less than one but possibly more, such as one, two, three, etc. For example, the term “at least one surfactant” refers to one or more surfactants, such as one surfactant, two surfactants, three surfactants etc.

[00108] As used herein, the term “absolute bioavailability” refers to the area under the curve of a drug from a formulation after oral administration divided by the area under the curve for the drug after intravenous administration.

[00109] As used herein, the term “binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness). Exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose, or any combination thereof.

[00110] As used herein, the term “disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof.

[00111] As used herein, the term “effective amount” refers to an amount of the active ingredient that, when administered to a subject, alleviates at least some of the symptoms or stops the progression of the identified disease condition. Exemplary dosage amounts can be found herein and, for example, in U.S. Patent No. 8,188,085, the relevant portions of which are incorporated herein by reference.

[00112] As used herein, the term “excipient” includes functional and non-functional ingredients in a pharmaceutical composition.

[00113] As used herein, the term “filler” is an excipient that adds bulkiness to a pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses (e.g. sodium carboxy methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol, lactose, sucrose, or the like), or any combination thereof.

[00114] As used herein, the term “glidant” is an excipient that imparts a pharmaceutical composition with enhanced flow properties. Exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof.

[00115] As used herein, the terms “immediate-release” and “IR” are intended to be synonymous and to mean the drug product is formulated to begin to release the active ingredient without delay as the drug product begins to dissolve.

[00116] As used herein, the term “lubricant” is an excipient that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die, and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press. Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, or any combination thereof.

[00117] As used herein, the term “nucleation inhibitor” is an excipient that has the property of slowing the rate of precipitation or crystallization of the drug after the drug is initially dissolved. Exemplary nucleation inhibitors include synthetic products such as acrylic acid polymers, vinyl derivates; inorganic and mineral products; modified natural polymers, such as cellulosic and starch derivates; and natural polymers. Non-polymeric nucleation inhibitors may also be suitable.

[00118] As used herein, the term “shelf-life” refers to the amount of time the pharmaceutical composition may be stored without loss of potency and/or performance profile.

[00119] As used herein, the term “subject” refers to an animal. Exemplary animals including humans and non-human mammals, such as non-human primates, dogs, horses, cats, mice, hamsters, rats, horses, cows, pigs, rabbits, sheep, and goats. [00120] As used herein, the term “subject in the fasted state” refers to a subject who has not eaten for at least 8 hours prior to ingestion of the dosage form.

[00121] As used herein, the term “subject in the fed state” refers to a subject who has eaten a high fat and high-calories meal. In a human subject, a high fat and high calorie meal is one where approximately 50 percent of total caloric content comes from fat and the meal consists of approximately 800 to 1000 calories in total. An example meal for a human subject consists of two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk. Substitutions in this test meal can be made as long as the meal provides a similar amount of calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity. See Food and Drug Administration, Guidance for industry: Food-Effect Bioavailability and Fed Bioequivalence Studies (FDA, Rockville, MD, 2002).

[00122] As used herein, the term “at least substantially amorphous” means the amount in crystalline form is less than 5% as determined by XRPD.

[00123] As used herein, the term “surfactant” is an excipient that imparts a pharmaceutical composition with enhanced solubility and/or wettability. Exemplary surfactants include sodium lauryl sulfate (SLS, sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., Tween), or any combination thereof.

[00124] As used herein, the “weight ratio of the pharmaceutically acceptable salt of compound 1 to the lipophilic component” is calculated based on equivalent weight of SCY- 078 free base (i.e. compound 1). For example, if the composition comprises 134.8 mg of the citrate salt of compound 1 (equivalent to 100 mg of SCY-078 free base) and 100 mg of the total lipophilic component, the weight ratio of the pharmaceutically acceptable salt of compound 1 to the lipophile component would be 1:1.

[00125] As used herein, the “plasma area under the curve, 0-48 h, by dose for compound 1” is calculated by dividing the plasma area under the curve, 0-48 h, by the dose equivalent weight of SCY-078 free base (i.e. compound 1). For example, if the plasma area under the curve after administering a composition comprising 134.8 mg of the citrate salt of compound 1 (equivalent to 100 mg of SCY-078 free base) is 3000 hr*ng/mL, the plasma area under the cure, 0-48 h, by dose for compound 1 would be 30 hr*ng/mL/mg. Further, the “plasma area under the curve, 0-48 h, by dose for compound 1” upon oral administration to a beagle dog is determined according to the procedure described in Example 11.

[00126] As used herein, the “plasma area under the curve, inf, by dose for compound 1” is calculated by dividing the plasma area under the curve, inf, by the dose equivalent weight of SCY-078 free base (i.e. compound 1). For example, if the plasma area under the curve after administering a composition comprising 134.8 mg of the citrate salt of compound 1 (equivalent to 100 mg of SCY-078 free base) is 5000 hr*ng/mL, the plasma area under the cure, inf, by dose for compound 1 would be 50 hr*ng/mL/mg. Further, the “plasma area under the curve, inf, by dose for compound 1” upon oral administration to a beagle dog is determined according to the procedure described in Example 11.

[00127] As used herein, the “maximum plasma concentration by dose for compound 1” is calculated by dividing the maximum plasma concentration by the dose equivalent weight of SCY-078 free base (i.e. compound 1). For example, if the maximum plasma concentration after administering a composition comprising 134.8 mg of the citrate salt of compound 1 (equivalent to 100 mg of SCY-078 free base) is 250 ng/mL, the maximum plasma concentration by dose for compound 1 would be 2.5 ng/mL/mg. Further, the “maximum plasma concentration by dose for compound 1” upon oral administration to a beagle dog is determined according to the procedure described in Example 11.

EXAMPLES

EXAMPLE 1 Melt Granulation Process

[00128] Thirteen melt granulation formulations (MG1-13) were prepared at laboratory batch scale ranging from 10 to 50 g. The compositions of these formulations are shown in Figures la-c and described below.

[00129] MG1: The Phospholipon was first dispersed into ethanol at room temperature and a white opaque dispersion was obtained. When heated and mixed, a clear solution was obtained at a temperature of around 40°C. Then, the Capmul was heated separately and became clear at a temperature of not more than 30°C before being introduced into melted Phospholipon in ethanol. Thereafter, the Glycerol monostearate was added, stirred until a clear solution obtained at a temperature of not more than 70°C. Finally, SCY-078 citrate was added, stirred and heated until a homogenous yellowish dispersion obtained at a temperature of not more than 74°C. A hot plate stirrer Super-Nuova (model SP88850190, Thermo Scientific) coupled to a PT100 temperature sensor was used.

[00130] MG2-13: The formulations MG2, MG3, and MG5 all formulated with same excipients as per MG1 were prepared according to the process flow presented in Figure 2.

MG4 and MG8-MG10 were also prepared according to the same process flow but by skipping Step 2. MG6, MG7, MG11, and MG13 were also prepared according to the same Figure 2 but with some minor differences related to their composition. MG12 was prepared using a portion of final blend from MG11 that was diluted with microcrystalline cellulose 102 to achieve 16.2% drug load.

[00131] For all melt granulation formulations, the granulation liquid was added using a WVR disposable graduated transfer pipet (5.8 ml capacity, polyethylene). The wet mass was dispersed over an aluminum paper and dried in a scientific Fischer Isotemp Oven Model 655F.

[00132] The active dispersion preparation and process parameters used for these melt granulation formulations can be found in Figure 3.

EXAMPLE 2

Fluid Bed Granulation Process

[00133] Five fluid bed granulation formulations (FBI-5) were prepared, the compositions of which are shown in Figure 4.

[00134] FBI: Fluid bed granulation formulation FB 1 was prepared according to the process flow presented in Figure 5 by using a fluid bed (Aeromatic Strea-1, Aeromatic Fielder equipped with a top nozzle 1.2 mm diameter) and where the MCC and Croscarmellose were prewarmed and mixed at low flow motion (up to 3 min at up to 39°C outlet temperature) prior to spraying the granulation liquid. The hot dispersion was sprayed using a Cole-Parmer peristaltic pump (model 7521-50, Vernon Hills, IL, USA) equipped with Masterflex tubing #16. After spraying, the tubing was rinsed using heated ethanol only. [00135] FB2-5: The process flow for FB2-4 prepared by incorporation of PVP is presented in Figure 6. FB5 was also prepared according to the same Figure 6 but where an additional step was added to introduce PlasAcryl just after the SCI-078 citrate (i.e. API) dispersion Step 4.

[00136] The fluid bed granulation process parameters can be found in Figures 7a and 7b.

EXAMPLE 3

Pellet Mounting (PM) Process

[00137] Four pellet mounting formulations (PM 1-4) were prepared, the compositions of which are shown in Figure 8.

[00138] The pellet mounting formulations were coated using the same fluid bed as per the fluid bed granulation formulations and equipped with a bottom nozzle 1.2 or 1.0 mm diameter and where cellulose pellets were prewarmed for 3 min at up to 44-50 °C outlet temperature prior spraying the coating active liquid. PM3 and PM4 were prepared according to the process flow presented in Figure 9. PM1 formulated without PlasAcryl was prepared according to the same process flow but by skipping the Step 5. For PM2, PlasAcryl was first introduced into ethanol container and mixed at room temperature to obtain an off-white opaque liquid. Other steps were similar to that presented in Figure 9 (except for Step 5). The pellet mounting process parameters are displayed in Figures 10a and 10b.

EXAMPLE 4

High Shear Granulation Process

[00139] Four high shear granulation (HSG1-4) formulations were prepared, the compositions of which are shown in Figure 11.

[00140] HSG1-3: The high shear granulation formulations HSG1-3 were prepared in a 6- liter bowl capacity using a Glatt Tabletop Mixer Granulator 1/6, (Dresden, Germany) according to the process flow presented in the Figure 12. The hot active dispersion/solution were sprayed using the same pump as fluid bed granulation formulations. The granulation of HSG2 and HSG3 were allowed a deaeration time without mixing before spraying. After spraying, the tubing was rinsed using heated ethanol only. The solution / dispersion preparation and HSG process parameters can be found in Figures 13a and 13b. [00141] The wet granules were dried using a Glatt GPCG 1 using parameters presented in Figure 14. The wet mass (where applicable) and the dried granules were milled using a Quadro Comil U5 Scalable Lab System (Fitzpatrick Company and Quadro Engineering Corp), a Quadro Comil model 197S or manually through various screen openings and different parameters as presented in Figure 15.

[00142] HSG4: The granulation process for HSG2 was scaled up to 850 grams in a high shear mixer granulator (Glatt). Ethanol was added to Capmul in a suitable container and heated at a temperature of NMT 35°C to form a clear solution. Glycerol monostearate was added followed by PVP and stirred until a clear solution was obtained at a temperature of not more than 70°C. Screened (40 mesh) SCY-078 citrate was added and heated until a clear brownish solution was obtained at a temperature of not more than 73 °C.

[00143] The hot granulating fluid was sprayed over premixed microcrystalline cellulose and croscarmellose sodium and granulated in a 6-L bowl capacity high shear mixer granulator (Glatt). The wet granules were milled (Quadro Comil), dried in a fluid bed dryer (Glatt GPCG 1), screened (Quadro Comil) and added to a V-blender. Screened (30 mesh) croscarmellose sodium and magnesium stearate were added and lubricated for 2 minutes.

[00144] The granulation liquid preparation and granulating / drying parameters are summarized in Figures 13a, 13b, and 14.

EXAMPLE 5 Moisture Measurement

[00145] The LOD (loss-on-drying) measurements was determined using a Mettler Toledo halogen Moisture Analyzer, type HR83, method 01 (Switzerland) by gravimetric. Depending on the batch size, dried material samples ranging from 0.2 - 3.3 g were heated at 105°C until the rate of weight loss dropped to less or equal to than 0.10% in 60 sec two times consecutively.

EXAMPLE 6

Bulk/Tapped Density and Powder Flow Properties

[00146] Bulk and tapped density were determined by using a tap density tester (JV 1000, Copley Scientific) and were carried out on final blend granules of different formulations and where applicable. The dried internal phase granules were screened over an 18-mesh sieve (1.0 mm), except for FBI whose dried granules were screened over a 16-mesh sieve (1.18 mm). All the external phases ingredients were screened over a 30-mesh sieve prior final blending. Each parameter was determined in duplicate using 10 or 50-mL graduated glass cylinder depending on the batch size.

[00147] The bulk density was determined by measuring the volume of a known mass of powder sample in a graduated cylinder while the tapped density was measured by mechanically tapping the measuring cylinder until no further volume change was observed.

[00148] The powder flow properties were evaluated using the Carr’s Compressibility Index and Hausner ratio both derived using the measured values for bulk and tapped density as described in the next paragraphs.

[00149] Carr’s compressibility index (Cl): This flow property was calculated using bulk and tapped density data when fitted into the equation: Compressibility Index = (Tapped density - Bulk density) / Tapped density x 100%. Hausner ratio (H): This flow property was calculated as the ratio of tapped to bulk density. The Compressibility Index (Cl) and Hausner ratio (H) values interpretation as per USP <1174> as well as a descriptive qualitative example are presented in Figure 16.

[00150] Figure 17 shows the bulk/tapped density values and flow characteristics of final lubricated granules where applicable. All MG and FB formulations evaluated showed bulk density values ranging from 0.35 to 0.45 g/cm ³ and tapped density values varying from of 0.40 g/cm ³ to 0.49 g/cm ³ and all with fair to excellent flow characters. The scale up HSG lots HSG2-4 presented the highest bulk density value of around 0.54-0.59 g/cm ³ and tapped density value of 0.57-0.60 g/cm ³ and all with excellent flow characters that will be an asset for tablet compression.

EXAMPLE 7 Crystal State Evaluation

[00151] Samples of the citrate salt of compound 1 as received, and the final lubricated granules blend prior to compression were studied by XRPD using a Bruker X-ray diffractometer model D2 Phaser (Karlsruhe, Germany), with Cu Ka radiation (l=1.54184 A) at an increment of 0.01° 2Q with a 0.2 sec step time (scan rate of 3° 20/min) over a range of 3-56° 2Q, a 0.6 mm opening slit, a 1.0 mm scatter plate and a 3.0 mm detector window. The samples were analyzed using a low volume sample holder and the samples were kept under a constant rotation of 15 rpm during the analysis.

[00152] MG8, FBI, MG13, HSG2, and HSG4 formulations each showed similar X-ray diffractograms with no crystalline peaks between 3°- 22° 2Q characteristic of SCY-078 drug substance as shown in Figure 18. This data demonstrates that the preparation of granulating solution of SCY-078 citrate and lipid components in ethanol and subsequent drying resulted in a homogenous amorphous dispersion of SCY-078 in lipid matrix.

EXAMPLE 8 Thermal Analysis by DSC

[00153] Differential scanning calorimetry (DSC) analysis was completed with a TA Instrument Q20 DSC. The sample was heated at 10°C min ¹ and over a temperature range of 0 to 300 C under a nitrogen purge of 50 mL min ¹ . The samples were analyzed using a closed aluminum pan.

[00154] DSC thermograms of MG8, FBI, MG13, HSG2, and HSG4 formulations are shown in Figure 19. Each were characterized by the presence of similar endothermic peaks at an early onset temperature of 40-43 °C and followed by an identical slight slope at an onset of around 59-67°C that may be related to melting transition of homogenously dispersed lipid components in formulation and evaporation of volatile components respectively.

[00155] In addition, the characteristic melting peak of SCY-078 drug substance at about 190°C was not observed (Figure 19). Overall, the data demonstrates homogeneous dispersion of SCY-078 in the lipid matrix.

EXAMPLE 9

Tablet Compression and Tablet Characterization

[00156] Tablet Compression: Tablet compression was conducted using either a Carver (Model C) hydraulic hand press equipped with 12.0 mm, round, standard concave punches or a stationary Korsch press type XP1 (Berlin, Germany) equipped with gravity feeder and “D” tooling 11 mm round standard concave, 12 mm round, concave and with 9.91X18.97 mm oval, concave, both chrome tipped tooling type “D”. Tablet compression was also performed using a 6 stations rotary tablet press machine type PR6 (SVIAC, Antony, France) equipped with gravity and with 12.0 mm round concave, and 9.91X18.97 mm oval, concave, both chrome tipped tooling type “D”, as well as a 10 stations rotary GlobePharma tablet press, Model Mini Press II (NJ, USA), equipped also with gravity feeder and “B” tooling 9.91X18.97 mm oval, concave punches (not chrome tipped).

[00157] Uncoated Tablets Characterization:

Measurement of weight: Formulation components and tablets’ weights were carried out using Sartorius Entris balances model 224-1S and 6202-1S.

Measurement of crushing strength: Crushing strength was determined via a diametral crushing using a Vanderkamp VK 200RC hardness tester according to USP <1217>.

Measurement of thickness: Thickness of the tablets was measured using a Mitutoyo model no CD- 6" CS gage.

Measurement of friability: Friability of the tablets was evaluated according to USP method <1216> from the percentage weight loss of NLT 6.5g of tablets tumbled in a friabilator (model EF-2, Electrolab) for 100 rounds at 25 rpm. For tablets with individual weight of > 650 mg, 10 units were weighed for friability test. The tablets were dedusted, and the loss in weight caused by fracture or abrasion was recorded as the percentage weight loss. Friability below 0.5% is considered acceptable.

Measurement of disintegration time: The disintegration times of the tablets were determined according to USP method <701> in purified water at 37°C using a disintegration bath (model ED 2SAPOx, Electrolab, Mumbai, India).

[00158] Figures 20a-c present in process average results obtained for core tablets. Unless otherwise stated, results of tablets weight, thickness, hardness, and disintegration time, where applicable, are based on an average of 3 units. [00159] The MG formulations MG3-MG7 compressed using the single punch Carver Model C (laboratory hand press) equipped with 12.0 mm round standard concave tooling all at 2000 lbf allowed to attain targeted tablet weight and a hardness value of NLT 12 kP but failed all to comply with disintegration time targeted of NMT 15 minutes.

[00160] The MG8A compressed with same tooling size and shape as per MG3-MG7 and compressed using the single punch Korsch XP1 allowed also to achieve targeted tablet weight, a maximum hardness value of 12 kP and failed also the disintegration test. Again, lot MG8B compressed using the same Korsch XP1 press as per MG8A but with reduced diameter tooling of 11 mm round, standard, concave allowed also to achieve targeted tablet weight but with noticeable reduced maximum hardness value at 4 kP. Also, the MG9A and MG10A compressed with same tooling size and shape as per MG8A but by using the rotary SVIAC type PR6 tablet press failed to reach targeted tablet weight. The same final granules blend from MG8 and compressed using the SVIAC type PR6 equipped tooling size of 9.91X18.97 mm oval, concave and chrome tipped to form MG8C permitted to achieve targeted tablet weight that complied with disintegration time but with reduced maximum hardness value at 9 kP when compared to that of MG8A of 12 kP. MG9B compressed using same tooling and equipment as per MG8C showed a maximum hardness value of 7.6 kP and with desired tablet weight and disintegration time. The tablets MG10B and MG10C from the same final granule blend MG10 and compressed using same tooling as per MG9B (9.91X18.97 mm oval, concave chrome tipped) but with Kosch XP1 and SVIAC PR6 respectively, presented a maximum tablet average hardness values of 9.2 kP and 7.6 kP, correspondingly, and both with good tablet weight and disintegration time. All the subsequent formulations were compressed using same tooling and equipment as per MG10C.

[00161] The MG11 trial #1 (prepared with 7.1% PVP) and compressed at the maximum hardness of around 11 kP, as well as lot L011 trial #2 compressed at reduced hardness value of 8 kP both showed extended disintegration time up to around 66 and 44 min, respectively. Moreover, for the lot MG 12 diluted from final granules blend MG11 with MCC102 to reduce PVP at 6.1%, the tablets MG12 trial #1 and #2 failed also to comply with targeted disintegration time. The MG lot MG 13 prepared with 5% PVP presented slight improved disintegration time but still over 15 min. [00162] For FB 1 and FB2, the tablet weight could not be achieved. For the FB 1 trial #3, the maximum hardness value attained was 8.5 kP with a disintegration time within 5 min, and with desired average tablet weight.

[00163] For HSG1 presented an average hardness value of 10.4 kP but with an extended disintegration time over 30 minutes while the HSG2 and HSG3 showed an average hardness value of around 5 kP and with a disintegration time of NMT 14 minutes complying with targeted limits. HSG showed an average hardness value of around 6 kP with a disintegration time of NMT 10 min also complying with targeted limits.

[00164] The friability test, where applicable, presented a result of NMT 0.3% (even tablets with hardness value less than 10 kP) and complied with targeted limits.

[00165] In general, off-white to yellowish uncoated tablets were obtained with few brown spots except for FBI trial #1 where scattered brown spots were noticeable.

[00166] Tablets Coating: Different portion of uncoated tablets from HSG2 were coated with Opadry II 33G28707 white (HPMC based coat system) to form HSG2A and HSG2B, and with Opadry II 85F18422 white (PVA based coat system, specially to protect tablets from moisture uptake) and to form HSG2C and HSG2D. Lots HSG2A-D were coated using Aeromatic Strea-1 fluid bed equipped with a Wurster column while HSG4 was coated using pan coating system (LABCOAT-1, O’Hara) equipped with a 15-inch diameter fully perforated pan and a 1.0 mm Schlick spray nozzle model 930/7- 1S45.

[00167] Figure 21 presents the composition of coating suspension. The coating suspension was prepared by introducing Opadry II at 20% solids level into vortex and mixing for at least 45 minutes or until a homogenous dispersion was formed. The suspension was sieved through a 60-mesh screen prior to use. The coating process parameters are summarized in Figure 22. The coating suspension was applied to a target weight gain of 3 - 3.5% that was achieved with both Opadry coating systems.

[00168] The weight gain of film coated tablets presented in Figure 23 were those calculated from the weight of batch size before and after each coating and the values obtained were next to the target. However, the film layer of HSG2A and HSG2B coated using Opadry II white HPMC based coat system at 45-48°C and 32-33°C outlet air temperature, respectively, could not adhere firmly on tablets and showed film peeling. Acceptable FCT but still needing optimization were obtained for HSG2D coated using Opadry II white PVA based coat system coated at 34-37°C outlet air temperature when compared to HSG2C coated using the same PVA based coat system but at 31°C outlet air temperature.

EXAMPLE 10

Immediate Release Control Formulation A

[00169] An immediate release control formulation was prepared, the composition of which is shown in Figure 25.

[00170] The immediate release control formulation A of compound 1 citrate was prepared as round, white to off-white, biconvex shaped tablets, 1.1 cm wide with an average thickness of about 0.51 cm. The tablets were compressed with a total weight of 480 mg, containing 150 mg free base equivalent of compound 1. The manufacturing flow chart is presented in Figure 26.

[00171] The ingredients for pre-roller compaction (RC) blend - silicified microcrystalline cellulose, Mannitol, SCY-078 citrate, crospovidone XL, colloidal silicon dioxide are de- lumped and mixed. The pre-roller compaction (RC) blend is lubricated with screened magnesium stearate and mixed. The lubricated pre-RC blend is roller compacted and sized. Mannitol and butylated hydroxyl anisole (BHA) are de-lumped, blended via geometric dilution and added to the granulation and mixed. The final blend is lubricated with screened magnesium stearate and compressed.

EXAMPLE 11

Pharmacokinetic Profiles in the Beagle Dog

[00172] The immediate release control formulation A and three representative formulation compositions were evaluated in a comparative 4 phase (i.e. one phase per composition) single dose pharmacokinetic study in non-narve male beagle dogs, each weighing between approximately 9 to 12 kg. All dogs were approximately 3 years to 4 years of age at initiation of the study.

[00173] A total of 4 beagle dogs were assigned to the study. The same animals were used for each phase with a minimum 7-day washout period between dosing for each phase. All animals were fasted overnight prior to dosing and through the first two hours of blood sample collection, where applicable (food was returned within 30 minutes following collection of the last blood sample from the 2-hour collection interval, where applicable). Total fasting time did not exceed 24 hours.

[00174] Each animal in Group 1 received a single tablet dose of the appropriate test article formulation as outlined in Figure 24. Following dosing, approximately 50 mF of tap water was administered via oral gavage for each phase. Blood samples (approximately 1 mF/sample) were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 ,8, 10, 12, 18, 14, and 48 -hour postdose. Blood collection occurred through the jugular vein using K2EDTA as anticoagulant and samples were maintained on ice until processed. The samples were centrifuged under refrigerated (2 to 8°C) conditions and the resulting plasma was separated. The plasma samples were frozen at -60 to -90°C until analyzed. The mean (+SD) and CV% compound 1 pharmacokinetic parameters is presented in Figures 27a and 27b.

[00175] The results show that all lipid-based formulations showed a 2-3 fold increase in both C _max and exposure (AUC) compared to that of the immediate release control formulation A. Additionally, compositions prepared using wet granulation process showed better variability compared to that prepared from fluid bed granulation.

[00176] One skilled in the art will readily recognize from such discussion and from the accompanying figures and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.