Oral dosage form of erraglusib

Abstract

The present invention relates to solid dispersions comprising amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer; liquid solutions comprising 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione; liquid suspensions comprising 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione; pharmaceutical compositions containing these compositions, and their use for treating diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 355,718, filed June 27, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to oral dosage forms of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, also known as erraglusib. [Background technology]

[0003] 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, also referred to herein as 9-ING-41 or erraglusib, has the chemical structure:

[0004] [ka] having the empirical formula C 22 H 13 It is a small molecule of N2O5F.

[0005] The structure, properties, and / or biological activity of erraglusib are described in U.S. Pat. No. 8,207,216; Gaisina et al., From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl) maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863; and Hilliard, et al., Glycogen Synthase Kinase 3β Inhibitors Induce Apoptosis in Ovarian Cancer Cells and Inhibit In-Vivo Tumor Growth, Anti-Cancer Drugs 2011, 22, 978-985.

[0006] Erragulusib is a glycogen synthase kinase-3 beta (GSK-3β) inhibitor that is being investigated as a single agent and in combination with other chemotherapy regimens in patients with refractory hematologic malignancies or solid tumors. GSK-3β is a constitutively active serine-threonine kinase. Increased expression and abnormal function of GSK-3β are involved in the biology of many diseases, including cancer, inflammation, fibrosis, and neurodegeneration.

[0007] The water solubility of erraglusib is extremely low, limiting its use in clinical practice to slow intravenous infusion. An intravenous infusion of erraglusib involves a 10 mg / mL solution of erraglusib API in a co-solvent vehicle, which is then added to a sterile intravenous diluent, e.g., 5% w / v dextrose injection. This infusion regimen requires once or twice weekly dosing and long infusion times (≥4 hours), which are burdensome for caregivers and patients alike. Thus, there is a need for an administrable liquid or solid oral dosage formulation of erraglusib. Summary of the Invention

[0008] The present disclosure provides novel solid amorphous dispersions, liquid solutions, and liquid suspensions of erraglusib suitable for oral administration.

[0009] The present disclosure also provides novel amorphous solid dispersions ("ASDs") of erraglusib, tablets, liquid solutions, and liquid suspensions suitable for oral administration.

[0010] In some embodiments, the present disclosure provides an ASD comprising amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer.

[0011] In some embodiments, the present disclosure provides an ASD incorporated into a tablet dosage form.

[0012] In some aspects, the present disclosure provides a pharmaceutical composition comprising 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (erraglusib); an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; a pharmaceutically acceptable alcohol; and A liquid solution is provided that includes surfactants that are sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether.

[0013] In another aspect, the disclosure provides a liquid suspension comprising erraglusib; an emulsifier which is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; a pharmaceutically acceptable alcohol; a surfactant which is sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether; and a pharmaceutically acceptable diluent.

[0014] The present disclosure also provides methods for making these novel erraglusib ASDs, tablets, liquid solutions, and liquid suspensions, as well as methods for using these novel erraglusib ASDs, tablets, liquid solutions, and liquid suspensions to treat diseases.

[0015] The present disclosure also provides methods of using the disclosed novel erraglusib ASD, tablets, liquid solutions, and liquid suspensions. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of amorphous erraglusib solid dispersion (ASD) after dissolution in simulated gastric fluid (SGF). [Figure 2] 1 shows the XRPD of ASD after dissolution in fasted-state simulated intestinal fluid (FaSSIF). [Figure 3] 1 shows the XRPD of ASD after dissolution in fed-state simulated intestinal fluid (FeSSIF). [Figure 4-1] 1 shows XRPD overlays of various ASDs after two weeks of exposure to 40° C. and 33% RH. [Figure 4-2] 1 shows XRPD overlays of various ASDs after two weeks of exposure to 40° C. and 33% RH. [Figure 5-1] 1 shows XRPD overlays of various ASDs after 3 weeks of exposure to 40° C. and 75% RH. [Figure 5-2] 1 shows XRPD overlays of various ASDs after 3 weeks of exposure to 40° C. and 75% RH. [Figure 6] 1 shows an XRPD overlay of an ASD stability sample after 9 weeks of exposure to 40° C. / 33% RH. [Figure 7] 1 shows an XRPD overlay of an ASD stability sample after 9 weeks of exposure to 40° C. / 75% RH. [Figure 8]Figure 1 shows the XRPD of a specific ASD, "Elra:PVAP," made with phthalabine (polyvinyl acetate phthalate or PVAP) with a 50% w / w loading of erraglusib and prepared by spray drying from tetrahydrofuran (THF) solvent. [Figure 9] 1 shows a polarized light microscopy (PLM) image of Elra:PVAP prepared by spray drying from THF. [Figure 10] 1 shows the TGA / DSC curves of Elra:PVAP prepared by spray drying from THF—(no pinholes in the DSC pan). [Figure 11-1] (A) TGA and mDSC of Elra:PVAP prepared by spray drying from THF after additional drying using a pinhole-free DSC pan. [Figure 11-2] (B) TGA and mDSC of Elra:PVAP prepared by spray drying from THF after additional drying using a DSC pan with a pinhole. [Figure 12] 1 shows an HPLC chromatogram of Elra:PVAP prepared by spray drying from THF. [Figure 13-1] (A) First particle size distribution (PSD) analysis of Elra:PVAP-. [Figure 13-2] (B) Second particle size distribution (PSD) analysis of Elra:PVAP-. [Figure 13-3] (C) Third particle size distribution (PSD) analysis of Elra:PVAP- is shown. [Figure 14] 1 shows the XRPD of a specific ASD "Elra:CAP" made with cellulose acetate phthalate (CAP) with 50% w / w erraglusib loading and prepared by spray drying from THF solvent. [Figure 15] 1 shows a PLM image of Elra:CAP spray dried using THF. [Figure 16] 1 shows the TGA / DSC curves of Elra:CAP prepared by spray drying from THF. [Figure 17-1] (A) TGA and mDSC of Elra:CAP prepared by spray drying from THF after further drying using a pinhole-free DSC pan. [Figure 17-2] (B) TGA and mDSC of Elra:CAP prepared by spray drying from THF after further drying using a DSC pan with a pinhole. [Figure 18] 1 shows an HPLC chromatogram of Elra:CAP prepared by spray drying from THF. [Figure 19-1] (A) Shows the first PSD analysis of Elra:CAP spray dried from THF. [Figure 19-2] (B) A second PSD analysis of Elra:CAP spray dried from THF is shown. [Figure 19-3] (C) Third PSD analysis of Elra:CAP spray dried from THF. [Figure 20] 1 shows the XRPD of the solids recovered after kinetic solubility analysis for Elra:PVAP and Elra:CAP prepared by spray drying from THF. [Figure 21-1] (A) XRPD of Elra:CAP prepared by spray drying from THF after 6 weeks under various storage conditions. [Figure 21-2] (B) XRPD of Elra:CAP prepared by spray drying from THF after 12 weeks under various storage conditions. [Figure 22] TGA and mDSC of Elra:PVAP in pinhole-free DSC pans are shown after (A) 6 weeks of sample exposure at 5°C, (B) 6 weeks of sample exposure at 40°C and 33% RH, (C) 6 weeks of sample exposure at 40°C and 75% RH, (D) 12 weeks of sample exposure at 5°C, (E) 12 weeks of sample exposure at 40°C and 33% RH, and (F) 12 weeks of sample exposure at 40°C and 75% RH. [Figure 23]TGA and mDSC of Elra:CAP in pinhole-free DSC pans are shown after (A) 6 weeks of exposure to 5°C, (B) 6 weeks of exposure to 40°C and 33% RH, (C) 6 weeks of exposure to 40°C and 75% RH, (D) 12 weeks of exposure to 5°C, (E) 12 weeks of exposure to 40°C and 33% RH, and (F) 12 weeks of exposure to 40°C and 75% RH. [Figure 24] 1 shows an ssNMR overlay of the API standard, phthalabine, and CAP, focusing on the baseline isolated peak at 91.5 ppm for the API. [Figure 25] Shown are ssNMR overlays of API standard, phthalabine, and CAP when the first derivative is applied to each spectrum. [Figure 26] 1 shows ssNMR overlays of first derivative spectra of 6014415-13-A5, API standard, and phthalabine at 5° C. for 12 weeks. [Figure 27] 1 shows ssNMR overlay of first derivative spectra of 6014415-13-A5, API standard, and phthalabine at 40° C. / 75% RH for 12 weeks. [Figure 28] 1 shows ssNMR overlays of first derivative spectra of 6014415-14-A1, API standard, and CAP at 5° C. for 12 weeks. [Figure 29] Shown is an ssNMR overlay of first derivative spectra of 6014415-14-A1, API reference, and CAP at 40°C / 75%RH for 12 weeks. [Figure 30] 1 shows erraglusib plasma concentration versus time profiles from the pharmacokinetic study outlined in Example 3. [Figure 31]

[0023] Figure 1 shows the XRPD of Elra:CAP produced by spray drying from THF ASD material batch 35044-004, showing the monomodal distribution characteristic of amorphous material. See Example 2B. [Figure 32]1 shows SEM images of ASD material showing hollow, collapsed, and shattered sphere morphologies (Batch 35044-004). See Example 2B. [Figure 33] 1 shows SEM images showing erraglusib particles before (top) and after (bottom) milling. See Example 2B. [Figure 34] 1 shows the PSD of erraglusib before (left) and after (right) milling with changes in distribution. See Example 2B. [Figure 35] 1 shows the XRPD of erraglusib before (top) and after (bottom) milling with a consistent profile. See Example 2B. [Figure 36] 1 shows the dissolution profiles of erraglusib dosage forms in 6% w / w CTAB (hexadecyltrimethylammonium bromide) in 0.7 M sodium chloride at paddle speeds of 75 rpm vs. 100 rpm, demonstrating different final solubilities. See Example 2B. [Figure 37] 1 shows the dissolution profiles of 1% and 6% w / w CTAB in 0.7M sodium chloride, demonstrating the improved dissolution profile of the ASD material. See Example 2B. [Figure 38] FIG. 1 shows the plasma concentration versus time profiles of erraglusib from the pharmacokinetic experiments outlined in Example 3. The IV and oral solution profiles represent the mean values for Experiments 2 and 3. [Figure 39] Figure 1 shows the DSC of erraglusib API. TA-Q2000 Differential Scanning Calorimetry Analyzer for DSC. [Figure 40] Figure 1 shows a TGA of erraglusib API. TA-Q500 Thermogravimetric Analyzer for TGA. [Figure 41]

[0023] Figure 1 shows elragulusib plasma concentrations after IV infusion, oral administration in the fasted state, and oral administration in the fed state. See Example 5. [Figure 42]Figure 1 shows the relationship between erraglusib exposure measures C (upper panel) and AUC (lower panel) for three treatments for individual subjects (PK-evaluable population). See Example 5. [Figure 43] Figure 1 shows the relative oral bioavailability of erraglusib as a function of dose, based on Cmax and AUC∞ of erraglusib in the fasted state compared to IV infusion (PK-evaluable population). See Example 5. [Figure 44] Figure 1 shows the relative oral bioavailability as a function of erraglusib dose based on Cmax and AUC∞ of erraglusib in the fed state compared to IV infusion (PK-evaluable population). See Example 5. [Figure 45] Figure 1 shows the relative oral bioavailability as a function of erraglusib dose based on Cmax and AUC∞ of erraglusib in the fed state compared to the fasted state (PK-evaluable population). See Example 5. [Figure 46] 1 shows SEM images of ASD prototypes showing a mixed morphology of intact, collapsed, and shattered spheres. See Example 6. [Figure 47] 1 shows the XRPD of an ASD lot that does not show any detectable crystalline peaks in the dispersion compared to native erraglusib. See Example 6. [Figure 48]

[0033] Figure 1 shows the biorelevant solubility of erraglusib ASD prototypes in FaSSIF pH 6.5 (Note: X represents "free" drug concentration). See Example 6. [Figure 49]

[0033] Figure 1 shows biorelevant dissolution profiles of erraglusib ASD prototypes in FeSSIF pH 5.0 (Note: X represents "free" drug concentration). See Example 6. [Figure 50]

[0023] Figure 1 shows the compression profiles of erraglusib:CAP and erraglusib:EL100ASD formulations, demonstrating increased compressibility of the erraglusib:EL100 formulation. See Example 6. [Figure 51]

[0023] Figure 1 shows a visual comparison of erraglusib:EL100 and erraglusib:CAP ASD tablets. See Example 6. [Figure 52] Figure 1 shows the dissolution overlay of tablet formulations (Note: Data shown is normalized to percent dissolution at 120 minutes due to percent dissolution exceeding 110% and high vessel-to-vessel variability (>4.2% RSD)). See Example 6. [Figure 53] 1 shows SEM images of five ASD sublots described in Example 7. [Figure 54] PXRD testing of the five ASD sublots described in Example 7 is shown. Each sublot exhibits an amorphous halo with no evidence of crystallinity. [Figure 55] 1 shows the dissolution profile of a conjugate lot of the lead ASD described in Example 7 compared to a previous batch of ASD (non-sink biorelevant; conditions: 50 mL beaker, 30 mL FaSSIF pH=6.5). [Figure 56]

[0033] Figure 1 shows particle size analysis by sieving of granules for Erraglucibreed tablet formulation (Reference data: BBS0002-062). See Example 8. [Figure 57]

[0023] Figure 1 shows the results of a non-sink dissolution test performed on a lead tablet formulation compared to an ingress ASD. See Example 8. [Figure 58] Intragranular blending - deagglomeration - shows the process used for blending (Reference: BBS0002-019). See Example 6. [Figure 59] The prototype formulation demonstrates the compressibility of a pre-granulated erraglusib blend (Reference: BBS0002-019). See Example 6. [Figure 60] The process used for the final blend of the erraglusib prototype formulation is shown (Reference: BBS0002-019). See Example 6. [Figure 61]1 shows non-sink dissolution of the erraglusib prototype formulation compared to the ingress ASD (Reference: BBS0002-024). See Example 6. [Figure 62]

[0033] Figure 1 shows non-sink dissolution of erraglusib prototype formulations compared to ingress ASD. See Example 6. [Figure 63] Shows non-sink dissolution of erraglusib prototype formulation compared to ingress ASD (Reference: BBS0002-044). See Example 6. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods that are briefly described in the context of a single embodiment may also be provided separately or in any subcombination.

[0018] Unless otherwise defined, scientific and technical terms used in connection with this application shall have the meanings commonly understood by those skilled in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0019] As employed above, and throughout this disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

[0020] The term "solid dispersion," when applied to a material containing an amorphous active ingredient, is referred to herein as an amorphous solid dispersion, or "ASD."

[0021] The term "SDD" refers to a spray-dried dispersion, i.e., a solid dispersion made by spray drying. ASD made by spray drying is one type of SDD.

[0022] As used in this specification, including the appended claims, the singular forms "a," "an," and "the" include plural references and references to a particular value, including at least that particular value, unless the context clearly dictates otherwise.

[0023] When a range of values is expressed, exemplary embodiments include from one particular value and / or to the other particular value. All ranges are inclusive and combinable. Furthermore, reference to values stated in ranges includes each and every value within that range. When values are expressed as approximations, by use of the preposition "about," it is understood that the particular value forms another embodiment. As used herein, the term "about," when referring to a measurable value, e.g., an amount, a temporal period, etc., is intended to encompass reasonable variations of that value, e.g., values ±10% from the specified value. For example, the phrase "about 50%" can include ±10% of 50, or 45% to 55%, inclusive of 50%.

[0024] It should be appreciated that certain features of the present disclosure, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0025] As used herein, "pharmaceutically acceptable," by itself or in conjunction with another term(s), indicates that the specified entity, e.g., a pharmaceutically acceptable excipient, is generally chemically and / or physically compatible with other ingredients in the composition and / or generally physiologically compatible with the recipient thereof.

[0026] As used herein, "subject(s)," "individual(s)," and "patient(s)," by themselves or in conjunction with another term(s), refer to mammals, including humans. The term human(s) refers to and includes a human child, adolescent, or adult.

[0027] It should be understood that as used herein, the phrases "method of treating" and "method of treatment," by themselves or in conjunction with another term(s), can be used interchangeably with the phrase "use in treatment for" a particular disease.

[0028] As used herein, "treat," "treating," "treated," and "treatment," by themselves or in conjunction with another term(s), refer to and include ameliorative, symptom-relieving, and / or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylactically, i.e., preventatively. It is understood that a "prophylaxis" or prophylactic use or result does not refer to and does not require absolute or total prevention (i.e., 100% preventative or protective use or result). As used herein, a prophylaxis or prophylactic (preventing) use or result refers to administration of a compound or composition to reduce or decrease the severity of a particular condition, symptom, disorder, or disease described herein; reduce or decrease the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein; or delay the onset or recurrence (recurrence) of a particular condition, symptom, disorder, or disease described herein; or any combination of the foregoing uses and results.

[0029] As used herein, whether used alone or in conjunction with another term(s), "for treatment" and "therapeutically effective amount" refer to an amount of a compound or composition that (a) treats a specific condition, symptom, disorder, or disease described herein; (b) attenuates, ameliorates, or eliminates one or more symptoms of a specific condition, disorder, or disease described herein; (c) delays the onset or recurrence (recurrence) of a specific condition, symptom, disorder, or disease described herein; or (d) prevents the onset of a specific condition, symptom, disorder, or disease described herein. It should be understood that "for treatment" and "therapeutically effective" encompass any one of the above-mentioned effects (a)-(d), alone or in combination with any of the other (a)-(d).

[0030] "Pharmaceutically acceptable salts" refers to salts of compounds of the present disclosure that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, carboxylic acid, and the like; or (2) salts formed with an acidic proton, if present in the parent compound, by replacement with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or by coordination with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0031] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically acceptable substance that is biologically suitable for administration to a subject, such as an inert substance that is added to a pharmacological composition or used as a vehicle, carrier, or diluent to facilitate the administration of a drug and is compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Pharmaceutically acceptable excipients are known to those skilled in the art and include, for example, excipients described in specialized textbooks, such as Paul J. Sheskey, et al. (eds), Handbook of Pharmaceutical Excipients, Pharmaceutical Press; 9th Revised Edition (October 20, 2020).

[0032] "Solvate" refers to a physical association of a compound of this disclosure with one or more solvent molecules.

[0033] As used herein, the term "isomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers, tautomers.

[0034] The term "administering" means administering a compound or composition of the present invention per se, or administering a prodrug, derivative, or analog that forms an equivalent amount of the active compound or substance in the body.

[0035] The terms "glycogen synthase kinase-3β" and "GSK-3β" are used interchangeably and according to their common, ordinary meaning and refer to proteins of the same or similar names and functional fragments and homologs thereof. The terms include any recombinant or naturally occurring forms or variants thereof that retain GSK-3β activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the activity compared to GSK-3β).

[0036] Amorphous solid dispersion of erraglusib In some aspects, the present disclosure is directed to a solid dispersion comprising amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (i.e., erraglusib) and a stabilizing polymer.

[0037] As used herein, the term "solid dispersion" refers to a solid material in which an active pharmaceutical ingredient is dispersed within another material. In some embodiments, the solid dispersion is homogeneous such that amorphous erraglusib is dispersed evenly throughout the polymer.

[0038] In some embodiments, the dispersion itself has a single glass transition temperature (Tg), demonstrating that the dispersion is homogeneous.

[0039] Tg, as used herein, is the characteristic temperature at which a glassy material undergoes a relatively rapid (e.g., 10-100 seconds) physical change from a glassy state to a fluid state upon slow heating. The Tg of an amorphous material, e.g., a polymer, drug, or dispersion, can be measured by several techniques, including dynamic mechanical analyzer (DMA), dilatometer, dielectric analyzer, and differential scanning calorimeter (DSC). The exact values measured by each technique can vary somewhat but are usually within 10°C to 30°C of each other. Regardless of the technique used, if an amorphous dispersion exhibits a single Tg, this indicates that the dispersion is substantially homogeneous.

[0040] As used herein, "stabilizing polymer" refers to a polymer that maintains 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (i.e., erraglusib) in an amorphous form.

[0041] In some embodiments, the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate (CAP), hypromellose:hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (phthalabine or PVAP), polyvinylpyrrolidone, poly(methyl methacrylate-co-methacrylic acid), or miscible mixtures thereof. Miscible mixtures of these polymers are those in which the mixture of polymers forms a single phase.

[0042] In some embodiments, the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone).

[0043] In some embodiments, the stabilizing polymer is cellulose acetate phthalate (CAP).

[0044] In some embodiments, the stabilizing polymer is hydroxypropyl methylcellulose phthalate.

[0045] In some embodiments, the stabilizing polymer is hydroxypropyl methylcellulose acetate succinate.

[0046] In some embodiments, the stabilizing polymer is polyvinyl acetate phthalate (phthalabine or PVAP).

[0047] In some embodiments, the stabilizing polymer is polyvinylpyrrolidone.

[0048] In some embodiments, the stabilizing polymer is hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyvinylpyrrolidone, or a mixture thereof.

[0049] In some embodiments, the stabilizing polymer is a methacrylic acid polymer.

[0050] In some embodiments, the stabilizing polymer is a methacrylic acid copolymer with an alkyl methacrylate.

[0051] In some embodiments, the stabilizing polymer is poly(methyl methacrylate-co-methacrylic acid), also known as methacrylic acid-methyl methacrylate copolymer or poly(methacrylic acid-co-methyl methacrylate), for example, Eudragit® L100 polymer (herein "EL100" or "L100").

[0052] In some embodiments, the stabilizing polymer is poly(methyl methacrylate-co-methacrylic acid) (1:1).

[0053] In some embodiments, the stabilizing polymer is Eudragit® L100.

[0054] In some embodiments, the stabilizing polymer is Eudragit® L100-55 polymer.

[0055] In some embodiments, the stabilizing polymer dissolves at a pH above 5.

[0056] In some embodiments, the stabilizing polymer dissolves at a pH above 5.5.

[0057] In some embodiments, the stabilizing polymer is soluble at a pH above 6.

[0058] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 10% to about 70% by weight, based on the weight of the stabilizing polymer.

[0059] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 10% to about 60% by weight, based on the weight of the stabilizing polymer.

[0060] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 10% to about 50% by weight, based on the weight of the stabilizing polymer.

[0061] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 20% to about 60% by weight, or about 25% to about 50% by weight, based on the weight of the stabilizing polymer.

[0062] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 50% by weight, based on the weight of the stabilizing polymer.

[0063] In other embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 20% to about 60% by weight based on the weight of the stabilizing polymer, e.g., about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, or about 31% by weight based on the weight of the stabilizing polymer. , about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, or about 60 wt%.

[0064] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 25% to about 50% by weight based on the weight of the stabilizing polymer, e.g., about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 10 9%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight.

[0065] In some embodiments, the weight ratio of amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione to stabilizing polymer is in the range of about 30:70 to about 50:50, e.g., 30:70, 31:69, 32:68, 33:67, 34:66, 35:65, 36:64, 37:63, 38:62, 39:61, 40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:54, 47:53, 48:52, 49:51, or 50:50.

[0066] In some embodiments, the ASD comprises about 40-50% erraglusib by weight and about 50-60% cellulose acetate phthalate (CAP) by weight.

[0067] In some embodiments, the ASD comprises about 50% erraglusib by weight and about 50% cellulose acetate phthalate (CAP) by weight.

[0068] In some embodiments, the ASD comprises about 40-50% by weight erraglusib and about 50-60% by weight poly(methyl methacrylate-co-methacrylic acid).

[0069] In some embodiments, the ASD comprises about 50% by weight erraglusib and about 50% by weight poly(methyl methacrylate-co-methacrylic acid).

[0070] In some embodiments, the ASD comprises about 40-50% erraglusib by weight and about 50-60% Eudragit® L00 by weight.

[0071] In some embodiments, the ASD comprises about 50% erraglusib by weight and about 50% Eudragit® L00 by weight.

[0072] In some embodiments, the solid dispersion has a single glass transition temperature.

[0073] In some embodiments, the solid dispersion is stable for at least 48 hours when exposed to 60°C and 75% relative humidity, e.g., for at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours. As used herein, the term "stable" means that the erraglusib in the solid dispersion remains amorphous as determined by XRPD or other analytical techniques.

[0074] In other embodiments, the solid dispersion is stable for at least 4 weeks when exposed to 40° C. and 75% relative humidity, for example, for at least 4 weeks, at least 8 weeks, or at least 12 weeks.

[0075] In other embodiments, the solid dispersion is stable for at least 12 weeks when exposed to 40° C. and 75% relative humidity.

[0076] In some embodiments, oral administration of a solid dispersion of the present disclosure to a patient results in at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, resulting in an erraglusib AUC∞ that is at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 80%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, or at least 97%.

[0077] In some embodiments, oral administration of a solid dispersion of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 68% of the erraglusib AUC∞ that results from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0078] In some embodiments, oral administration of a solid dispersion of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 97% of the erraglusib AUC∞ that results from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0079] In some aspects, the present disclosure is directed to methods for preparing the solid dispersions of the present disclosure.

[0080] In some embodiments, the dispersion is formed by a "solvent process" in which erraglusib and the polymer are dissolved in a common solvent. Here, "common" means that the solvent, which can be a mixture of compounds, simultaneously dissolves the drug and polymer(s). After both erraglusib and the polymer are dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. Exemplary processes are spray drying and precipitation by rapidly mixing the polymer and drug solution with CO2, water, or some other non-solvent. In some embodiments, solvent removal results in a homogeneous solid dispersion. As previously described, in such a homogeneous dispersion, erraglusib is uniformly dispersed throughout the polymer and can be considered a solid solution of erraglusib in the polymer(s).

[0081] The solvent may be removed via the process of spray drying. The term spray drying is conventionally and broadly used to refer to a process involving breaking up a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a vessel (spray dryer) where a strong driving force exists for the solvent to evaporate from the droplets. The strong driving force for solvent evaporation is typically provided by maintaining the partial pressure of the solvent within the spray dryer at a pressure well below the vapor pressure of the solvent at the drying temperature of the droplets. This is accomplished by either: (1) maintaining the pressure within the spray dryer at a partial vacuum (e.g., 0.01-0.50 atm); (2) mixing the liquid droplets with a warm drying gas; or (3) both. Additionally, at least a portion of the heat required for solvent evaporation can be provided by heating the spray solution.

[0082] A suitable solvent for spray drying can be any organic compound in which erraglusib and the polymer are mutually soluble, with the total dissolved solids being at least 8% by weight of the solution. In some embodiments, the solvent is also volatile, having a boiling point of 150°C or less. In addition, the solvent should have relatively low toxicity and be removed from the dispersion to a level acceptable according to the International Committee on Harmonization (ICH) guidelines. Removal of the solvent to this level may require a processing step, such as tray drying, after spray drying. Solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; ethers such as tetrahydrofuran (THF), and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Less volatile solvents, such as dimethylacetamide or dimethyl sulfoxide, can also be used. Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used with water, as long as the polymer and erraglusib are sufficiently soluble and chemically stable to make the spray-drying process feasible. Generally, due to the hydrophobic nature of erraglusib, non-aqueous solvents or mixtures of non-aqueous solvents with water are used. In some embodiments, the non-aqueous solvent contains about 10% or less water by weight. In other embodiments, the non-aqueous solvent contains less than about 10% water by weight, and in some embodiments, less than 1% water by weight.

[0083] In some embodiments, the solvent for the spray-dried erraglusib / polymer solution is THF, acetone, ethanol, methanol, a mixture thereof, or a mixture with water.

[0084] In some embodiments, the solvent for the spray-dried erraglusib / CAP solution is an acetone / water mixture.

[0085] In some embodiments, the solvent for the spray-dried erraglusib / CAP solution is a mixture of 90-95% by weight acetone and 5-10% by weight water.

[0086] In some embodiments, the solvent for the spray-dried erraglusib / CAP solution is a mixture of 90% acetone and 10% water by weight.

[0087] In some embodiments, the solvent for the spray-dried erraglusib / CAP solution is a mixture of 95% acetone and 5% water by weight.

[0088] In some embodiments, the solvent for the spray-dried erraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of acetone with water.

[0089] In some embodiments, the solvent for the spray-dried erraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of 90-95% by weight acetone and 5-10% by weight water.

[0090] In some embodiments, the solvent for the spray-dried erraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of 90% acetone and 10% water by weight.

[0091] In some embodiments, the solvent for the spray-dried erraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of 95% by weight acetone and 5% by weight water.

[0092] In some embodiments, the solvent for the spray-dried erraglusib / EL100 solution is a mixture of acetone with water.

[0093] In some embodiments, the solvent for the spray-dried erraglusib / EL100 solution is a mixture of 90-95% by weight acetone and 5-10% by weight water.

[0094] In some embodiments, the solvent for the spray-dried erraglusib / EL100 solution is a mixture of 90% acetone and 10% water by weight.

[0095] In some embodiments, the solvent for the spray-dried erraglusib / EL100 solution is a mixture of 95% acetone and 5% water by weight.

[0096] Generally, the temperature and flow rate of the drying gas are selected so that the polymer / drug-solution droplets are essentially solid by the time they reach the walls of the apparatus and are sufficiently dry so that they form a fine powder and do not stick to the apparatus walls. The actual length of time to achieve this level of dryness depends on the size of the droplets. Due to the large surface-to-volume ratio of the droplets and the large driving force for solvent evaporation, the actual drying time is a few seconds or less, and more typically less than 0.1 seconds. This rapid drying is often important for the particles to maintain a uniform, homogeneous dispersion instead of separating into a drug-rich phase and a polymer-rich phase.

[0097] The spray drying process and spray drying equipment are generally described in Perry's Chemical Engineers Handbook, Sixth Edition (RH Perry, DW Green, JO Maloney, eds.) McGraw-Hill Book Co. 1984, pages 2054 to 2057. Further details about the spray drying process and equipment are reviewed in Marshall "Atomization and Spray-Drying." 50 Chem. Eng. Prog. Monogr. Series 2 (1954).

[0098] In some embodiments, a method for preparing a solid dispersion comprises the steps of: (a) dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer in a suitable solvent to form a solution, and (b) removing the solvent by evaporation to form a solid dispersion.

[0099] In the methods of the present disclosure, suitable solvents for dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and the stabilizing polymer include dichloromethane, tetrahydrofuran, aqueous tetrahydrofuran, acetone, aqueous acetone, methanol, ethanol, ethyl acetate, and mixtures thereof.

[0100] In some embodiments, in the methods of the present disclosure, the solvent suitable for dissolving erraglusib and the stabilizing polymer is aqueous acetone.

[0101] In some embodiments, in the methods of the present disclosure, a suitable solvent for dissolving erraglusib and the stabilizing polymer is aqueous acetone comprising about 90% by weight acetone and about 10% by weight water.

[0102] In some embodiments, in the methods of the present disclosure, a suitable solvent for dissolving erraglusib and the stabilizing polymer is aqueous acetone comprising about 95% by weight acetone and about 5% by weight water.

[0103] In some embodiments, stabilizing polymers suitable for use in the methods for preparing solid dispersions of the present disclosure include N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (phthalabine), polyvinylpyrrolidone, or miscible mixtures thereof. These miscible mixtures of polymers are those in which the mixture of polymers forms a single phase.

[0104] In some embodiments, stabilizing polymers suitable for use in the methods for preparing solid dispersions of the present disclosure include N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (phthalabine), polyvinylpyrrolidone, poly(methyl methacrylate-co-methacrylic acid), exemplified by Eudragit® L100 polymer ("EL100"), or miscible mixtures thereof. Miscible mixtures of these polymers are those in which the mixture of polymers forms a single phase.

[0105] In some embodiments, a stabilizing polymer suitable for use in the methods for preparing solid dispersions of the present disclosure is poly(methyl methacrylate-co-methacrylic acid).

[0106] In some embodiments, a stabilizing polymer suitable for use in the methods for preparing solid dispersions of the present disclosure is Eudragit® L100 polymer (“EL100”).

[0107] In some embodiments, a stabilizing polymer suitable for use in the methods for preparing solid dispersions of the present disclosure is cellulose acetate phthalate (CAP).

[0108] In some embodiments of the disclosed methods, the solvent is removed by evaporation. The solvent can be removed by any evaporation technique that results in the preparation of a solid dispersion of the present disclosure, i.e., a solid dispersion containing amorphous erraglusib.

[0109] In some embodiments, the solvent is evaporated by spray drying.

[0110] In some embodiments, the solvent is evaporated under reduced pressure, for example, a partial vacuum.

[0111] In some embodiments, the solvent is evaporated using an inert gas. For example, in some aspects, the solvent is evaporated by passing a stream of inert gas through the solution. In some embodiments, the inert gas comprises nitrogen. In other embodiments, the inert gas comprises argon.

[0112] Erraglusib oral liquid suspension and solution Oral liquid solution In other aspects, the disclosure provides a pharmaceutical composition comprising 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (erraglusib); an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; a pharmaceutically acceptable alcohol; and A liquid solution is provided that includes surfactants that are sodium tearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether.

[0113] In some embodiments, the present disclosure provides a soluble emulsion containing about 4.0-6.0% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione; about 75-95% by weight of an emulsifier that is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; and about 2-17% by weight of a pharmaceutically acceptable alcohol. A liquid solution is provided that contains about 0.5 to 10% by weight of surfactants selected from the group consisting of cholate, sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers.

[0114] In some embodiments, the liquid solution comprises about 4.0 to 6.0% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, e.g., about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6.0% by weight.

[0115] In some embodiments, the emulsifier is polyethylene glycol (PEG).

[0116] In another embodiment, the emulsifier is polyethylene glycol having a molecular weight of 100 to 1000 Da.

[0117] In another embodiment, the emulsifier is PEG400.

[0118] In some embodiments, the emulsifier is mustard lecithin.

[0119] In some embodiments, the emulsifier is soy lecithin.

[0120] In some embodiments, the emulsifier is egg lecithin.

[0121] In some embodiments, the emulsifier is a monoglyceride.

[0122] In some embodiments, the emulsifier is a diglyceride.

[0123] In some embodiments, the emulsifier is a polysorbate.

[0124] In some embodiments, the emulsifier is stearoyl lactylate.

[0125] In some embodiments, the emulsifier is a sorbitan ester.

[0126] In some embodiments, the emulsifier is a polyglycerol ester.

[0127] In some embodiments, the emulsifier is a sucrose ester.

[0128] In some embodiments, the emulsifier is present in an amount of about 75-95% by weight, e.g., one of about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, or about 95% by weight.

[0129] A pharmaceutically acceptable alcohol is an alcohol that is not toxic when orally administered to humans in the amount present in the composition.A non-toxic alcohol is an alcohol that is identified by the US Food and Drug Administration as generally recognized as safe ("GRAS").An exemplary pharmaceutically acceptable alcohol is ethanol.

[0130] In some embodiments, the pharmaceutically acceptable alcohol is ethanol.

[0131] In some embodiments, the pharmaceutically acceptable alcohol is present in an amount of about 2-17% by weight, e.g., one of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, or about 17% by weight.

[0132] In some embodiments, the surfactant is sodium stearate.

[0133] In some embodiments, the surfactant is 4-(5-dodecyl)benzenesulfonate.

[0134] In some embodiments, the surfactant is sodium lauryl sulfate.

[0135] In some embodiments, the surfactant is docusate sodium.

[0136] In some embodiments, the surfactant is phosphatidylcholine.

[0137] In some embodiments, the surfactant is benzalkonium chloride.

[0138] In some embodiments, the surfactant is a polyoxyethylene sorbitan fatty acid ester.

[0139] In some embodiments, the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

[0140] In some embodiments, the surfactant is polyoxyethylene 15 hydroxystearate.

[0141] In some embodiments, the surfactant is a polyoxyethylene castor oil derivative.

[0142] In some embodiments, the surfactant is polyoxyethylene stearate.

[0143] In some embodiments, the surfactant is a sorbitan fatty acid ester.

[0144] In some embodiments, the surfactant is a polyoxyethylene alkyl ether.

[0145] In some embodiments, the surfactant is a polyoxyethylene nonylphenol ether.

[0146] In some embodiments, the surfactant is present in an amount of about 0.5-10% by weight, e.g., one of about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% by weight.

[0147] In some embodiments, the present disclosure is directed to a liquid solution comprising about 4.3-5.5% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione; about 75-95% by weight of polyethylene glycol 400, about 1-16% by weight of ethanol, about 0.5-8.5% by weight of polysorbate 80, and about 0-5% by weight of water.

[0148] In some embodiments, the present disclosure is directed to a liquid solution comprising about 4.5-5.5% by weight 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione; about 75-95% by weight polyethylene glycol 400, about 1-16% by weight ethanol, about 0.5-8.5% by weight polysorbate 80, and about 0-5% by weight water.

[0149] In some embodiments, the liquid solution comprises about 4.7-4.8% erraglusib by weight, about 76-91% polyethylene glycol 400 by weight, about 4.7-14.3% ethanol by weight, and about 0.5-1% polysorbate 80 by weight.

[0150] In another embodiment, the liquid solution comprises about 4.7-4.8% erraglusib by weight, about 89-90% polyethylene glycol 400 by weight, about 4.7-4.8% ethanol by weight, and about 0.9-1% polysorbate 80 by weight.

[0151] In another embodiment, the liquid solution comprises about 4.2-4.4% erraglusib by weight, about 89-90% polyethylene glycol 400 by weight, about 4.7-4.8% ethanol by weight, and about 0.9-1% polysorbate 80 by weight.

[0152] In some embodiments, the concentration of erraglusib in the liquid solution is at least 45 mg / mL, e.g., one of 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, etc.

[0153] In some embodiments, the concentration of erraglusib in the liquid solution is about 50 mg / mL.

[0154] In some embodiments, the concentration of erraglusib in the liquid solution is at least 50 mg / mL.

[0155] In some embodiments, the liquid solution contains less than 3% total related substances as measured by high performance liquid chromatography (HPLC) area %. As used herein, the term "related substances" refers to compounds structurally related to erraglusib that are present as impurities.

[0156] As used herein, HPLC area % is determined using the HPLC method set forth in Table 5 herein.

[0157] In some embodiments, the solution contains less than 2% total related substances as measured by HPLC area %.

[0158] In some embodiments, the solution contains less than 1% total related substances as measured by HPLC area %.

[0159] In some embodiments, the erraglusib in solution has a purity of greater than 97% as measured by HPLC area %.

[0160] In some embodiments, the erraglusib in solution has a purity of greater than 98% as measured by HPLC area %.

[0161] In some embodiments, the erraglusib in solution has a purity of greater than 99% as measured by HPLC area %.

[0162] In some embodiments, the solution contains less than 2% related substances having a relative retention time of 0.96 or 0.97 relative to the retention time of erraglusib as measured by HPLC area %.

[0163] In some embodiments, the solution contains less than 1% related substances that have a relative retention time of 0.96 or 0.97 relative to the retention time of erraglusib.

[0164] In some embodiments, the solution contains less than 0.5% related substances that have a relative retention time of 0.96 or 0.97 relative to the retention time of erraglusib.

[0165] In some embodiments, the solution contains less than 0.2% related substances having a relative retention time of 0.96 or 0.97 relative to the retention time of erraglusib as measured by high performance liquid chromatography (HPLC) area %.

[0166] In some embodiments, the related substance is one of the following compounds:

[0167] [ka]

[0168] In some embodiments, administration of an oral solution of the present disclosure to a patient results in at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, or less of the erraglusib AUC∞ resulting from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient. The method of claim 1, wherein the erraglusib AUC∞ is at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80%.

[0169] In some embodiments, administration of an oral solution of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 13% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0170] In some embodiments, administration of an oral solution of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 17% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0171] In some embodiments, administration of an oral solution of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 20% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0172] In some embodiments, administration of an oral solution of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 40% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0173] In some embodiments, administration of an oral solution of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 60% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0174] In some embodiments, administration of an oral solution of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 80% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0175] In some embodiments of the present disclosure, administration of an oral solution of the present disclosure to a patient in a fed state results in an erraglusib AUC∞ that is at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, at least 3.0-fold, at least 3.1-fold, at least 3.2-fold, at least 3.3-fold, at least 3.4-fold, at least 3.5-fold, at least 3.6-fold, at least 3.7-fold, or at least 3.8-fold the erraglusib AUC∞ that results from administration of an oral solution of the present disclosure to a fasted patient.

[0176] Oral liquid suspension In some aspects, the disclosure provides a liquid suspension comprising erraglusib; an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; a pharmaceutically acceptable alcohol; a surfactant that is sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether; and a pharmaceutically acceptable diluent.

[0177] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 0.04-0.6% by weight of erraglusib; about 0.8-10% by weight of an emulsifier which is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; about 0.04-1.7% by weight of a pharmaceutically acceptable alcohol; sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, The present invention relates to a liquid suspension comprising about 0.009 to 1% by weight of a surfactant selected from the group consisting of hydroxypropyl methylcellulose, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers; and about 87 to 99% by weight of a pharmaceutically acceptable diluent.

[0178] In some aspects, the present disclosure provides a pharmaceutical composition comprising about 0.08-0.6% by weight of erraglusib; about 1.5-10% by weight of an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; about 0.08-1.7% by weight of a pharmaceutically acceptable alcohol; sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate. The present invention relates to a liquid suspension comprising about 0.01 to 1% by weight of a surfactant selected from the group consisting of docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers; and about 87 to 99% by weight of a pharmaceutically acceptable diluent.

[0179] In some aspects, the present disclosure provides a pharmaceutical composition comprising about 0.15-0.6% by weight of erraglusib; about 3-10% by weight of an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; about 0.15-1.7% by weight of a pharmaceutically acceptable alcohol; sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, The present invention relates to a liquid suspension comprising about 0.03 to 1% by weight of a surfactant selected from the group consisting of docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers; and about 87 to 99% by weight of a pharmaceutically acceptable diluent.

[0180] In some aspects, the present disclosure provides a pharmaceutical composition comprising about 0.1-0.6% by weight of erraglusib; about 1.5-10% by weight of an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; about 0.1-1.7% by weight of a pharmaceutically acceptable alcohol; sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, The present invention relates to a liquid suspension comprising about 0.01 to 1% by weight of a surfactant selected from the group consisting of docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers; and about 87 to 98% by weight of a pharmaceutically acceptable diluent.

[0181] In some embodiments, the liquid suspension contains about 0.04 to 0.6% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, e.g., about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% by weight, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, or about 0.6% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione.

[0182] In some embodiments of the liquid suspension, the emulsifier is polyethylene glycol (PEG).

[0183] In another embodiment of the liquid suspension, the emulsifier is polyethylene glycol having a molecular weight of 100 to 1000 Da.

[0184] In another embodiment of the liquid suspension, the emulsifier is PEG400.

[0185] In some embodiments, the emulsifier is mustard lecithin.

[0186] In some embodiments, the emulsifier is soy lecithin.

[0187] In some embodiments, the emulsifier is egg lecithin.

[0188] In some embodiments, the emulsifier is a monoglyceride.

[0189] In some embodiments, the emulsifier is a diglyceride.

[0190] In some embodiments, the emulsifier is a polysorbate.

[0191] In some embodiments, the emulsifier is stearoyl lactylate.

[0192] In some embodiments, the emulsifier is a sorbitan ester.

[0193] In some embodiments, the emulsifier is a polyglycerol ester.

[0194] In some embodiments, the emulsifier is a sucrose ester.

[0195] In some embodiments, the emulsifier is present in the liquid suspension in an amount of about 0.8-10% by weight, e.g., one of about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% by weight.

[0196] In some embodiments of liquid suspensions, the pharmaceutically acceptable alcohol is ethanol.

[0197] In some embodiments, the pharmaceutically acceptable alcohol is present in an amount of about 0.04 to 1.7% by weight, e.g., one of about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, or about 1.7% by weight.

[0198] In some embodiments, the surfactant in the liquid suspension is sodium stearate.

[0199] In some embodiments, the surfactant is 4-(5-dodecyl)benzenesulfonate.

[0200] In some embodiments, the surfactant is sodium lauryl sulfate.

[0201] In some embodiments, the surfactant is docusate sodium.

[0202] In some embodiments, the surfactant is phosphatidylcholine.

[0203] In some embodiments, the surfactant is benzalkonium chloride.

[0204] In some embodiments, the surfactant is a polyoxyethylene sorbitan fatty acid ester.

[0205] In some embodiments, the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

[0206] In some embodiments, the surfactant is polyoxyethylene 15 hydroxystearate.

[0207] In some embodiments, the surfactant is a polyoxyethylene castor oil derivative.

[0208] In some embodiments, the surfactant is polyoxyethylene stearate.

[0209] In some embodiments, the surfactant is a sorbitan fatty acid ester.

[0210] In some embodiments, the surfactant is a polyoxyethylene alkyl ether.

[0211] In some embodiments, the surfactant is a polyoxyethylene nonylphenol ether.

[0212] In some embodiments, the surfactant is present in the liquid suspension in an amount of about 0.009-1% by weight, e.g., one of about 0.009%, about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1% by weight.

[0213] In some embodiments, the oral suspensions of the present disclosure comprise about 87-99% by weight of a pharmaceutically acceptable diluent, e.g., 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight of a pharmaceutically acceptable diluent. As used herein, a pharmaceutically acceptable diluent is a liquid that can be safely ingested by humans. Examples of pharmaceutically acceptable diluents include water and aqueous solutions, such as saline, electrolyte solutions, sugar solutions, flavored solutions, and the like.

[0214] In some embodiments, the pharmaceutically acceptable diluent is water.

[0215] In another embodiment, the pharmaceutically acceptable diluent is dextrose in water (5%) (also known as D5W).

[0216] In some embodiments, the present disclosure is directed to a suspension comprising about 0.04-0.05% by weight erraglusib, about 0.8-1.0% by weight polyethylene glycol 400, about 0.04-0.05% by weight ethanol, about 0.009-0.05% by weight polysorbate 80, and about 98-99% by weight glucose (5%) in aqueous solution.

[0217] In some embodiments, the present disclosure is directed to a suspension comprising about 0.08-0.1% by weight erraglusib, about 1.5-2.0% by weight polyethylene glycol 400, about 0.08-0.1% by weight ethanol, about 0.018-0.1% by weight polysorbate 80, and about 97-99% by weight glucose (5%) in aqueous solution.

[0218] In some embodiments, the present disclosure is directed to a suspension comprising about 0.15-0.2% by weight erraglusib, about 3-4% by weight polyethylene glycol 400, about 0.15-0.2% by weight ethanol, about 0.03-0.2% by weight polysorbate 80, and about 96-97% by weight D5W.

[0219] In some embodiments, the present disclosure is directed to a suspension comprising about 0.1-0.4% by weight erraglusib, about 2-8% by weight polyethylene glycol 400, about 0.1-0.5% by weight ethanol, about 0.01-0.05% by weight polysorbate 80, and about 98% by weight D5W.

[0220] In some embodiments, the suspension comprises about 0.1-0.5% by weight erraglusib; about 2.6-9.4% by weight polyethylene glycol 400; about 0.1-0.5% by weight ethanol, and about 0.03-0.1% by weight polysorbate 80; and about 97% by weight glucose (5%) in aqueous solution.

[0221] In some embodiments, the suspension comprises about 0.15-0.6% by weight erraglusib, about 2.7-9.5% by weight polyethylene glycol 400, about 0.5-1.7% by weight ethanol, and about 0.01% by weight polysorbate 80; and about 96% by weight D5W.

[0222] In some embodiments, the concentration of erraglusib in the suspension is at least 0.5 mg / mL.

[0223] In some embodiments, the concentration of erraglusib in the suspension is at least 1 mg / mL.

[0224] In some embodiments, the concentration of erraglusib in the suspension is at least 2 mg / mL.

[0225] In some embodiments, the liquid suspension has particles with diameters in the range of 100 to 1000 nm.

[0226] In some embodiments, oral administration of a liquid solution or liquid suspension of the present disclosure to a subject results in an erraglusib plasma concentration in the range of 1000-10000 ng / mL.

[0227] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, or at least 45% of the erraglusib AUC∞ resulting from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient. or at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80%.

[0228] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 13% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0229] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 17% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0230] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 20% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0231] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 40% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0232] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 60% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0233] In some embodiments, administration of an oral suspension of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 80% of the erraglusib AUC∞ that would result from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0234] In some embodiments of the present disclosure, administration of an oral suspension of the present disclosure to a fed patient results in an erraglusib AUC∞ that is at least 2.4-fold, at least 2.5-fold, at least 2.6-fold, at least 2.7-fold, at least 2.8-fold, at least 2.9-fold, at least 3.0-fold, at least 3.1-fold, at least 3.2-fold, at least 3.3-fold, at least 3.4-fold, at least 3.5-fold, at least 3.6-fold, at least 3.7-fold, or at least 3.8-fold the erraglusib AUC∞ that results from administration of an oral solution of the present disclosure to a fasted patient.

[0235] Pharmaceutical Composition for Oral Administration The pharmaceutical compositions of the present disclosure are typically formulated to provide a therapeutically effective amount of erraglusib as the active ingredient. In some embodiments, the pharmaceutical compositions contain erraglusib and one or more pharmaceutically acceptable excipients or carriers (including inert solid diluents and fillers), liquid diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, adjuvants, surfactants, etc.

[0236] In some aspects, the present disclosure provides a pharmaceutical composition for oral administration comprising an erraglusib solid dispersion disclosed herein, an erraglusib liquid suspension disclosed herein, or a liquid solution disclosed herein.

[0237] In some aspects, the present disclosure provides a pharmaceutical composition for oral administration comprising an erraglusib ASD disclosed herein, an erraglusib liquid suspension disclosed herein, or an erraglusib liquid solution disclosed herein.

[0238] In some embodiments, the pharmaceutical composition consists of an amorphous solid dispersion of erraglusib disclosed herein, a liquid solution of erraglusib disclosed herein, or a liquid suspension of erraglusib disclosed herein.

[0239] In some embodiments, the pharmaceutical composition of the present disclosure can be administered alone or in combination with one or more other drugs, which are also usually administered in the form of a pharmaceutical composition. If desired, erraglusib and the other drug(s) can be mixed into one preparation, or both components can be formulated into separate preparations that can be used separately or in combination at the same time.

[0240] In some embodiments, the present disclosure provides a solid pharmaceutical composition for oral administration containing (i) an effective amount of erraglusib; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third agent.

[0241] In some aspects, the present disclosure is directed to a pharmaceutical composition comprising a therapeutically effective amount of an amorphous solid dispersion of the present disclosure and a pharmaceutically acceptable excipient.

[0242] In some embodiments, the pharmaceutical composition is in a form suitable for oral (e.g., ingested by mouth) administration, such as a tablet, capsule, caplet, reconstitutable powder, elixir, liquid, colloidal or other type of suspension, beads, beadlets, granules, microparticles, nanoparticles, and combinations thereof.

[0243] In some embodiments, the pharmaceutical composition is a tablet.

[0244] In other embodiments, the pharmaceutical composition is a capsule.

[0245] In some embodiments, the amount of erraglusib in the pharmaceutical composition is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.0 8g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a number within a range defined by and including any two of the foregoing numbers).

[0246] In some embodiments, the amount of erraglusib is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.00 4g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05 g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g , 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g , 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or more than 10g (or a number within a range defined by and including any two of the above numbers).

[0247] In some embodiments, the amount of erraglusib is within the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0248] In some embodiments, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, and 1 to 50 mg per day are exemplary doses that can be used in treating adult humans. The exact dose will depend on the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0249] In some aspects, the liquid solutions or suspensions of the present disclosure are administered orally. In such embodiments, the liquid solutions or suspensions may further comprise sweeteners or flavoring agents, colorants or pigments, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerin, polysorbates, and combinations thereof.

[0250] In other aspects, the solid dispersions of the present disclosure are administered orally.

[0251] Pharmaceutical compositions containing the solid dispersions of the present disclosure can be formulated into discrete dosage forms, such as capsules, cachets, or tablets, liquids, or aerosol sprays, each containing a predetermined amount of erraglusib as a powder or granules, or as a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any method of pharmacy. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired dosage form. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules (optionally mixed with excipients, such as, but not limited to, binders, lubricants, inert diluents, and / or surface-active or dispersing agents), in a suitable machine. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0252] Capsules In some aspects, the present disclosure is directed to a pharmaceutical dosage form that is a capsule comprising the erraglusib ASD of the present disclosure.

[0253] In some embodiments, the present disclosure is directed to a pharmaceutical dosage form that is a capsule comprising the erraglusib ASD of the present disclosure.

[0254] In some embodiments, the capsule comprises the erraglusib ASD of the present disclosure and one or more pharmaceutically acceptable excipients.

[0255] In some embodiments, the capsule comprises the erraglusib ASD of the present disclosure and one or more pharmaceutically acceptable excipients, wherein the weight ratio of ASD to pharmaceutically acceptable excipients is about 19:1.

[0256] In some embodiments, the capsule comprises erraglusib ASD of the present disclosure and croscarmellose sodium.

[0257] In some embodiments, the capsule comprises the erraglusib ASD of the present disclosure and silica.

[0258] In some embodiments, the capsule comprises the erraglusib ASD of the present disclosure and a blend of croscarmellose sodium and silica.

[0259] In some embodiments, the capsule comprises the erraglusib ASD of the present disclosure and a blend of croscarmellose sodium and silica in a weight ratio of croscarmellose sodium:silica of 90:10.

[0260] In some embodiments, the capsule comprises the erraglusib ASD of the present disclosure and a blend of croscarmellose sodium and silica, wherein the weight ratio of ASD to the blend of croscarmellose sodium and silica is about 19:1.

[0261] In some embodiments, the ASD in the capsules of the present disclosure is Elra:PVAP.

[0262] In some embodiments, the ASD in the capsules of the present disclosure is Elra:CAP.

[0263] In some embodiments, the ASD in the capsules of the present disclosure is Elra:poly(methyl methacrylate-co-methacrylic acid) (i.e., amorphous erraglusib with poly(methyl methacrylate-co-methacrylic acid)).

[0264] In some embodiments, the ASD in the capsules of the present disclosure is Elra:EL100 (i.e., amorphous erraglusib with Eudragit® EL100 polymer).

[0265] In some embodiments, the capsule of the present disclosure comprises a hard gelatin capsule.

[0266] In other embodiments, the capsule of the present disclosure comprises a soft gelatin capsule.

[0267] tablet In some aspects, the present disclosure is directed to a pharmaceutical dosage form that is a tablet comprising the erraglusib ASD of the present disclosure.

[0268] In some embodiments, the tablet of the present disclosure comprises: (i) ASD containing erraglusib and a stabilizing polymer; (ii) binder; (iii) fillers; (iv) a disintegrant; and (v) Lubricant Includes:

[0269] In some embodiments, the tablet of the present disclosure comprises: (i) approximately 40-60 wt. % ASD comprising erraglusib and a stabilizing polymer; (ii) about 19-27 wt. % binder; (iii) about 10-25 wt. % filler; (iv) about 4 to 9 wt. % of a disintegrant; and (v) about 1 to 3% by weight of a lubricant Includes:

[0270] In some embodiments, the tablet of the present disclosure comprises: (i) about 50% by weight of an ASD comprising erraglusib and a stabilizing polymer; (ii) about 19.5 wt. % binder; (iii) about 19.5 wt. % filler; (iv) about 9% by weight of a disintegrant; and (v) about 2% by weight of a lubricant Includes.

[0271] In some embodiments of the tablets of the present disclosure, the ASD comprises erraglusib and poly(methyl methacrylate-co-methacrylic acid).

[0272] In some embodiments of the tablets of the present disclosure, the ASD comprises about 50% by weight erraglusib and about 50% by weight poly(methyl methacrylate-co-methacrylic acid).

[0273] In some embodiments of the tablets of the present disclosure, the ASD comprises erraglusib and EL100.

[0274] In some embodiments of the tablets of the present disclosure, the ASD comprises about 50% erraglusib by weight and about 50% EL100 by weight.

[0275] In some embodiments of the tablets of the present disclosure, the ASD comprises erraglusib and CAP.

[0276] In some embodiments of the tablets of the present disclosure, the ASD comprises about 50% erraglusib by weight and about 50% CAP by weight.

[0277] In some embodiments of the tablets of the present disclosure, the binder is microcrystalline cellulose.

[0278] In some embodiments of the tablets of the present disclosure, the filler is mannitol.

[0279] In some embodiments of the tablets of the present disclosure, the disintegrant is croscarmellose sodium or polyvinylpyrrolidone.

[0280] In some embodiments of the tablets of the present disclosure, the disintegrant is croscarmellose sodium.

[0281] In some embodiments of the tablets of the present disclosure, the lubricant is one or more of syloidal silica or magnesium stearate.

[0282] In some embodiments of the tablets of the present disclosure, the lubricant comprises syloidal silica and magnesium stearate.

[0283] In some embodiments, the tablet of the present disclosure comprises: (i) an ASD comprising about 50% by weight of erraglusib and about 50% by weight of poly(methyl methacrylate-co-methacrylic acid); (ii) microcrystalline cellulose; (iii) mannitol; (iv) croscarmellose sodium; (v) silicon dioxide; and (vi) magnesium stearate Includes.

[0284] In some embodiments, the tablet of the present disclosure comprises: (i) about 50% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of poly(methyl methacrylate-co-methacrylic acid); (ii) about 19.5% by weight microcrystalline cellulose; (iii) about 19.5% by weight of mannitol; (iv) about 9% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) approximately 1% magnesium stearate Includes.

[0285] In some embodiments, the tablet of the present disclosure comprises: (i) 50 wt% ASD comprising about 50 wt% erraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid); (ii) 19.5 wt. % microcrystalline cellulose; (iii) 19.5 wt% mannitol; (iv) 9% by weight of croscarmellose sodium; (v) 1 wt. % silicon dioxide; and (vi) 1% magnesium stearate Includes:

[0286] In some embodiments, the tablet of the present disclosure comprises: (i) an ASD comprising about 50% by weight erraglusib and about 50% by weight EL100; (ii) microcrystalline cellulose; (iii) mannitol; (iv) croscarmellose sodium; (v) silicon dioxide; and (vi) magnesium stearate Includes:

[0287] In some embodiments, the tablet of the present disclosure comprises: (i) about 50% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of EL100; (ii) about 19.5% by weight microcrystalline cellulose; (iii) about 19.5% by weight of mannitol; (iv) about 9% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes:

[0288] In some embodiments, the tablet of the present disclosure comprises: (i) 50% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of EL100; (ii) 19.5 wt. % microcrystalline cellulose; (iii) 19.5 wt% mannitol; (iv) 9% by weight of croscarmellose sodium; (v) 1 wt. % silicon dioxide; and (vi) 1% magnesium stearate Includes.

[0289] In some embodiments, the tablet of the present disclosure comprises: (i) approximately 42 wt. % ASD comprising erraglusib and a stabilizing polymer; (ii) about 27% by weight of binder; (iii) about 25 wt. % filler; (iv) about 4% by weight of a disintegrant; and (v) about 2% lubricant Includes.

[0290] In some embodiments, the tablet of the present disclosure comprises: (i) an ASD comprising about 50% by weight of erraglusib and about 50% by weight of poly(methyl methacrylate-co-methacrylic acid); (ii) microcrystalline cellulose; (iii) mannitol; (iv) croscarmellose sodium; (v) silicon dioxide; and (vi) magnesium stearate Includes.

[0291] In some embodiments, the tablet of the present disclosure comprises: (i) about 42 wt% ASD comprising about 50 wt% erraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid); (ii) about 27% by weight microcrystalline cellulose; (iii) about 25% by weight mannitol; (iv) about 4% by weight of croscarmellose sodium; (v) about 0.5% by weight of silicon dioxide; and (vi) approximately 1.5% magnesium stearate Includes.

[0292] In some embodiments, the tablet of the present disclosure comprises: (i) an ASD comprising about 50% by weight erraglusib and about 50% by weight EL100; (ii) microcrystalline cellulose; (iii) mannitol; (iv) croscarmellose sodium; (v) silicon dioxide; and (vi) magnesium stearate Includes:

[0293] In some embodiments, the tablet of the present disclosure comprises: (i) about 42% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of EL100; (ii) about 27% by weight microcrystalline cellulose; (iii) about 25% by weight mannitol; (iv) about 4% by weight of croscarmellose sodium; (v) about 0.5% by weight of silicon dioxide; and (vi) approximately 1.5% magnesium stearate Includes:

[0294] In some embodiments, the tablet of the present disclosure comprises: (i) an ASD comprising about 50% by weight erraglusib and about 50% by weight CAP; (ii) microcrystalline cellulose; (iii) mannitol; (iv) croscarmellose sodium; (v) silicon dioxide; and (vi) magnesium stearate Includes:

[0295] In some embodiments, the tablet of the present disclosure comprises: (i) about 42% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of a CAP; (ii) about 27% by weight microcrystalline cellulose; (iii) about 25% by weight mannitol; (iv) about 4% by weight of croscarmellose sodium; (v) about 0.5% by weight of silicon dioxide; and (vi) approximately 1.5% magnesium stearate Includes.

[0296] In some embodiments, the tablet of the present disclosure comprises: (i) about 50 wt% ASD comprising erraglusib and a stabilizing polymer; (ii) about 22% by weight of binder; (iii) about 22 wt. % filler; (iv) about 5% by weight of a disintegrant; and (v) about 2% lubricant Includes.

[0297] In some embodiments, the tablet of the present disclosure comprises: (i) about 50% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of EL100; (ii) about 21.5% by weight microcrystalline cellulose; (iii) about 21.5% by weight mannitol; (iv) about 5% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes.

[0298] In some embodiments, the tablet of the present disclosure comprises: (i) about 50 wt% ASD comprising about 50 wt% erraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid); (ii) about 21.5% by weight microcrystalline cellulose; (iii) about 21.5% by weight mannitol; (iv) about 5% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes.

[0299] In some embodiments, the tablet of the present disclosure comprises: (i) about 55.6 wt. % ASD comprising erraglusib and a stabilizing polymer; (ii) about 24.9 wt. % binder; (iii) about 12.5 wt. % filler; (iv) about 5% by weight of a disintegrant; and (v) about 2% lubricant Includes.

[0300] In some embodiments, the tablet of the present disclosure comprises: (i) about 55.6 wt. % ASD comprising about 50 wt. % erraglusib and about 50 wt. % poly(methyl methacrylate-co-methacrylic acid); (ii) about 21.5% by weight microcrystalline cellulose; (iii) about 12.5% by weight of mannitol; (iv) about 5% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes.

[0301] In some embodiments, the tablet of the present disclosure comprises: (i) about 55.6% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of EL100; (ii) about 21.5% by weight microcrystalline cellulose; (iii) about 12.5% by weight of mannitol; (iv) about 5% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes.

[0302] In some embodiments, the tablet of the present disclosure comprises: (i) about 58.8 wt. % ASD comprising erraglusib and a stabilizing polymer; (ii) about 20.8 wt. % binder; (iii) about 10.4 wt. % filler; (iv) about 8% by weight of a disintegrant; and (v) about 2% lubricant Includes:

[0303] In some embodiments, the tablet of the present disclosure comprises: (i) about 58.8 wt. % ASD comprising about 50 wt. % erraglusib and about 50 wt. % poly(methyl methacrylate-co-methacrylic acid); (ii) about 20.8% by weight microcrystalline cellulose; (iii) about 10.4% by weight of mannitol; (iv) about 8% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes:

[0304] In some embodiments, the tablet of the present disclosure comprises: (i) about 58.8% by weight of an ASD comprising about 50% by weight of erraglusib and about 50% by weight of EL100; (ii) about 20.8% by weight microcrystalline cellulose; (iii) about 10.4% by weight of mannitol; (iv) about 8% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) about 1% by weight of magnesium stearate Includes:

[0305] In some embodiments, oral administration of a tablet of the present disclosure to a patient achieves at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110% 7%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80%.

[0306] In some embodiments, oral administration of a solid dispersion of the present disclosure to a patient results in an erraglusib AUC∞ that is at least 68% of the erraglusib AUC∞ that results from IV administration of an equivalent dose (on a mg / kg basis) of erraglusib to a patient.

[0307] In some embodiments, the pharmaceutical compositions of the present disclosure are anhydrous. The anhydrous pharmaceutical compositions of the present disclosure can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains their anhydrous nature. Therefore, the anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-volume containers, blister packs, and strip packs.

[0308] Erraglusib can be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used as a carrier, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations (e.g., suspensions and solutions) or aerosols; or, in some embodiments, for oral solid preparations, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, polymers, and disintegrants can be used without the use of lactose. For example, suitable carriers include powders, capsules, and tablets for solid oral preparations. If desired, tablets can be coated using standard aqueous or nonaqueous techniques.

[0309] Suitable binders for use in the pharmaceutical compositions of the present disclosure include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl cellulose, hydroxypropylmethylcellulose (hypromellose), microcrystalline cellulose, and mixtures thereof.

[0310] Examples of fillers suitable for use in the pharmaceutical compositions disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0311] Disintegrants can be used in pharmaceutical compositions to provide tablets that disintegrate when exposed to an aqueous environment. The amount of disintegrant used can vary based on the type of formulation and mode of administration, and is readily discernible to those skilled in the art. In some embodiments, about 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions of the present disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato starch or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0312] Lubricants that can be used to form the pharmaceutical compositions of the present disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, colloidal silicon dioxide gel, solidified aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added, for example, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0313] Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.The preparation for oral use can also be a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsule in which the active ingredient is mixed in water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0314] Surfactants that can be used to form the pharmaceutical compositions of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be utilized, a mixture of lipophilic surfactants can be utilized, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be utilized.

[0315] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.

[0316] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guide that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0317] Hydrophilic surfactant can be either ionic or nonionic.Suitable ionic surfactant includes but is not limited to alkylammonium salt; fusidate salt; fatty acid derivatives of amino acid, oligopeptide and polypeptide; glyceride derivatives of amino acid, oligopeptide and polypeptide; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salt; alkyl sulfate salt; fatty acid salt; docusate sodium; acyl lactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citrate esters of mono- and diglycerides; and mixtures thereof.

[0318] Within the above group, examples of ionic surfactants include: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; docusate sodium; acyl acrylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citrate esters of mono- and diglycerides; and mixtures thereof.

[0319] Ionic surfactants include ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactylate, stearoyl lactate, stearic acid ... The glycerin may be selected from the group consisting of glycerin, glycerin, glycerol, glycerols ...

[0320] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0321] Other hydrophilic nonionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, P EG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hard Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 Lauryl Ether glyceryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10-oleate, Tween 40, Tween 60, Tween 80, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0322] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and diglycerides, hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof. Among these groups, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0323] Examples of suitable solubilizing agents include, but are not limited to, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and their isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone. , 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0324] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0325] The amount of solubilizer that can be included is not particularly limited. The amount of solubilizer to be added may be limited by a biotolerable amount, which can be easily determined by one skilled in the art. In some situations, for example, to maximize drug concentration, it may be advantageous to include an amount of solubilizer that far exceeds the biotolerable amount and remove the excess solubilizer using conventional techniques, such as distillation or evaporation, before providing the composition to a subject. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0326] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, without limitation, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0327] In addition, acids or bases can be incorporated into the composition to facilitate processing, promote stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient, pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0328] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0329] In some embodiments, the erraglusib composition is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times daily. Dosing may be about once per month, once every two weeks, once per week, twice per week, or once every two days. In another embodiment, the erraglusib composition and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the erraglusib composition and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing can be achieved and maintained for as long as necessary.

[0330] Administration of the erraglusib composition can be continued for as long as needed. In some embodiments, the erraglusib composition can be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the erraglusib composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the erraglusib composition is administered for more than 1, 2, 3, 4, 5, 6, 12, 18, or 24 months. In some embodiments, the erraglusib composition is administered on a chronic, continuous basis for as long as needed, for example, to treat a chronic disease or disorder.

[0331] An effective amount of the erraglusib composition may be administered in either a single dose or multiple doses by any of the generally accepted modes of administration for drugs with similar utilities, including rectal, oral buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0332] In some embodiments, the methods of the present disclosure result in plasma concentrations of erraglusib that exhibit food effect. The term "food effect," as used herein, means that the extent and / or rate of drug absorption depends on whether the subject is in a fed or fasted state at the time the drug is administered.

[0333] The term "fed state," as used herein, means that a subject eats food immediately before and / or after taking erraglusib or a pharmaceutically acceptable salt thereof. For example, in some embodiments, "fed state" means that a subject eats food 30 minutes or more before taking erraglusib or a pharmaceutically acceptable salt thereof.

[0334] The term "fasted state," as used herein, means that the subject has not eaten food within 8 hours immediately prior to or 4 hours immediately after taking erraglusib or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject results in a plasma erraglusib C (fed state):C (fasted state) ratio of about 2.5 to 5, e.g., about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5.0.

[0336] In some embodiments, oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject results in a plasma erraglusib C (fed state):C (fasted state) ratio of 2.5 or greater, such as 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.

[0337] In some embodiments, oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject results in a plasma erraglusib Cmax (fed state) that is at least 250%, e.g., 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, 500%, etc., of the corresponding plasma erraglusib Cmax (fasted state).

[0338] As used herein, the term "Cmax (fasted state)" refers to the peak plasma concentration after oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject in a fasted state. As used herein, the term "Cmax (fed state)" refers to the peak plasma concentration after oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject in a fed state. The peak concentration of erraglusib in a subject's plasma sample can be determined using an appropriate pharmacokinetic model applied to the plasma concentration versus time profile determined using standard analytical methods. Suitable pharmacokinetic models for determining Cmax are known to those of skill in the art.

[0339] In some embodiments of the disclosed methods, the arithmetic mean of the individual Cmax (fed state) values calculated in a population of subjects and the arithmetic mean of the individual Cmax (fasted state) values calculated in a population of subjects are used to calculate the Cmax (fed state):Cmax (fasted state) ratio.

[0340] In some embodiments of the disclosed methods, the geometric mean of the individual Cmax (fed state) values calculated in a population of subjects and the geometric mean of the individual Cmax (fasted state) values calculated in a population of subjects are used to calculate the Cmax (fed state):Cmax (fasted state) ratio.

[0341] In some embodiments, oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject results in a plasma erraglusib AUC∞ (fed state):AUC∞ (fasted state) ratio of about 2.4 to 3.6, e.g., about 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, or 3.6.

[0342] In some embodiments, oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject results in a plasma erraglusib AUC∞ (fed state):AUC∞ (fasted state) ratio of 2.4 or greater, e.g., 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, etc.

[0343] In some embodiments, oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject results in a plasma erraglusib AUC∞ (fed state) that is at least 240%, e.g., 240%, 245%, 250%, 255%, 260%, 265%, 270%, 275%, 280%, 285%, 290%, 295%, 300%, 305%, 310%, 315%, 320%, 325%, 330%, 335%, 340%, 345%, 350%, etc., of the corresponding plasma erraglusib AUC∞ (fasted state).

[0344] As used herein, the term "AUC∞ (fasted state)" refers to the area under the plasma concentration-time curve from extrapolation of AUC to ∞ following oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject in a fasted state. As used herein, the term "AUC∞ (fed state)" refers to the area under the plasma concentration-time curve from extrapolation of AUC to ∞ following oral administration of an erraglusib pharmaceutical composition of the present disclosure to a subject in a fed state. Methods for determining concentration-time curves and AUC are known to those skilled in the art.

[0345] In some embodiments of the disclosed methods, the AUC∞ (fed state):AUC∞ (fasted state) ratio is calculated using the arithmetic mean of the individual AUC∞ (fed state) values calculated in the population of subjects and the arithmetic mean of the individual AUC∞ (fasted state) values calculated in the population of subjects.

[0346] In other embodiments of the disclosed methods, the AUC∞(fed state):AUC∞(fasted state) ratio is calculated using the geometric mean of the individual AUC∞(fed state) values calculated in a population of subjects and the geometric mean of the individual AUC∞(fasted state) values calculated in a population of subjects.

[0347] How to use In some aspects, the present disclosure is directed to a method for treating a disease or disorder in a subject in need thereof, comprising orally administering to the subject a solid dispersion according to any embodiment disclosed herein or a liquid solution or liquid suspension according to any embodiment disclosed herein.

[0348] In some embodiments, the present disclosure is directed to a method for treating a disease or disorder in a subject in need thereof, the method comprising orally administering to the subject a solid dispersion of the present disclosure.

[0349] In some embodiments, the present disclosure is directed to a method for treating a disease or disorder in a subject in need thereof, comprising orally administering to the subject a solution or suspension of the present disclosure.

[0350] In some embodiments of such methods, the solution or suspension is administered orally as a pharmaceutical composition.

[0351] In another embodiment of such a method, the solid dispersion is administered orally as a pharmaceutical composition.

[0352] In some embodiments, the effective amount of erraglusib for use in the methods of treatment of the present disclosure is based on the patient's weight and condition and the disease being treated. In some embodiments, the effective amount of erraglusib is about 0.1 mg / kg to 20 mg / kg, e.g., about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg.

[0353] In some embodiments, the disease or disorder is cancer.

[0354] In some embodiments, the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, pancreatic cancer, sarcoma, or glioblastoma.

[0355] In some embodiments, the cancer is glioblastoma.

[0356] In other embodiments, the disease or disorder is a lymphoproliferative disorder.

[0357] In some embodiments, the lymphoproliferative disorder is a malignant B-cell lymphoproliferative disorder, e.g., diffuse large B-cell lymphoma, acute lymphocytic leukemia, chronic myeloid leukemia in lymphoblastic blast crisis phase, chronic lymphocytic leukemia / small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, mantle cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, hairy cell leukemia, primary central nervous system lymphoma, splenic marginal zone B-cell lymphoma, Waldenstrom's macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, plasma cell dyscrasia, plasma cell neoplasm, primary mediastinal B-cell lymphoma, Hodgkin's disease, or Castleman's disease.

[0358] In some embodiments, the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma.

[0359] In another embodiment, the diffuse large B-cell lymphoma is a double-hit lymphoma.

[0360] In other embodiments, the malignant lymphoproliferative disorder is a malignant T-cell lymphoproliferative disorder, e.g., T-cell leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, enteropathic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large T-cell / null cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, lymphoblastic blast crisis phase chronic myeloid leukemia, post-transplant lymphoproliferative syndrome, human T-cell leukemia virus type 1-positive (HTLV-1) + ) adult T-cell leukemia / lymphoma (ATL), T-cell prolymphocytic leukemia (T-PLL), or T-cell lymphoma not otherwise specified.

[0361] In another embodiment, the disease or disorder is traumatic brain injury.

[0362] In another embodiment, the disease or disorder is idiopathic pulmonary fibrosis.

[0363] In another embodiment, the disease or disorder is pleural fibrosis.

[0364] The present disclosure is also directed to the following aspects: Embodiment 1. A solid dispersion comprising amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer. Aspect 2. The solid dispersion of Aspect 1, wherein the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyvinylpyrrolidone, or a miscible mixture thereof. Aspect 3. The solid dispersion of aspect 2, wherein the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone). Embodiment 4. The solid dispersion of embodiment 2, wherein the stabilizing polymer is cellulose acetate phthalate. Embodiment 5. The solid dispersion of embodiment 2, wherein the stabilizing polymer is hydroxypropyl methylcellulose phthalate. Aspect 6. The solid dispersion of aspect 2, wherein the stabilizing polymer is hydroxypropyl methylcellulose acetate succinate. Aspect 7. The solid dispersion of aspect 2, wherein the stabilizing polymer is polyvinyl acetate phthalate. Embodiment 8. The solid dispersion of embodiment 2, wherein the stabilizing polymer is polyvinylpyrrolidone. Aspect 9. The solid dispersion of any one of aspects 1 to 8, wherein the 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 10% to about 70% by weight, based on the weight of the stabilizing polymer. Aspect 10. The solid dispersion of any one of aspects 1 to 9, wherein the 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 20% to about 60% by weight, based on the weight of the stabilizing polymer. Aspect 11. The solid dispersion of any one of aspects 1 to 10, wherein 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 25% to about 50% by weight based on the weight of the stabilizing polymer. Aspect 12. The solid dispersion of any one of aspects 1 to 11, wherein the weight ratio of amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione to stabilizing polymer ranges from about 30:70 to about 50:50. Embodiment 13. The solid dispersion of any one of embodiments 1 to 12, wherein the solid dispersion has a single glass transition temperature. Embodiment 14. The solid dispersion of any one of embodiments 1 to 13, wherein the solid dispersion is stable at 60° C. and 75% relative humidity for at least 48 hours. Aspect 15. The solid dispersion of any one of aspects 1 to 14, wherein the solid dispersion is stable at 40° C. and 75% relative humidity for at least 4 weeks. Aspect 16. The solid dispersion of any one of aspects 1 to 15, wherein the solid dispersion is stable at 40° C. and 75% relative humidity for at least 12 weeks. Aspect 17. A pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion of any one of aspects 1 to 16 and a pharmaceutically acceptable excipient. Embodiment 18. A method for preparing the solid dispersion of any one of embodiments 1 to 17, comprising the steps of: a) dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer in a solvent to form a solution; and b) removing the solvent by evaporation to form the solid dispersion. Embodiment 19. The method of embodiment 18, wherein the solvent is dichloromethane, tetrahydrofuran, aqueous tetrahydrofuran, acetone, aqueous acetone, methanol, ethanol, ethyl acetate, and mixtures thereof. Embodiment 20. The method of any one of embodiments 18 or 19, wherein the solvent is evaporated by spray drying. Embodiment 21 The method of any one of embodiments 18 or 19, wherein the solvent is evaporated under reduced pressure. Embodiment 22 The method of any one of embodiments 18 or 19, wherein the solvent is evaporated using an inert gas. Embodiment 23. 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (erraglusib); an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; a pharmaceutically acceptable alcohol; and A liquid solution containing surfactants which are sodium triphosphate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether. Embodiment 24. About 4.0-6.0% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (erraglusib); about 75-95% by weight of an emulsifier that is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; about 2-17% by weight of a pharmaceutically acceptable alcohol; and about 0.5-10% by weight of a surfactant that is sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers. Embodiment 25. The liquid solution of embodiment 23 or embodiment 24, wherein the emulsifier is polyethylene glycol (PEG). Embodiment 26. The liquid solution of embodiment 25, wherein the polyethylene glycol has a molecular weight of 100 to 1000 Da. Embodiment 27. The liquid solution of embodiment 25 or embodiment 26, wherein the emulsifier is PEG400. Embodiment 28. The liquid solution of any one of embodiments 23 to 27, wherein the pharmaceutically acceptable alcohol is ethanol. Embodiment 29. The liquid solution according to any one of embodiments 23 to 28, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate). Embodiment 30. The liquid solution of any one of embodiments 23 to 29, comprising about 4.3 to 5.5% by weight erraglusib. Embodiment 31. The liquid solution of any one of embodiments 23 to 30, wherein the concentration of erraglusib in the solution is at least 45 mg / mL. Embodiment 32. The liquid solution of any one of embodiments 23 to 30, wherein the concentration of erraglusib in the solution is at least 50 mg / mL. Aspect 33. The solution of any one of aspects 23 to 32, wherein the erraglusib purity is greater than 97% as measured by HPLC area %. Aspect 34. The solution of aspect 33, wherein the erraglusib purity is greater than 98% as measured by HPLC area %. Aspect 35. The solution of aspect 34, wherein the erraglusib purity is greater than 99% as measured by HPLC area %. Embodiment 36. The solution of any one of embodiments 23 to 35, wherein the solution contains less than 2% of an impurity having a relative retention time of 0.97 or 0.96 relative to the retention time of erraglusib, as measured by HPLC area %. Embodiment 37. The solution of any one of embodiments 23 to 36, wherein the solution contains less than 1% of an impurity having a relative retention time of 0.97 or 0.96 relative to the retention time of erraglusib, as measured by HPLC area %. Aspect 38. A liquid suspension comprising erraglusib; an emulsifier which is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; a pharmaceutically acceptable alcohol; a surfactant which is sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether; and a pharmaceutically acceptable diluent. Aspect 39. A composition comprising about 0.04 to 0.6% by weight erraglusib, about 0.8 to 10% by weight of an emulsifier which is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester, or sucrose ester; and about 0.04 to 1.7% by weight of a pharmaceutically acceptable alcohol, sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, docusate. 39. The liquid suspension of claim 38, comprising about 0.009 to 1% by weight of a surfactant selected from the group consisting of sodium carbonate, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15 hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers; and about 87 to 98% by weight of a pharmaceutically acceptable diluent. Embodiment 40. The liquid suspension according to embodiment 38 or embodiment 39, wherein the emulsifier is polyethylene glycol (PEG). Embodiment 41. The liquid suspension according to embodiment 40, wherein the polyethylene glycol has a molecular weight of 100 to 1000 Da. Embodiment 42. The liquid suspension according to embodiment 40 or embodiment 41, wherein the emulsifier is PEG400. Embodiment 43. The liquid suspension according to any one of embodiments 38 to 42, wherein the pharmaceutically acceptable alcohol is ethanol. Embodiment 44. A liquid suspension according to any one of embodiments 38 to 43, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate). Embodiment 45. The liquid suspension of any one of embodiments 38 to 44, comprising about 0.04% by weight of erraglusib. Embodiment 46. The liquid suspension of any one of embodiments 38 to 44, comprising about 0.1% by weight of erraglusib. Embodiment 47. The liquid suspension of any one of embodiments 38 to 44, comprising about 0.2% by weight of erraglusib. Embodiment 48. The liquid suspension of any one of embodiments 38 to 44, comprising about 0.5% by weight of erraglusib. Embodiment 49. The solution or suspension according to any one of embodiments 38 to 48, wherein the concentration of erraglusib in the suspension is at least 0.4 mg / mL. Embodiment 50. The solution or suspension according to any one of embodiments 38 to 48, wherein the concentration of erraglusib in the suspension is at least 0.5 mg / mL. Aspect 51. The liquid suspension according to any one of aspects 38 to 50, wherein the pharmaceutically acceptable diluent is water, saline, an electrolyte solution, a sugar solution, or a flavored liquid. Embodiment 52. The liquid suspension of embodiment 51, wherein the pharmaceutically acceptable diluent is dextrose in water (5%) (D5W). Embodiment 53. The suspension of any one of embodiments 38 to 52, wherein the erraglusib purity is greater than 97% as measured by HPLC area %. Embodiment 54. The suspension of any one of embodiments 38 to 52, wherein the erraglusib purity is greater than 98% as measured by HPLC area %. Embodiment 55. The suspension of any one of embodiments 38 to 52, wherein the erraglusib purity is greater than 99% as measured by HPLC area %. Embodiment 56. The suspension of any one of embodiments 38 to 52, wherein the suspension contains less than 2% of an impurity having a relative retention time of 0.97 or 0.96 relative to the retention time of erraglusib, as measured by HPLC area %. Embodiment 57. The suspension of any one of embodiments 38 to 52, wherein the suspension contains less than 1% of an impurity having a relative retention time of 0.97 or 0.96 relative to the retention time of erraglusib, as measured by HPLC area %. Embodiment 58. A method for achieving an erraglusib plasma concentration in a range of 1000 to 10000 ng / mL in a human, the method comprising orally administering to the human a solid dispersion, liquid solution, liquid suspension, or pharmaceutical composition of the present disclosure. Embodiment 59. A method for treating a disease or disorder in a subject in need thereof, said method comprising orally administering to the subject a solid dispersion according to any one of embodiments 1 to 16, a pharmaceutical composition according to embodiment 17, a solution according to any one of embodiments 23 to 37, or a suspension according to any one of embodiments 38 to 57. Embodiment 60. The method of embodiment 59, wherein the disease or disorder is cancer. Embodiment 61. The method of embodiment 60, wherein the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, pancreatic cancer, or glioblastoma. Embodiment 62. The method of embodiment 60, wherein the cancer is glioblastoma. Embodiment 63. The method of embodiment 59, wherein the disease or disorder is a lymphoproliferative disorder. Embodiment 64. The method of embodiment 63, wherein the lymphoproliferative disorder is a malignant lymphoproliferative disorder. Embodiment 65. The method of embodiment 64, wherein the malignant lymphoproliferative disorder is a malignant B-cell lymphoproliferative disorder. Aspect 66. The method of aspect 65, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma, acute lymphocytic leukemia, chronic myeloid leukemia in lymphoblastic blast crisis phase, chronic lymphocytic leukemia / small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, mantle cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, hairy cell leukemia, primary central nervous system lymphoma, splenic marginal zone B-cell lymphoma, Waldenstrom's macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, plasma cell dyscrasia, plasma cell neoplasm, primary mediastinal B-cell lymphoma, Hodgkin's disease, or Castleman's disease. Embodiment 67. The method of embodiment 66, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma. Embodiment 68. The method of embodiment 67, wherein the diffuse large B-cell lymphoma is a double-hit lymphoma. Embodiment 69. The method of embodiment 63, wherein the lymphoproliferative disorder is a malignant T-cell lymphoproliferative disorder. Aspect 70. The malignant T-cell lymphoproliferative disorder is selected from the group consisting of T-cell leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, enteropathy-type T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large T-cell / null cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, lymphoblastic blast crisis-phase chronic myeloid leukemia, post-transplant lymphoproliferative syndrome, human T-cell leukemia virus type 1-positive (HTLV-1) + 70. The method of embodiment 69, wherein the tumor is adult T-cell leukemia / lymphoma (ATL), T-cell prolymphocytic leukemia (T-PLL), or T-cell lymphoma not otherwise specified. Embodiment 71. The method of embodiment 59, wherein the disease or disorder is traumatic brain injury. Embodiment 72. The method of embodiment 59, wherein the disease or disorder is idiopathic pulmonary fibrosis. Embodiment 73. The method of embodiment 59, wherein the disease or disorder is pleural fibrosis.

[0365] Although the present disclosure has been described with reference to certain preferred embodiments, other embodiments will become apparent to those skilled in the art in light of the specification. The disclosure is further illustrated with reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure. [Example]

[0366] [Example 1] Preparation of oral liquids An erraglusib liquid dosage form was prepared that can be administered orally as is or diluted into 5% dextrose in water to form a liquid suspension suitable for oral administration. Table 1-1 shows the batch formulation.

[0367] [Table 1]

[0368] Day 1: 5.040 kg of PEG400 was weighed into a 6 L flask in a dosing booth. The solution was capped and transferred to a biosafety cabinet. Four separate amounts of erraglusib powder were weighed into the dosing booth: 64.42 g, 69.89 g, 76.76 g, and 35.97 g. The total weight was 247.04 g. Each portion was transferred to a biosafety cabinet and added sequentially to the flask containing PEG400 and allowed to stir overnight, protected from light.

[0369] Day 2: A layer of erraglusib was at the bottom of the flask. A combination of a shaker plate and a stir plate was used to soften the bottom layer of the flask. The flask was then placed on the shaker plate and mixed overnight, protected from light.

[0370] Day 3: Erraglusib appeared in solution. Using a serological pipette, a 57 mL aliquot of polysorbate 80 (Tween 80) was added to the solution and placed on a shaker plate for 60 minutes. After 60 minutes, 270.05 g of dehydrated ethanol was added to the solution, which was placed on a shaker plate and mixed for an additional 60 minutes.

[0371] Pre-filtration of bulk samples: On day 3, new serological pipettes were used to draw 20 mL samples from the top, middle, and bottom of the pre-filtration bulk material. Samples were stored in 20 mL amber vials at room temperature, protected from light, in a cardboard box.

[0372] Filtration of bulk solution: The solution was transferred to a laminar flow hood and filtered using a 4 inch (10 cm) 0.2 μm Opticap XL4 Durapore clarification filter via a peristaltic pump into a clean, dry 6 L flask.

[0373] Filling vials with filtered bulk solution: Using a calibrated repeater pipette with a 50 mL tip, 20 mL amber vials (molded glass) were filled with 11 ± 0.1 mL of filtered bulk solution in a laminar flow hood. The vials were sealed with FluroTec rubber stoppers and metal crimps with white flip-off closures. The vials were stored in cardboard boxes at ambient conditions, protected from light.

[0374] The characterization of the 50 mg / mL solution of the oral suspension batch is summarized in Table 1-2.

[0375] [Table 2]

[0376] formulation The starting point for the development of an erraglusib oral solution formulation was an erraglusib 10 mg / mL IV injection drug product containing 10 mg / mL erraglusib dissolved in a vehicle of PEG400:EtOH:Tween80, 75:17:8% w / w. The development of the erraglusib oral solution drug product had the following goals: Increase erraglusib concentration (thus reducing the required dose volume); Maintaining the same excipients as the erraglusib 10mg / mL injection drug product; · Decreasing EtOH concentration (thus reducing the ethanol dose administered to the patient); Decreasing the Tween 80 concentration (thus reducing the Tween 80 dose administered to patients); Achieve >50% bioavailability with oral administration versus intravenous (IV) administration.

[0377] Initial study of 50 mg / mL erraglusib solutions prepared in 12 vehicle variants. Tables 1-3 show the compositions of the vehicle variants.

[0378] [Table 3]

[0379] Each vehicle variant was made up to 50 mg / mL with erraglusib and tested (with and without syringe filtration) for: (1) erraglusib main peak area %, (2) related substances RRT 0.96 area %, and (3) related substances area % RRT 0.97. RRT is the HPLC relative retention time, i.e., the retention time of a substance relative to the retention time of erraglusib. Erraglusib remained soluble at 50 mg / mL with no precipitation or turbidity and no obvious visible particulates. Erraglusib concentrations averaged 99.0 ± 2.9% of 50 mg / mL across all vehicle variations without the filter. Across all syringe-filtered vehicle variations, erraglusib concentrations averaged 98.6 ± 2.7% of 50 mg / mL. Variants 7-12 (Tables 1-3), which were prepared by mixing the API into PEG400 within 24 hours, showed more consistent values for the main peak (i.e., erraglusib peak) area % = 99%, with recoveries ranging from 97-102%. · Related substances RRT0.96 area % values were higher in variants 1–6 (>1.2%) than in variants 7–12 (<0.5%). Related substance RRT0.96 levels appear to increase with increasing EtOH% or Tween80%, or both, in vehicle variants.

[0380] Two in vitro experiments were conducted to evaluate the application of these 12 vehicle variants formulated to 50 mg / mL erraglusib to generate liquid oral suspension drug products. One study determined erraglusib solubility at ambient temperature after diluting each of the 12 vehicle variants into two potential oral solution diluents: 5% dextrose injection (D5W) and Pedialyte® (PED) to erraglusib concentrations of 0.50, 1.0, and 2.0 mg / mL.

[0381] All 12 vehicle variants formulated to give 50 mg / mL erraglusib produced precipitates when diluted to 0.50, 1.0, and 2.0 mg / mL concentrations in PED. Vehicle variants 1-5 produced a clear precipitate when diluted in D5W, whereas vehicle variants 6-12 produced a cloudy, fine dispersion that persisted for at least 4 hours after dilution. For 50 mg / mL erraglusib in vehicle variant 7 diluted to 2 mg / mL in D5W, dynamic light scattering (DLS) analysis showed a mean particle diameter of approximately 200 nm. HPLC analysis using the methods shown in Tables 1-5 indicated a possible correlation between the vehicle variants' high EtOH and / or Tween 80 content and the formation of higher levels of the related substance RRT 0.97.

[0382] In another study, the concentrations of soluble erraglusib and soluble plus particulate erraglusib in each of three biorelevant dissolution media (FaSSGF, FaSSIF, and FeSSIF) were determined after adding 1.0 and 2.0 mg / mL dilutions in D5W from a 50 mg / mL vehicle variant 7 formulation. When either a 1.0 mg / mL (700 mL) or 2.0 mg / mL (350 mL) D5W suspension was brought to a total volume of 900 mL with biorelevant dissolution media, a suspension containing both soluble erraglusib and particulate erraglusib was produced. The concentration of soluble erraglusib was somewhat higher in FeSSIF medium (approximately 50% of theoretical [9-ING-41]) than in either FaSSGF medium (approximately 20% of theoretical [9-ING-41]) or FaSSIF medium (approximately 10% of theoretical [9-ING-41]).

[0383] Erraglusib at 50 mg / mL in vehicle variant 7 (PEG400:EtOH:Tween80 94:5:1% w / w) was further developed as an oral solution dosage form. The specifications for the 50 mg / mL oral solution are summarized in Tables 1-4.

[0384] [Table 4]

[0385] HPLC was used to test for identity, assay purity, and related substances. Tables 1-5 show the operating parameters for the HPLC method chromatography.

[0386] [Table 5]

[0387] Characterization of drug product impurities HPLC showed two related substances, namely: Related substances eluting at a relative retention time (RRT) of 0.96, and An anhydrous analog of erraglusib eluting at a relative retention time of RRT1.21

[0388] Example 2A Preparation of amorphous solid dispersions (ASD) Characterization of erraglusib starting material The starting erraglusib was characterized using XRPD, PLM, TGA, and DSC. XRPD showed that the material was crystalline. The PLM image showed plate-like birefringent particles characteristic of a semi-crystalline solid. The TGA plot showed a weight loss of 0.91%, indicating the anhydrous nature of the material, while the DSC plot showed an endothermic peak corresponding to a melting point of 227.1°C (onset). These data plots indicate that erraglusib is a crystalline solid in Form I. Methods for preparing erraglusib Form I are known in the art. See U.S. Pat. No. 11,136,334.

[0389] Erraglusib has a Tg of about 111°C (384.15K) and a Tm of about 228°C (501.15K), resulting in a Tm(K) / Tg(K) ratio of about 1.3 and a cLogP value of about 4.3. To maintain the API in an amorphous state, the Tg of the ASD is preferably above 80°C. Both the erraglusib:CAP ASD and the erraglusib:EL100 ASD are characterized by a Tg of about 106°C.

[0390] The HPLC reference standard was a standard stock solution of 0.2 mg / mL erraglusib in acetonitrile. The acquisition method included 438 nm detection. The HPLC analysis detected both the API and related substance peaks with a relative retention time (RRT) of 0.97.

[0391] Amorphous Solid Dispersion (ASD) Screening and Characterization Solubility analysis of erraglusib and polymers The approximate solubility of both erraglusib (Table 2A-1) and the target stabilizing polymer (Table 2A-2) was tested individually in solvents commonly used for spray drying. Additionally, more quantitative solubility values for erraglusib were also obtained by high-performance liquid chromatography (HPLC) in the presence of organic solvents, with or without surfactants (Table 2A-3). Among the organic solvents tested, tetrahydrofuran (THF) or a THF-containing solvent mixture demonstrated the highest solubility for erraglusib. XRPD analysis of solids recovered from some solubility experiments at 24 hours showed that samples containing THF solvent converted to THF solvates, whereas samples with only water and surfactant did not show any morphological change. Approximate solubility checks were performed on the polymers to ensure that sufficient amounts could be dissolved to achieve a 50% w / w drug loading as the solubility of the API in a particular solvent. The results of the experiments showed that, except for hypromellose acetate succinate (HPMCAS) in dichloromethane:acetone (5:1), all other polymer and solvent combinations tested could be used to prepare 1:1 mixtures of API and polymer (Table 2A-4).

[0392] [Table 6]

[0393] [Table 7-1]

[0394] [Table 7-2]

[0395] [Table 8]

[0396] [Table 9]

[0397] ASD screening ASD screening was performed using erraglusib starting material and various polymers. A total of 24 screening experiments were performed to prepare ASDs. Of these, five experiments were performed by blowing the solvent at 50% w / w drug loading, four experiments were performed by rotavap drying at 25% w / w drug loading, and 15 experiments were performed by rotavap drying at 50% w / w drug loading. ASDs were first obtained by rapid evaporation of the solvent, which was achieved by blowing. In these experiments, to achieve a 50% w / w drug loading, a solution containing 150 mg of API and 150 mg of polymer was prepared in 4 ml of the desired solvent. The solution was sonicated for 5 minutes, followed by visual analysis to ensure it was clear, and then the solution was rapidly evaporated by exposure to a stream of air. The resulting solid was analyzed by XRPD.

[0398] The characterization results are summarized in Table 2A-5.

[0399] [Table 10]

[0400] The results showed that only the Plasdone S-630 polymer resulted in amorphous material, while all others produced crystalline acetone solvates.

[0401] To successfully obtain more amorphous hits, the rotavap was used with only 25% drug loading. To prepare ASDs on the rotavap, a solution of API and polymer (containing 25% API) was prepared in the desired solvent. The solution was sonicated for 5 minutes, followed by visual analysis to ensure clarity, and then the solution was kept in the rotavap at 50 mbar vacuum for 15 minutes. The resulting solid was kept in a vacuum oven at 30°C over the weekend. Samples were analyzed for glass transition temperature, Tg, by XRPD, TGA, and DSC. All results are summarized in Table 2A-6.

[0402] [Table 11]

[0403] A 50% drug loading screen was performed using a rotavap. In this screen, a larger volume of solvent (e.g., more dilution), ≥ 6 mL (compared to the 4 mL used previously), was used to dissolve 150 mg of erraglusib and 150 mg of polymer, to prevent the risk of material precipitating in solution before performing the rotavap or spray drying experiments. The results of these screens and formulation characterization are summarized in Table 2A-7.

[0404] [Table 12]

[0405] These experiments demonstrated that most experiments produced amorphous material, with the exception of hypromellose (HPMC) K4M produced from THF:water (7:3), HPMCP55 produced from DCM:EtOH (1:1), HPMCAS produced from DCM:MeOH (7:3), and povidone K30 produced from THF:water (4:3), which showed crystalline material. Thus, a total of 11 amorphous formulations were obtained at 50% drug loading. These ASDs were characterized by mDSC and TGA to determine their Tg and total residual solvent / water content, respectively. mDSC was performed in both pinhole-free and pinhole-containing sealed pans to determine the Tg in the presence of residual solvent (i.e., wet Tg) and the Tg of the solid after solvent removal (i.e., dry Tg), respectively. The results related to the mDSC and TGA analyses are summarized in Table 2A-7.

[0406] Kinetic solubility in biologically relevant media The kinetic solubilities of six erraglusib ASD compositions were measured in biorelevant media at 37°C. The three biorelevant media were SGF, FaSSIF, and FeSSIF. These were prepared using FaSSIF / FeSSIF / FaSSGF powders and procedures obtained from Biorelevant.com (https: / / biorelevant.com / learning_center / how-make-fassif / ). Suspensions of each ASD were prepared in SGF, FaSSIF, and FeSSIF, respectively, and stirred at 400 rpm. Aliquots of the supernatant were removed at 1 and 2 hours, syringe-filtered using cellulose acetate filters (0.22 μM pore size), and analyzed by HPLC. The solubility of each ASD in SGF, FaSSIF, and FeSSIF is presented in Tables 2A-8, 2A-9, and 2A-10, respectively. Solubility assessments showed that all ASDs had higher solubilities in FaSSIF and FeSSIF compared to SGF. Additionally, at the 2-hour time point, the remaining solids were analyzed by XRPD. The data indicated that all ASDs remained amorphous after the solubility analysis. XRPD of some of the samples recovered from SGF and FaSSIF showed the presence of a peak at approximately 32°2θ, which corresponds to residual NaCl (from the buffer) that had crystallized on the ASD solid. Additionally, the data also showed that after 2 hours of dissolution in FeSSIF, most ASDs had peaks at approximately 9°2θ, 17.5°2θ, 26°2θ, and approximately 36°2θ. These peaks correspond to residual FeSSIF buffer that had crystallized on the ASD solid upon drying. (See Tables 2A-8, -9, and -10.)

[0407] [Table 13]

[0408] [Table 14]

[0409] [Table 15]

[0410] ASD stability analysis Six selected ASDs were stored at accelerated conditions of 40°C / 33% RH and 40°C / 75% RH and experiments were conducted to monitor the stability of the ASDs by XRPD, mDSC, and TGA at different time intervals. All six ASDs stored at 40°C / 33% RH for two weeks remained amorphous according to the XRPD data. See Figure 4. Similarly, all six ASDs stored at 40°C / 75% RH for three weeks also remained amorphous according to XRPD. See Figure 5. All six ASDs (both stored at 40°C / 33% RH and 40°C / 75% RH) were reanalyzed by XRPD again at nine weeks and found to be amorphous. See Figures 6 and 7. In addition to determining the Tg values and total residual solvent / water content of the ASD formulations, the six ASDs after exposure to accelerated conditions were characterized by mDSC and TGA. mDSC for stability samples was performed in sealed pans without pinholes to determine the Tg in the presence of residual solvent or moisture (i.e., wet Tg). Results related to the mDSC and TGA analyses are summarized in Table 2A-11.

[0411] [Table 16]

[0412] Scaled-up preparation of Elra:PVAP (50% amorphous erraglusib in PVAP) by spray drying from THF Elra:PVAP ASD (50% w / w amorphous erraglusib in PVAP polymer) was prepared by dissolving 24 mg of erraglusib and 24 mg of PVAP in 600 mL of THF, followed by spray drying using a Buchi™ B-290 spray dryer equipped with a B-295 inert loop. The spray drying parameters are listed in Table 2A-12. Approximately 26 mg of Elra:PVAP was obtained and dried at room temperature in a vacuum oven for 2 days. The XRPD of Elra:PVAP, shown in Figure 8, indicates that the material is amorphous. The PLM image, shown in Figure 9, indicates that the material consists of aggregates of spherical, nonbirefringent particles. mDSC indicated that the material had a Tg of 60.3°C, and its TGA showed a 7.33% weight loss up to 150°C (see Figure 10). The material was subjected to further drying, and residual solvent was monitored intermittently by TGA. The results are presented in Table 2A-13. TGA indicates that the material further dried in a vacuum oven at temperatures between 30°C and 40°C for 9 days lost 5.09% of its weight up to 150°C. By performing mDSC on this further dried material, the Tg of the material in the DSC pan without a pinhole and the material in the DSC pan with a pinhole was determined and found to be 71.8°C and 77.8°C, respectively (Figure 11). KF (Karl Fisher water analysis) indicated the presence of 3.0% water (KF oven temperature 200°C).

[0413] Drug loading was assessed by HPLC triplicate by dissolving approximately 25 mg of Elra:PVAP in 100 mL of THF:HO:ACN (20:40:40). The resulting drug loading was further corrected by accounting for the weight loss by TGA of the material used in the HPLC assay. The corrected drug loading was found to be 46.42% w / w (Table 2A-14), and the HPLC chromatogram (monitored at 438 nm) showed only the presence of the API peak and a peak of a known (erraglusib anhydrate) related substance at RRT 1.23 (Figure 12). PSD (particle size distribution) of the sample was performed using a Malvern Mastersizer instrument. Approximately 50 mg of sample was dispersed in 10 mL of 0.25% lecithin in Isopar-G, followed by PSD analysis in triplicate without sonication. The data showed that the D10, D50, and D90 particle size distributions were 0.22, 7.94, and 24.97 μm, respectively (Table 2A-15). The PSD profile of this material was clearly bimodal, as shown in Figure 13.

[0414] [Table 17]

[0415] [Table 18]

[0416] [Table 19]

[0417] [Table 20]

[0418] Scaled-up preparation of Elra:CAP (50% amorphous erraglusib in CAP) from THF by spray drying Elra:CAP ASD (50% w / w amorphous erraglusib in CAP polymer) was prepared by dissolving 24 mg of erraglusib and 24 mg of CAP in 600 mL of THF, followed by spray drying using a Buchi™ B-290 spray dryer equipped with a B-295 inert loop. The parameters used for spray drying are listed in Table 2A-16. Approximately 29 mg of ASD was obtained, which was dried in a vacuum oven at room temperature for 2 days. The XRPD of Elra:CAP ASD is shown in Figure 14 and indicated that the material was amorphous. A PLM image is shown in Figure 15 and indicates that the material has aggregates of irregularly shaped, non-birefringent particles. mDSC indicated that the material had a Tg of 84.2 °C, while TGA showed a 4.62% weight loss up to 150 °C (Figure 16). Further drying was carried out while intermittently monitoring residual solvent by TGA, as shown in Table 2A-17. TGA of the further dried material showed a weight loss of 2.90% up to 150°C, while mDSC of the further dried material was also performed to determine the Tg of the material in DSC pans without and with a pinhole, which were found to be 87.0°C and 87.0°C, respectively (Figure 17). KF indicated the presence of 2.9% water (KF oven temperature 200°C).

[0419] Drug loading was assessed by HPLC triplicate by dissolving approximately 25 mg of Elra:CAP ASD in 100 mL of THF:HO:ACN (20:40:40). The resulting drug loading was further corrected by accounting for the weight loss by TGA for the material used in the HPLC assay. Elra:CAP ASD had a corrected drug loading of 46.98% w / w (Table 2A-18), and the HPLC chromatogram showed only the API peak and a known related substance peak (erraglusib anhydrate) at RRT 1.23 (Figure 18).

[0420] Particle size distribution (PSD) of the samples was also performed using a Malvern Mastersizer instrument. Approximately 50 mg of sample was dispersed in 10 mL of 0.25% lecithin in Isopar-G, followed by PSD analysis in triplicate without ultrasonic treatment. The average D10, D50, and D90 particle size distributions were 2.38, 7.34, and 16.73 μm, respectively (Table 2A-19). The PSD profile of this material showed either a unimodal or bimodal distribution of particles, as shown in Figure 19.

[0421] [Table 21]

[0422] [Table 22]

[0423] [Table 23]

[0424] [Table 24]

[0425] Elra:PVAP and Elra:CAP (scaled up) kinetic solubility experiments The kinetic solubility profiles of Elra:PVAP ASD and Elra:CAP ASD were measured in biorelevant media at 37°C. Suspensions of each ASD were prepared in three biorelevant media: SGF, FaSSIF, and FeSSIF. These suspensions were stirred at 400 rpm. Aliquots of the supernatant were removed at 5, 10, 30, and 4 hours. The samples were syringe-filtered using cellulose acetate filters (0.22 μM pore size) and analyzed by HPLC. The solubility profiles of these ASDs in SGF, FaSSIF, and FeSSIF are presented in Table 2A-20. The solubility evaluation showed that both ASDs had higher solubility in FaSSIF and FeSSIF compared to SGF, and that Elra:PVAP had higher solubility compared to Elra:CAP under similar conditions. Additionally, XRPD of the solids collected at the 4 hour time point after solubility analysis showed that both ASDs remained amorphous after dissolution (Figure 20). XRPD of samples collected from SGF and FaSSIF showed the presence of a peak approximately 32°2θ, which corresponds to crystallized residual NaCl (from the buffer).

[0426] [Table 25]

[0427] Elra:PVAP and Elra:CAP ASD stability experiments To check the susceptibility of both Elra:PVAP and Elra:CAP ASDs to crystallization under accelerated stability conditions, each ASD was stored at 5°C, 40°C / 33% RH, and 40°C / 75% RH and monitored by XRPD, mDSC, TGA, and HPLC at 6 and 12 weeks. Both stored ASDs remained amorphous up to 12 weeks of storage under the conditions described above (Figure 21). mDSC of the stability samples was performed in pinhole-free sealed pans to determine the Tg in the presence of residual solvent or moisture (i.e., wet Tg). Results related to the mDSC and TGA analyses are summarized in Table 2A-21 and presented in Figures 22 and 23. Both ASDs stored at 40°C / 33% RH for 6 weeks exhibited the lowest weight loss and highest Tg compared to the other storage conditions, which may be a result of partial drying of the samples at 40°C / 33% RH (compared to the initial storage conditions of the starting materials, 25°C and 60-70% RH). In most of these conditions, the Tg of both ASDs was within 10% of the initial Tg value, except for Elra:CAP, which showed a reduction in Tg value of approximately 11.5% compared to the initial Tg.

[0428] HPLC analysis of ASD stored under all three conditions showed no degradation when monitored at 438 nm, but only showed a peak for a known impurity at an RRT of approximately 1.26. The HPLC samples monitored at 438 nm and their respective % area purity profiles are presented in Tables 2A-22 and 2A-23. The data showed that the % area purity remained approximately 99% for all initial (t=0) and stability samples. HPLC chromatograms using HPLC monitored at 210 nm were also obtained for samples stored under different conditions for 12 weeks. The results showed that the % area purity remained approximately 99% for all stability samples (Tables 2A-24 and 2A-25). These results collectively indicated that both ASD samples were physically and chemically stable at 40°C / 33% RH and 40°C / 75% RH for up to 12 weeks.

[0429] An overlay of erraglusib, Elra:CAP, and Elra:PVAP ASD by ssNMR shows a baseline-resolved peak for the API at 87 ppm, indicating a suitable location for monitoring the stability of ASD batches for crystallization under stability-enhancing conditions (Figure 24). First derivatives were applied to the stability sample spectra (Figures 25-29). For pure amorphous samples, ssNMR produces a Gaussian curve, which, when applied to the first derivative, results in a flat baseline. Crystalline material produces a Laplacian curve by ssNMR, which can be clearly observed after applying the first derivative.

[0430] The signal-to-noise ratio of the API standard was 8.18. In all four stability samples, the signal-to-noise ratio of the first derivative peak at 87 ppm remained <2. The results are summarized in Table 2A-26.

[0431] CPMAS ssNMR results showed that there was no detectable crystallization in any of the ASDs tested after exposure to both stability test conditions.

[0432] [Table 26]

[0433] [Table 27]

[0434] [Table 28]

[0435] [Table 29]

[0436] [Table 30]

[0437] [Table 31]

[0438] Analytical Methods: Characterization of ASD Powder HPLC testing of Elra:CAP. 10.254 mg of Elra:CAP ASD from bottle 1 and 10.465 mg from bottle 2 were transferred to separate 50 mL volumetric flasks. Diluted to volume with acetonitrile and mixed well to dissolve. The solution was filtered through a 0.45 μm PVDF filter to remove small clear crystals from the solution. The solution was transferred to an HPLC vial and stored at 5° C. The expiration date was 5 days.

[0439] HPLC testing of Elra:PVAP. 10.177 mg of 9-ING-41-Phth ASD from bottle 1 and 10.105 mg from bottle 2 were transferred to separate 50 mL volumetric flasks. Diluted to the specified volume with acetonitrile and mixed well to dissolve. The solution was sonicated to break up any white clumps that had formed. The solution was filtered through a 0.45 μm PVDF filter to remove any insoluble particles from the solution. The solution was transferred to an HPLC vial and stored at 5° C. The expiration date was 5 days.

[0440] ATR FT-IR analysis of ASD powders: CAP polymer, PVAP polymer, Elra:CAP ASD, Elra:PVAP ASD, and erraglusib API were analyzed using an FT-IR attenuated total reflectance (ATR) accessory. A background run (16 scans) was run before each sample. A small sample was placed on the ATR crystal and the pressure plate was tightened. 16 scans were performed for each sample. After each analysis, the crystal was washed with isopropanol.

[0441] XRPD analysis: XRPD was performed using a Panalytical X' Pert3 Powder XRPD on a Si zero background holder. 2θ positions were calibrated against Panalytical Si reference standard discs. XRPD parameters are listed in Table 2A-27.

[0442] [Table 32]

[0443] TGA / DSC Analysis: TGA data was collected using a TA Discovery 550 TGA manufactured by TA Instrument. DSC was performed using a TA Q2000 DSC manufactured by TA Instrument. The DSC was calibrated using an indium reference standard, and the TGA was calibrated using a nickel reference standard. The detailed parameters used are listed in Table 2A-28.

[0444] [Table 33]

[0445] mDSC Analysis: mDSC was performed using a TA Q2000 DSC from TA Instrument. The DSC was calibrated with an indium reference standard. The detailed parameters used are listed in Table 2A-29.

[0446] [Table 34]

[0447] PSD analysis: A Malvern (Mastersizer 3000E) particle size analyzer with a Hydro EV attachment was used. The parameters used are listed in Table 2A-30:

[0448] [Table 35]

[0449] ssNMR: Solid-state NMR experiments were performed on a two-channel Bruker NEO spectrometer (Bruker, Billerica, MA) operating at 100.52 MHz for 13C and 399.71 MHz for 1H. Data were acquired using a Chemagnetics APEX probe retrofitted with a 7 mm magic-angle spinning module (Spinning NMR, Fort Collins, CO). Each sample was packed into a 7 mm zirconia rotor using a Kel-F spacer. The magic-angle spinning (MAS) frequency used for all data acquisition was 5 kHz. 13C chemical shifts were reported with an accuracy of ±0.4 ppm relative to the methyl peak of 3-methylglutaric acid at 18.84 ppm.

[0450] The saturation recovery method was used to measure the 1H T1 relaxation time. 13C spectra were collected using a presaturation period (1H π / 2, 15 μs delay, loop 20×), a variable delay, an 1H π / 2 pulse followed by a complete suppression of spinning sidebands by cross-polarization (CPTOSS) sequence, and 1H SPINAL-64 decoupling. 1H T1 values of the samples were determined using the T1T2 function in the Bruker Topspin 4.0.8 software package. 1H T1rho values of the samples were determined using a 1H π / 2 pulse, a variable pulse duration (0.5–64 ms), followed by a complete suppression of spinning sidebands by cross-polarization (CPTOSS) sequence, and 1H SPINAL-64 decoupling. 1H T1rho values of the samples were determined using the T1T2 function in the Bruker Topspin 4.0.8 software package. High quality at 5 kHz MAS using a CPTOSS sequence, 1.5 ms contact time, and 3960 acquisition points (approximately 50 ms acquisition time). 13 C CPTOSS spectra were acquired. Data collection was performed at a nominal temperature of 18.5 °C. 13C (KAS-RS-011, MGA) Information: 13C chemical shifts are reported with an accuracy of ±0.4 ppm at 18.84 ppm relative to the methyl peak of 3-methylglutaric acid (MGA, KAS-RS-011). KAS-RS-011 (3-methylglutaric acid, batch number 0000062292) was purchased from SIGMA Aldrich and used as is without further purification.

[0451] Data were processed using the Topspin 4.0.8 (Copyright) software package from Bruker Biospin. Data were Fourier transformed using the full FID (1536 points) and 0 Hz line broadening, phase adjusted (apk), and baseline corrected (abs). Manual phase adjustment was performed when necessary.

[0452] Unsubtracted 13 C spectra were acquired and then fully automated processing was performed using the "Generate First Derivative" function in the Topspin software package. The first derivative spectra were then processed using the automatic phase adjustment (apk) in the Topspin software. S / N calculations were then performed using the "sinocal" AU-program in Topsin with the following parameters: left limit = 93 ppm, right limit = 91.5 ppm, left limit of noise range = 300 ppm, right limit of noise range = 250 ppm, noise width = 8 ppm.

[0453] HPLC Method 1 was used for solubility, stability monitoring at 438 nm, and drug loading determination of ASD, and is summarized in Table 2A-31. HPLC Method 2 was used for stability monitoring at 210 nm, and is summarized in Table 2A-32.

[0454] [Table 36]

[0455] [Table 37]

[0456] Preparation of bulk ASD powder for encapsulation Formulation of Elra:CAP Blend with Croscarmellose Sodium:Silica (90:10) A 90:10 croscarmellose sodium:silica blend was prepared by combining 45.02 g of croscarmellose sodium and 5.00 g of colloidal silica in a large mortar and pestle, and thoroughly mixed. In a humidity chamber, 1.00 g of the 90:10 croscarmellose:silica blend was added per 19.04 g of Elra:CAP ASD and mixed together in a mortar / pestle to produce 20 g of formulation (95:4.5:0.5 ASD:croscarmellose sodium:silica) for capsule filling.

[0457] Formulation of Elra:PVAP Blend with Croscarmellose Sodium:Silica (90:10) In a humidity chamber, 1.00 g of croscarmellose sodium:silica (90:10) blend was added per 19.00 g of Elra:PVAP ASD and mixed together in a mortar / pestle to produce 20 g of formulation (ASD:croscarmellose sodium:silica 95:4.5:0.5) which was filled into capsules.

[0458] Hard capsule filling Both ASD powders were formulated with a 90:10 blend of croscarmellose sodium:silica as a bulking agent (ratio of 19 to 1) to improve powder flow and capsule solubility. Fill size number 00 hard gelatin capsules were sized to fit 200 mg of ASD powder; target dose 90 mg erraglusib (= 45% w / w ASD of 200 mg). Two ASD formulations: Elra:CAP Elra:PVAP.

[0459] Preparation of Elra:CAP ASD capsules Approximately 235 mg of the Elra:CAP blend was filled into 60 size No. 00 light-resistant hard gelatin capsules at low humidity (≦20% RH) with croscarmellose sodium:silica. The capsules were placed in HDPE screw-cap bottles at low humidity (≦10% RH), 12 capsules per bottle. The bottles were stored at ambient temperature, protected from light. The Elra:CAP capsule contents appeared as an orange, free-flowing powder.

[0460] Preparation of Elra:PVAP ASD capsules Approximately 235 mg of the Elra:PVAP blend was filled into 60 size No. 00 light-resistant hard gelatin capsules at low humidity (≦20% RH) with croscarmellose sodium:silica. The capsules were placed in HDPE screw-cap bottles at low humidity (≦10% RH), 12 capsules per bottle. The bottles were stored at ambient temperature, protected from light. The Elra:PVAP capsule contents appeared as an orange, free-flowing powder.

[0461] Hard capsule characterization Ten empty capsules were weighed, and the mean and standard deviation were determined. Three Elra:CAP capsules and three Elra:PVAP capsules were opened, and the contents were weighed. The contents of three Elra:CAP capsules and three Elra:PVAP capsules were individually prepared for HPLC. The HPLC results are summarized in Tables 2A-33 to 2A-35.

[0462] [Table 38]

[0463] [Table 39]

[0464] [Table 40]

[0465] Dissolution chamber setup A 3% w / v sodium dodecyl sulfate (SDS) solution was prepared. 180.0239 g of SDS was transferred to a 6 L volumetric flask. The solution was diluted to the specified volume with milliQ water and mixed well. It was stored at ambient temperature with a one-month expiration date. Using a graduated cylinder, 900 mL of 3% SDS was added to each dissolution vessel (six vessels total). The bath temperature was set to 37.5°C, and the vessels were allowed to equilibrate for approximately 15 minutes with gentle agitation at 50 rpm. The average vessel temperature before capsule addition was 37.4°C. Two capsules were added to each vessel. Vessels 1-3 contained Elra:CAP capsules, and vessels 4-6 contained Elra:PVAP capsules. 5 mL samples were taken at 0.5, 1, 2, and 4 hours. Each Elra:CAP dissolution sample withdrawn at the indicated time point was a cloudy orange solution with no precipitate. Both Elra:CAP and Elra:PVAP capsules completely dissolved in 3% aqueous SDS dissolution medium within 0.5 hours. Visual inspection revealed that the Elra:CAP dissolution sample was slightly turbid, while the Elra:PVAP dissolution sample was clear. Each Elra:PVAP dissolution sample withdrawn at the indicated time point was a clear, orange solution with no precipitate. Samples were diluted 1:1 with acetonitrile and filtered through a 0.45 μm PVDF filter before transferring to amber HPLC vials. HPLC samples were stored at 5°C before analysis. Solubility characteristics are summarized in Tables 2A-36 and 2A-37.

[0466] [Table 41]

[0467] [Table 42]

[0468] Example 2B Elra:CAP ASD, erraglusib and micronized erraglusib tablet formulations Tablets containing either Elra:CAP ASD of the present disclosure, erraglusib API, or micronized erraglusib API were prepared as described below.

[0469] The materials used in the Elra:CAP ASD tablet experiments are summarized in Table 2B-1 (raw materials) and Table 2B-2 (analytical reagents). The equipment used in the Elra:CAP ASD tablet development experiments is presented in Table 2B-3.

[0470] [Table 43]

[0471] [Table 44]

[0472] [Table 45]

[0473] Test Method for Example 2B HPLC studies were performed using an Agilent 1100 series HPLC equipped with CHEMSTATION data acquisition software.

[0474] Chromatographic separation was achieved using a Waters Atlantis T3 4.6 x 150 mm, 3 μm column, with parameters provided in Table 2B-4. Testing was performed using an external standard prepared at 0.2 mg / mL erraglusib in diluent. Test samples for the tablet prototype were prepared by serial dilution to a target concentration of 0.2 mg / mL erraglusib. All samples were diluted as needed on a Sotax TPW automated sample preparation workstation. Case-by-case validation preparations were prepared using volumetric flasks.

[0475] [Table 46]

[0476] Dissolution test Dissolution was performed on a Sotax MD automated dissolution apparatus with in-line UV detection. An erraglusib standard was used for quantification of percent dissolved using UV absorbance at 282 nm. Dissolution studies were performed using the parameters shown in Table 2B-5.

[0477] [Table 47]

[0478] Karl Fischer water content Water content was determined by performing a volumetric Karl Fischer (KF) titration using a Mettler Toledo V20S KF titrator. Titration standardization was performed using Water Standard 10.0 and Check P solution. A 300 mg sample size was used for the KF water titration.

[0479] Bulk and tapped density USP <616> Bulk and tapped density determinations were performed according to Method I. To determine bulk density, the test article powder was dispensed into a 50 mL graduated cylinder and the weight of the test article was recorded. The mass of the powder in the measuring vessel was determined and divided by the volume of the test article.

[0480] To determine tap density, the graduated cylinder was tapped until the volume stopped changing. After tapping, the final powder volume was recorded. The tap density was calculated by dividing the initial mass by the final volume.

[0481] The Hausner ratio and compression index were calculated using the experimental bulk and tapped densities using Equation 1 and Equation 2, respectively.

[0482]

number

[0483]

number

[0484] hardness Using a Varian VK200 tablet hardness tester, USP <1217> Tablet hardness was determined according to the following.

[0485] Collapse Using Sotax DT50 and distilled water, USP <701> The disintegration test was carried out according to the method described above.

[0486] friability A Sotax FT2 friability tester was used for friability testing by tumbling tablets weighing 6.5 g or larger at 25 rpm for 4 minutes for a total of 100 revolutions.

[0487] Focused beam reflectance measurement A Focused Beam Reflectance Measurement (FBRM) probe (Model Lasentec® S400, Mettler Toledo, Columbia, MD) was used to measure particle size distribution. An overhead mixer on a beaker fixture stand (Lasentec® S400 Mixer Controller) was used to keep particles in suspension throughout the test. The acquisition and analysis software was iC-FBRM™ version 4.3 (Mettler Toledo, Columbia, MD).

[0488] Compression Profile A Globe Pharma manual tablet compression machine model MTCM-1 equipped with 5 / 16-inch flat upper and lower punches and dies was used to generate compression profiles for the prepared tablets.

[0489] Powder X-ray diffraction X-ray powder diffraction (XRPD) was performed on the micronized and blended materials using a Rigaku-Miniflex 6G benchtop X-ray diffractometer. Approximately 100 mg of sample was pressed onto a non-diffracting silicon substrate using a circular siliconized glass slide. The X-ray source was operated at 40 kV and 15 mA. Sample data were collected over a range of 3 to 40° at a scanning rate of 0.4 degrees / min with a step size of 0.02°. Sample spinning was activated for all measurements.

[0490] Scanning electron microscopy Scanning electron microscopy (SEM) images were taken using a Phenom Pro in 10 kV high-resolution mode. Carbon paper was used as the conductive substrate. Samples were prepared by rolling a plastic spatula over a <100 mg sample, then carefully rolling it onto the double-sided adhesive carbon paper above the stage. The sample holder was rotated counterclockwise three times to position the sample approximately 2 mm below the upper stage for imaging.

[0491] Preparation of Elra:CAP ASD and Elra:CAP Tablets for Example 2B Preparation of Elra:CAP ASD: Erraglusib and CAP were weighed and dispensed into 1.0 L or 2.0 L graduated media storage bottles. The materials were dissolved in THF to produce an approximately 8% weight / weight (w / w) total solids spray solution. The solution was stirred for 30 minutes before spraying to ensure dissolution of all solids. A B-290 mini-spray dryer was set up according to the parameters summarized in Tables 2B-6 and 2B-7. After reaching a target oxygen percentage (NMT) of 6% or less (actual values: Lot 35044-004 - 4.6%, Lot 35044-030 - 2.0%), the heater was turned on and the inlet temperature was set to 100°C. Once the inlet temperature was reached, the outlet temperature was allowed to stabilize. Pure solvent was used until steady state was reached. Once steady state was reached, spraying of the erraglusib / CAP mixture in THF was initiated using a 30% pump flow rate and 14 L / S tubing. After spraying as much product as possible and allowing the apparatus to cool, the product was collected and oven dried at 60°C overnight.

[0492] [Table 48]

[0493] [Table 49]

[0494] Spray drying of Elra:CAP in tetrahydrofuran was successfully completed and a spray drying summary is presented in Tables 2B-8 and 2B-9.

[0495] [Table 50]

[0496] [Table 51]

[0497] Elra: ASD characterization: Elra:CAP batch 35044-004 was characterized by XRPD, which showed a monomodal distribution characteristic of amorphous material (Figure 31). SEM imaging was used to investigate the morphology of the ASD, as shown in Figure 32. The images showed a mixed morphology of hollow, collapsed, and shattered spheres, typical of spray-dried material.

[0498] ASD production of a 50:50 mixture of Elra:CAP batch 35044-004 was completed with an overall yield of 78%. XRPD confirmed the amorphous nature of the final product, and SEM imaging showed a mixed morphology typical of the ASD process.

[0499] Elra:CAP ASD Granules Batch 35044-014: Prior to granulation, the Elra:CAP ASD was passed through a #20 mesh screen. All intragranular ingredients except magnesium stearate were then added to a 250 mL high density polyethylene (HDPE) bottle and blended for 50 revolutions. The magnesium stearate was added to the mixture, and the ingredients were blended for an additional 50 revolutions.

[0500] The preblends were roller compacted using a Gerteis compactor with the parameters summarized in Table 2B-10. The blends were collected in 500 mL HDPE bottles and weighed to calculate adjustment factors for extragranular excipients. The extragranular excipients were added and the mixture was blended to produce the final blends.

[0501] [Table 52]

[0502] Elra:CAP ASD Granules Batch 35044-019: Approximately 1 g of the preblend was used to prepare the compact using a manual tablet compression machine (MTCM-1, Globe Pharma) equipped with a Gerteis compression simulator (target force of 12.5 kN, which equates to approximately 3200 psi on the MTCM-1). The compact was milled through a 1.25 mm screen to produce a free-flowing granulated blend. Extragranular excipients were added and the mixture was blended for 50 revolutions to produce the final blend.

[0503] Elra:CAP ASD Tablets: Tablets were compressed using an MTCM-1 or Korsch XP-1.

[0504] Non-micronized API dry granulation - Feasibility: Prior to granulation, erraglusib non-micronized API was passed through a #20 mesh screen. All intragranular ingredients, except magnesium stearate, were then added to a 250 mL HDPE bottle and blended for 50 revolutions. The magnesium stearate was added to the mixture, and the ingredients were blended for an additional 50 revolutions. A compact was prepared using approximately 1 g of the pre-blend using an MTCM-1 equipped with a Gerteis compression simulator (a target force of 12.5 kN, which equates to approximately 3200 psi on the MTCM-1). The compact was milled through a 1.25 mm screen to produce a free-flowing granulated blend. Extragranular excipients were added, and the mixture was blended to produce the final blend.

[0505] Non-micronized API dry granulation - prototype: Prior to granulation, erraglusib non-micronized API was passed through a #20 mesh screen. All intragranular ingredients, except magnesium stearate, were then added to a 500 mL HDPE bottle and blended for 10 minutes at 25 revolutions per minute (rpm). Magnesium stearate was added to the mixture, and the ingredients were blended for an additional 5 minutes at 25 rpm. The preblend was roller-compacted using a Gerteis compactor with the parameters summarized in Table 2B-11. The blend was collected in a 500 mL HDPE bottle, weighed, and the adjustment factors for the extragranular excipients were calculated. Extragranular microcrystalline cellulose (MCC) and croscarmellose sodium (CSS) were added, and the mixture was blended for 5 minutes at 25 rpm. Magnesium stearate was sieved through a #20 mesh, added to the mixture, and blended for 5 minutes at 25 rpm to produce the final blend.

[0506] [Table 53]

[0507] Non-micronized API wet granulation - Feasibility: Prior to granulation, erraglusib non-micronized API was passed through a #20 mesh screen. The intragranular ingredients were added and blended in a mortar for 1 minute. Water for injection was added to 30% w / w at approximately 2.5 g / min. After wet massing the blend for 1 minute, the blend was transferred to an oven and placed in the oven at 60°C for 6 hours. At the end of this time, the loss on drying was measured and the dried blend was granulated using a 1.00 mm mesh. The blend was weighed and an adjustment factor for the extragranular excipients was calculated. The extragranular MCC and CSS were added to an HPDE container and the mixture was blended for 50 revolutions. Magnesium stearate was added to the mixture and blended for an additional 50 revolutions to produce the final blend.

[0508] Non-micronized API wet granulation - prototype: The intragranular ingredients were added to a high-shear wet granulator, followed by half of the MCC, followed by the non-micronized API and excipients and the remaining half of the MCC at the top of the 1.0 L bowl. The ingredients were homogenized by dry mixing for 3 minutes in a GlobePharma high-shear granulator 1-6 with an impeller speed of 300 rpm and a chopper speed of 1000 rpm. Wet granulation was initiated using an impeller speed of 300 rpm and a chopper speed of 1000 rpm with a spray rate of approximately 10 mL / min. After adding water to a target of 30% w / w, the spray was turned off and a 90-second wet massing period was performed to promote water distribution within the solids. The wet granules were then manually milled through a #6 screen (3.35 mm). The granules were fluid-bed dried using a SolidLab 1 with a 0.5 L bowl. The inlet air volume was set at 15 cubic feet per minute (CFM) at a temperature of 60.0°C. Once the product temperature reached 45°C, the wet-milled granules were charged into a fluid bed dryer. After 20 minutes of drying time, a loss on drying of less than 2.0% (Lot 35044-027-0.49%) was observed at 105°C. The dried granules were removed and manually milled through a 1.00 mm screen. The granulated blend was transferred to a 500 mL polypropylene bottle and weighed to calculate the adjustment factor for the extragranular excipients. Extragranular MCC and CSS were added, and the mixture was blended for 5 minutes at 25 rpm. Magnesium stearate was sieved through a #30 mesh (0.595 mm), added to the mixture, and blended for 3 minutes at 25 rpm to produce the final blend.

[0509] Elra:CAP ASD Tablets: Tablets were compressed using an MTCM-1 or Korsch XP-1.

[0510] Spray drying of Elra:CAP in tetrahydrofuran was successfully completed. The spray drying summary is presented in Tables 2B-12 and 2B-13.

[0511] [Table 54]

[0512] [Table 55]

[0513] Elra: ASD characterization: Elra:CAP from batch 35044-004 was characterized by XRPD (Figure 31), which shows a monomodal distribution characteristic of amorphous material. SEM imaging was used to examine the morphology of the ASD, which is shown in Figure 32. The images showed a mixed morphology of hollow, collapsed, and shattered spheres, typical of spray-dried material.

[0514] The preparation of ASD of a 50:50 mixture of Elra:CAP was completed with an overall yield of 78% (batch 35044-004). XRPD confirmed the amorphous nature of the final product, and SEM imaging showed a mixed morphology typical of the ASD process.

[0515] Micronized erraglusib API: Erraglusib API was micronized using a jet mill and evaluated for compressibility.

[0516] Characterization of micronized erraglusib API: To evaluate the micronization process, SEM images (Figure 33), particle size distribution (PSD, Figure 34), and XRPD (Figure 35) were performed on the erraglusib material before and after jet milling. The SEM, PSD, and XRPD data before and after milling were as expected. A bimodal particle size distribution was observed after milling, which may be due to a single pass through the mill.

[0517] API micronization has been successfully performed to produce a material with improved compressibility over the unmilled material. Particle size analysis showed a bimodal distribution for the micronized material, which can be further evaluated and optimized to produce a unimodal distribution.

[0518] Development of micronized API dry granulation formulations Formulation development is being designed for a micronized API dry granulation process to produce tablets with the formulation composition shown in Table 2B-14. Formulation 35044-008 was ultimately modified to utilize more extragranular microcrystalline cellulose (formulation 35044-015).

[0519] [Table 56]

[0520] Development of micronized API wet granulation formulations The formulation development is designed for micronized API wet granulation to produce tablets with the formulation composition shown in Table 2B-15.

[0521] [Table 57]

[0522] A GlobePharma high shear wet granulator was used to process the improved micronized API wet granulation formulation (35044-027). Granulation data is presented in Table 2B-16. The wet granules were manually milled through a #6 (3.35 mm) screen before the material was loaded into a 0.5 L fluid processing bowl. Fluid bed drying data is presented in Table 2B-17.

[0523] [Table 58]

[0524] [Table 59]

[0525] Wet granulation of micronized erraglusib API was successfully completed using high shear wet granulation, with minimal increases in power during granulation, indicating that additional water can be used to granulate.

[0526] Dissolution Dissolution of 6% w / w CTAB in 0.7 M sodium chloride was evaluated for wet and dry granulated ASD materials at paddle speeds of 75 rpm and 100 rpm.

[0527] Using the same conditions of 6% w / w CTAB in 0.7 M sodium chloride and a paddle speed of 100 rpm, the effect of compaction pressure on the observed dissolution profiles of dry and wet granulated materials was evaluated.

[0528] For testing of ASD materials, the dissolution medium was modified to 1% w / w CTAB in 0.7M sodium chloride. The dissolution profile of ASD tablets using 1% w / w CTAB in 0.7M sodium chloride was improved compared to 6% w / w CTAB in 0.7M sodium chloride, with no decrease in dissolution observed between 45 and 60 minutes. It is hypothesized that increasing the CTAB concentration may disrupt the ASD polymer, releasing the API from the complex.

[0529] [Example 3] Bioavailability Experiments PK Study 1: Bioavailability of IV Formulations in Dogs, Intravenous vs. Oral Administration The objective of this study was to evaluate the pharmacokinetic profile of erraglusib after single oral and intravenous doses in beagle dogs.

[0530] The test article (erraglusib in a vehicle of 85% PEG400, 10% ethanol, 5% water (all components wt / wt / wt)) was administered orally and via intravenous infusion to dogs according to the table below.

[0531] Male beagle dogs were selected for use in this study. Animals were male, at least 6 months of age, and weighing approximately 9.3 to 10.8 kilograms at the time of initiation of dosing.

[0532] Experimental animals received a single oral dose of erraglusib, followed by a washout period of approximately 7 days, followed by a single intravenous infusion of erraglusib. Animals underwent standard evaluations, such as weight and clinical observations, and blood was collected for pharmacokinetics after each dose. The experimental design is summarized in Table 3-1 below:

[0533] [Table 60]

[0534] Plasma concentrations of erraglusib were determined in dogs treated with 20 mg / kg erraglusib via oral administration on Day 1 and then again via intravenous infusion on Day 8. Systemic exposure was achieved in all animals after oral and intravenous administration of erraglusib. Intravenous administration resulted in higher erraglusib plasma concentrations compared with oral administration. Individual plasma concentrations were highest approximately 2 to 8 hours after oral administration (1,410 to 1,880 ng / mL) and approximately 5 minutes after intravenous administration (11,800 to 13,600 ng / mL).

[0535] Overall, half-lives were similar for both oral and IV routes of administration. Group mean C max The AUC value for the IV route was approximately 7.5 times larger than that for the PO route. last was approximately three times greater with the IV route than with the PO route. Comparing the plasma AUC values for oral gavage dosing (21,300 hr*ng / mL) with those for IV infusion (68,900 hr*ng / mL) allowed the oral percentage bioavailability (%BA) to be estimated as follows: 100*(21,300 / 68,900)=31%BA. A summary of the PK parameters by route is shown below:

[0536] [Table 61]

[0537] [Table 62]

[0538] PK Study 2 - Bioavailability of Oral Solution, Oral Suspension, and Elra:CAP and Elra:PVAP Capsule Dosage Forms in Dogs A five-way crossover study was conducted in which three animals were initially dosed at 10 mg / kg by IV infusion using 10 mg / mL erraglusib in PEG400:EtOH:water (85:10:5% w / w).

[0539] Three male treatment-experienced and / or treatment-naive beagle dogs were selected for use in this study. The animals were 7-12 months old and weighed 8-12 kilograms at the start of the quarantine period for this study. Actual weight and age may vary but will be recorded and maintained in the raw data.

[0540] Approximately 250-350 grams of Harlan Teklad Certified Canine Diet No. 2025 (or other appropriate diet as recorded in the study log) was provided to each animal daily. Each lot of diet was analyzed for contaminants to ensure the absence of any contaminants at concentrations expected to interfere with the conduct or purpose of the study. In addition, each dog was fed a commercially available canned dog food to ensure the animals were fed prior to dosing. One-half to one can of canned dog food was offered at least one hour before each dose. The lot and brand of dog food were recorded in the study log.

[0541] The study consisted of a single group of three dogs, each receiving five doses of erraglusib formulations, separated by a minimum three-day washout period. The first dose was a single intravenous (IV) infusion of erraglusib TA #1 (10 mg / mL in PEG400:EtOH:water, 85:10:5% w / w), followed by oral TA #2 (Elra:CAP capsules, 100 mg erraglusib), followed by oral TA #3 (Elra:PVAP capsules, 100 mg erraglusib), followed by oral gavage of TA #4 (2 mg / mL oral suspension), followed by oral gavage of TA #5 (50 mg / mL oral solution). Animals underwent standard evaluations, e.g., weight and clinical observations, and blood samples were taken for pharmacokinetics before and after each dose. The experimental design for Experiment 2 is summarized in Table 3-4.

[0542] [Table 63]

[0543] Dogs received a single 15-minute intravenous infusion of the test article into the cephalic vein (or other appropriate blood vessel). The test article (TA #1) was infused into the cephalic vein (or other appropriate blood vessel). After IV administration, dogs received four additional oral (gavage or capsule) doses of the test article (TA #2, 3, 4, and 5) in order of test article number. Doses for IV and gavage dosing were based on most recent body weight. For capsule administration, prefilled capsules were weighed prior to dosing and back-calculated based on the dog's body weight.

[0544] Blood samples were collected from the jugular vein (or other suitable blood vessel) of each dog into 2 mL vacutainer tubes containing K2EDTA as an anticoagulant at the following time points: a) Intravenous administration: (0) before and at 5, 15, 30, 60 minutes, and at 2, 4, 8, and 24 hours after the end of the infusion. The time zero (nadir) collection was taken approximately 24 hours before dosing. b) Oral administration: (0) before and at 15, 30, 60 minutes, and at 2, 4, 8, and 24 hours after dose administration. Collections at time zero (nadir) were collected within approximately 24 hours before dosing.

[0545] The animals were maintained on a specified feeding regimen and were provided with food immediately prior to dosing to ensure they remained fed during dosing. After a washout period, the same triplicates were dosed at either 20 mg / kg or 10 mg / kg with each of the four oral dosage formulations disclosed herein: 1) a dose of 20 mg / kg using a size 00 hard gelatin capsule containing 100 mg of Elra:CAP ASD; 2) 20 mg / kg dose using size 00 hard gelatin capsules containing 100 mg Elra:PVAP ASD; 3) a dose of 20 mg / kg using erraglusib 50 mg / mL oral solution in vehicle variant 7 (PEG400:EtOH:Tween80 94:5:1% w / w); 4) 10 mg / kg using erraglusib 50 mg / mL in vehicle variant 7 after dilution to a 2 mg / mL suspension in 5% dextrose for injection (D5W).

[0546] Blood samples were collected at regular intervals and plasma [erraglusib] determination was performed using a validated LC-MS / MS method.

[0547] [Table 64]

[0548] These results demonstrated a high percentage of oral bioavailability for the Elra:CAP solid oral dosage form (%BA=97) and the 50 mg / mL oral solution in vehicle variant 7 (%BA=80). Compared to the two solid oral dosage forms, the 50 mg / mL oral solution in vehicle variant 7 demonstrated a significantly shorter Tmax value (Tmax=8 hours for the solid dosage form vs. Tmax=2 hours for the oral solution).

[0549] PK Study 3.-Bioavailability of Oral Solution and Tablet Dosage Forms in Dogs Three male, experienced beagle dogs were selected for use in this study from the company's pool of colony animals. The animals were approximately 11-16 months old and weighed 10-12 kg at the start of the isolation period for this study.

[0550] Approximately 250-350 grams of Harlan Teklad Certified Canine Diet No. 2025 (or other appropriate diet as recorded in the study record) was provided to each animal daily. Each lot of diet was analyzed for contaminants to ensure the absence of any contaminants at concentrations expected to interfere with the conduct or purpose of the study. In addition, each dog was provided with commercially available canned dog food to ensure the animals were fed prior to dosing. 1 / 2 to 1 can of canned dog food was provided at least 1 hour before each dose.

[0551] All animals received tap water ad libitum through an automatic water dispenser. The water supply was analyzed for contaminants as defined by the USEPA "National Primary Drinking Water Regulations" (Title 40, Code of Federal Regulations, Part 141). No known contaminants were expected to be present in the water that would interfere with the interpretation of the experiments.

[0552] Each dog was identified by an ear tattoo and provided with an assigned animal identification number that was unique to the animal room used.

[0553] Controls were set to maintain a temperature range of approximately 22 ± 3°C (approximately 66-77°F) and a relative humidity range of approximately 30-70%. Lighting controls were set to maintain a 12-hour light / 12-hour dark cycle and were continuously monitored. Temperature and relative humidity were continuously monitored and reviewed at least daily to ensure the environmental system was functioning properly.

[0554] Upon arrival and throughout the experiment, dogs were group-housed by sex in kennels (where possible) or housed singly in tandem cages with connecting doors to allow socialization / exercise. Intermingling was limited to animals of the same sex and dose group. Animals were housed individually during the dosing and observation phases. Each kennel or cage was equipped with an automatic water dispenser.

[0555] Animal cages / kennels and rooms were cleaned and disinfected before animals were placed in them and then regularly cleaned and disinfected in accordance with generally accepted animal care practices and relevant standard operating procedures.

[0556] The test articles were as follows:

[0557] TA #1 is a 10 mg / mL erraglusib in a weight-to-volume solution of vehicle, microfiltered using a syringe filter (or other appropriate filtration system), and dispensed into sterile vials for use. The IV solution was prepared based on the erraglusib assay value. The IV solution was administered intravenously at 10 mg / mL, followed by a sufficient washout period. The vehicle was 85% PEG-400, 10% ethanol, 5% water (all components are weight / weight / weight).

[0558] Tablets (TA No. 2): Each dog was given one tablet TA No. 2 orally, followed by a sufficient washout period.

[0559] Tablets (TA No. 3): Each dog received one tablet TA No. 3 orally, followed by a sufficient washout period.

[0560] Tablets (TA No. 4): Each dog was given one tablet TA No. 4 orally, followed by a sufficient washout period.

[0561] Dogs were dosed orally at 0.4 mL / kg of a 50 mg / mL solution for oral suspension (TA #5).

[0562] Tables 3-6 below summarize the experimental design for Canine PK Study 3.

[0563] [Table 65]

[0564] The study consisted of a single group of three dogs, each receiving five doses of an erraglusib dosage form. Each dose was separated by a minimum three-day treatment-free period (washout). The first dose was a single intravenous (IV) infusion of erraglusib (TA #1), followed by oral administration of TA #2 tablets, followed by oral administration of TA #3 tablets, followed by oral administration of TA #4 tablets, followed by oral gavage of a 50 mg / mL oral solution (TA #5). Animals underwent standard evaluations, e.g., weight and clinical observations, and blood samples were taken for pharmacokinetics before and after each dose. The experimental design for Canine PK Study 3 is summarized in Tables 3-7.

[0565] [Table 66]

[0566] Pharmacokinetics (PK): Blood samples were collected from the jugular vein (or other appropriate blood vessel) of each dog into 2 mL vacutainer tubes containing K2EDTA as an anticoagulant at the following time points:

[0567] Intravenous administration: (0) before and at 5, 15, 30, 60 minutes, and at 2, 4, 8, and 24 hours after the final injection. Collections at time zero (nadir) were collected within approximately 24 hours before dosing.

[0568] Oral administration: (0) before and at 15, 30, 60 minutes, and at 2, 4, 8, and 24 hours after dose administration. Collections at time zero (nadir) were collected within approximately 24 hours before dosing.

[0569] Approximately 2.0 mL of whole blood was collected at each time point. Blood samples were placed in test tubes containing K2EDTA as an anticoagulant. The tubes were inverted several times to disperse the anticoagulant and placed on wet ice or in a cryorack to cool until centrifugation. The date and clock time of each blood sampling were recorded. Blood samples were centrifuged using a refrigerated centrifuge (approximately 3,000 rpm, 4±3°C for 10 minutes). Plasma was collected and transferred to pre-labeled plastic cryogenic test tubes. Each sample tube was labeled with at least the following: experiment number, animal number, sex, treatment (defined as TA number 1, 2, 3, 4, or 5), collection time (hours), date, and experimental date (dosing). Once blood sample processing and plasma collection were complete, plasma samples were placed on dry ice or in a freezer within approximately 1 hour of blood collection. All samples were then stored in a freezer at approximately -70±15°C.

[0570] FIG. 38 shows the mean plasma profile of erraglusib observed in Experiment 3 and the mean plasma profile of erraglusib for the IV and oral solutions in Experiments 2 and 3.

[0571] Tables 3-8 below summarize the bioavailability data for each of the dog PK studies 1, 2, and 3:

[0572] [Table 67]

[0573] PK Study 4 - IV vs Oral Solution in Normal Human Volunteers An oral clinical demonstration of concept using erraglusib was conducted as a companion study to an ongoing Phase 2 study of intravenous erraglusib. A subset of patients with recurrent or metastatic PDAC (pancreatic ductal adenocarcinoma) in the recurrent / metastatic setting who had not previously been treated with systemic agents received a single oral dose of erraglusib 50 mg / mL oral solution drug product administered in conjunction with gemcitabine and nab-paclitaxel. Patients received a single oral dose of erraglusib 50 mg / mL oral solution in lieu of intravenous (IV) dosing on Day 1 of Cycle 1, with all subsequent doses receiving the IV dose as per the primary protocol. The first three patients received an oral dose of 9.3 mg / kg. In the absence of any significant toxicity, a subsequent group of three patients will be orally dosed at 12.4 mg / kg, 15 mg / kg, and 17.8 mg / kg, corresponding to the dosing levels previously evaluated in Phase 1 patients and including one additional level equivalent to exposure to 15 mg / kg based on the bioavailability of erraglusib 50 mg / mL oral solution (80% vs. IV dosing) determined in fed dogs.

[0574] [Table 68-1]

[0575] [Table 68-2]

[0576] [Table 68-3]

[0577] [Table 68-4]

[0578] This clinical study demonstrated that oral administration of erraglusib 50 mg / mL oral solution demonstrated the AUC, C max , Tmax and t 1 / 2 This study also demonstrates that administration of erraglusib 50 mg / mL oral solution is not associated with any serious adverse events.

[0579] The bioavailability experiments described in Example 3 demonstrate the following points: 1) Oral administration of the IV solution formulation results in a bioavailability that is approximately 31% of the bioavailability of the IV solution formulation administered IV (PK Study 1) 2) The oral dosage forms of the present disclosure provide erraglusib bioavailability equivalent to that achieved with IV administration. (PK Study 2, PK Study 3) 3) Oral administration of erraglusib with food increases bioavailability compared to administration without food (PK Experiments 2 and 3 vs. PK Experiment 1). 4) Oral administration of the dosage forms of the present disclosure provides clinically meaningful erraglusib bioavailability. (PK Study 4)

[0580] [Example 4] Photostability experiment Background Drug product development studies have revealed occasional anomalous results regarding the percentage of labeled amount (%LC) of [erraglusib], the % area of the major peak of erraglusib, and the % peak area values of the related substances erraglusib RelS1 (HPLC RRT 0.96) and erraglusib RelS2 (HPLC RRT 0.97).

[0581] The apparently unusual results suggested that the erraglusib injection, solution drug product, may be more susceptible to light exposure than either solid erraglusib or erraglusib in acetonitrile solution.

[0582] Therefore, erraglusib photosensitivity studies were performed upon exposure to: UV or visible light in a calibrated photochamber, and ·Ambient light.

[0583] Photochamber and ambient light experiments were monitored using RP-HPLC methods for: Erraglusib concentration and %LC Erraglusib main peak area % Peak area % values of erraglusib RelS1, erraglusib RelS2, and erraglusib anhydrate.

[0584] The photochamber experiments included the following experimental variables: Pharmaceutical vehicles / solvents Formulation vehicle PEG400:EtOH:Polysorbate 80 75:17:8% w / w (“FV”) Vehicle Variant 7 PEG400:EtOH:Polysorbate 80 94:5:1% w / w (“V7”) PEG400 ("PEG only") ·PEG400:EtOH95:5%w / w (“PEG-E”) PEG400:Polysorbate 80 95:5% w / w ("PEG-T") Acetonitrile (AN) Erraglusib concentrations (2, 10, 15, and 50 mg / mL) Light source (UV vs. visible light) Exposure duration (0, 25, 50, 75 and 100% of ICH Q1B conditions) Containers (clear glass vials vs. cuvettes, foil-covered vs. uncovered) Dissolved gases (oxygen sparged vs. nitrogen sparged vs. no sparging)

[0585] The ambient lighting experiment included the following experimental variables: First container (clear glass vial vs. amber glass vial) A second container (a translucent plastic divider box), and Third container (light-blocking cardboard box)

[0586] The results of the three photochamber experiments support the following conclusions: Erraglusib %LC and major peak area % values decreased approximately linearly with increasing light exposure in various solvents and at concentrations ranging from 10 to 50 mg / mL. The rate of %LC loss upon exposure of erraglusib exceeds the main peak area % by approximately 6-fold (due to the shift of the erraglusib absorbance maximum from approximately 440 nm for erraglusib to approximately 330 nm for erraglusib RelS2). The loss rate upon exposure to erraglusib versus visible light increases in the following order for the solvents tested: AN< <PEGのみ~PEG-E<FV<V7<PEG-T The rate of erraglusib loss upon exposure to light versus visible light is essentially independent of erraglusib concentration over the 10- to 50-mg / mL range. The rate of loss of erraglusib upon exposure to visible light is approximately five times faster than that of exposure to ultraviolet light. The rate of erraglusib exposure loss in samples exposed to visible light is essentially independent of the dissolved gas (oxygen vs. nitrogen). Following 100% exposure to 1200 klux-hr visible light, erraglusib %LC loss was significant (approximately 20% loss) for erraglusib injection and solution. The % change in peak area of erraglusib RelS1 for erraglusib injection and solution with 100% exposure to 1200 klux-hr visible light is impossible to quantitate using RP-HPLC due to incomplete resolution between erraglusib RelS1 and erraglusib RelS2. The increase in erraglusib RelS2 peak area% with 100% exposure to 1200 klux-hr visible light was significant for erraglusib injection and solution (approximately a 3-5% increase in peak area%). With 100% exposure to 1200klux-hr visible light, the peak area % of erraglusib anhydrate remained unchanged or slightly decreased for erraglusib injection and solution.

[0587] The results of three ambient light experiments support the following conclusions: Upon exposure to ambient light for 28 days, erraglusib injection, solution drug product in clear glass serum vials converts to erraglusib RelS2. Exposure to ambient light for 3-7 days had a slight effect, but erraglusib %LC and major peak area % significantly decreased after 14-28 days of exposure, while erraglusib RelS2 peak area % increased over the 7-28 day interval. Amber glass vials and plastic divider cartons used as secondary packaging for clear glass vials reduce, but do not completely prevent, photoconversion of erraglusib due to exposure to ambient light. Placing clear glass vials within a plastic compartmentalized carton in a light-tight cardboard box sufficiently reduces the rate of erraglusib photoconversion due to environmental light exposure.

[0588] Photochamber experiment Photo chamber experiment 1 The effect of light exposure on erraglusib in three solutions was investigated: 10FV (10 mg / mL erraglusib in formulation vehicle, PEG400:EtOH:Polysorbate 80 75:17:8% w / w) 50FV (50 mg / mL erraglusib in formulation vehicle), and 50V7 (50 mg / mL erraglusib in vehicle variant 7, PEG400:EtOH:Polysorbate 80 94:5:1% w / w).

[0589] The 10FV solution is the same as the erraglusib injection solution.

[0590] The three solutions were maintained in both 5 mL glass serum vials and UV-transparent plastic cuvettes (foil-covered and uncovered, respectively) and tested under ICH Q1B photostability test conditions (1200 klux-hr in the visible region and 200 watt-h / m in the UV region) using a calibrated photochamber.2 ) were exposed to a proportion (approximately 0, 25, 50, 75, and 100%) of the

[0591] Upon exposure, erraglusib was converted to erraglusib RelS2. Solutions exposed to ≤25% of 1200 klux-hr visible light were characterized by two partially resolved peaks for erraglusib RelS1 and erraglusib RelS2, whereas the erraglusib RelS2 peak increased with increasing exposure interval, and the resolution between the two peaks decreased.

[0592] Erraglusib %LC and % main peak area decreased linearly with increasing intervals of exposure to visible and UV light. The rate of %LC loss was approximately 6 times faster than the rate of % main peak area loss.

[0593] The %LC photoconversion rate in the vial (without foil) exposed to visible light was approximately 60% of the rate in the cuvette (without foil). Foil covering drastically reduced the photoconversion rate in both the cuvette and the vial.

[0594] The %LC and major peak area % photoconversion rates in both vials and cuvettes were significantly faster under visible light exposure compared to UV light exposure. Photoconversion was approximately 5 times faster with exposure to visible light compared to UV light.

[0595] For samples kept in vials (without foil) and exposed to visible light, the %LC and major peak area % photoconversion rates for 10FV were approximately 1.6-fold higher than those for 50FV or 50V7, while the photoconversion rates for 50FV vs. 50V7 were approximately equal. Table 4-1 below summarizes the comparison of photoconversion rates.

[0596] [Table 69]

[0597] In a 10FV sample in a vial exposed to 1200 klux-hr, erraglusib %LC loss was significant (approximately 20% loss). Under the same conditions, the erraglusib RelS2 peak area % increased by approximately 3-5%. The erraglusib RelS1 peak area % could not be reliably quantified due to incomplete resolution between the erraglusib RelS1 and erraglusib RelS2 peaks.

[0598] Photo chamber experiment 2 10 mg / mL erraglusib in four vehicles, namely: FV (PEG400:EtOH:Polysorbate 75:17:8% w / w, which is the erraglusib injection vehicle), PEG only (100% PEG400), PEG-E (PEG400:EtOH95:5%w / w) and ·PEG-T (PEG400: Polysorbate 95: 5% w / w). Effect of photochamber visible light exposure on

[0599] In each of the four test samples, erraglusib was converted to erraglusib RelS2 upon exposure to visible light. In all test samples, the erraglusib anhydrate related substance peak area % values decreased slightly with increasing exposure.

[0600] For all four test articles, erraglusib %LC and % major peak area decreased linearly with increasing exposure interval.

[0601] Table 4-2 below shows that the %LC and main peak area % photoconversion rate (slope) values increased in the following order: PEG only to PEG-E <FV<PEG-T。

[0602] [Table 70]

[0603] Photochamber experiment 3 Effect of visible light exposure on erraglusib test formulations containing: 10FV (10 mg / mL erraglusib in formulation vehicle PEG400:EtOH:Polysorbate 75:17:8% w / w), · 2AN (2 mg / mL erraglusib in acetonitrile).

[0604] The 10FV test article is identical to the erraglusib injection and solution drug product. The 2AN test article was included in this study to demonstrate the effect of protic versus aprotic solvents on erraglusib photosensitivity and to complement the results of previous exposure experiments using erraglusib in acetonitrile.

[0605] The 10FV specimen was first sparged with either oxygen or nitrogen, the 2AN specimen was not sparged.

[0606] The test articles were maintained in glass serum vials (25 mL filled in 50 mL vials) and exposed to portions (0, 25, 50, 75, and 100%) of 1200 klux-hr using a calibrated photochamber.

[0607] For all four test articles, erraglusib %LC and % main peak area decreased linearly with increasing visible light exposure interval.

[0608] The % LC and erraglusib main peak area % phototransformation rate were essentially identical for both the oxygen-sparged and nitrogen-sparged samples.

[0609] Erraglusib photoconversion rate was significantly slower in the 2AN test specimen compared to the 10FV test specimen.

[0610] In the 10FV specimen, the erraglusib RelS2 peak area% increased approximately linearly with increasing exposure interval to 4% peak area%, regardless of sparging conditions. In the 2AN specimen, the erraglusib RelS2 peak area% remained below the method's limit of quantitation (0.08 peak area%) at all visible light exposure intervals. The peak area% values of erraglusib anhydrate-related substances either decreased slightly or did not change significantly with increasing visible light exposure intervals.

[0611] Ambient Light Experiment This ambient light experiment used the same test articles, analytical methods, and procedures as photochamber experiment 1, except that test articles were exposed to ambient light at regular intervals (t = 0, 1, 3, 7, 14, 21, and 28 days).

[0612] For all three test articles exposed to ambient light, erraglusib %LC and % main peak area remained essentially unchanged at t=0, 1, and 3d time points, then decreased approximately linearly with increasing exposure interval. Foil covering drastically decreased the phototransformation rate in both the cuvette and vial.

[0613] Ambient light exposure converted erraglusib to erraglusib RelS2. Erraglusib RelS2 area% remained undetectable at t=0, 1, and 3d, then increased approximately linearly with increasing ambient light exposure time. Erraglusib RelS2 area% increased significantly faster in the 10FV specimen than in the 50FV and 50V7 specimens, but the rate of increase was approximately equal for the 50FV and 50V7 specimens.

[0614] [Example 5] Bioavailability of oral solution versus intravenous administration in human volunteers. Example 5 describes the results of PK experiment 4 in Example 3.

[0615] This pharmacokinetic (PK) study in healthy subjects was conducted to characterize and compare plasma PK parameters following a single intravenous (IV) dose of erraglusib injection, erraglusib oral solution after a fasting period, and erraglusib oral solution after a high-fat meal (fed state). The study was intended to evaluate the potential feasibility of an oral formulation of erraglusib based on systemic exposure within the bioactive range. In clinical studies conducted to date, erraglusib injection (10 mg / mL) has been administered IV once or twice weekly over multiple days, which requires significant time and resources for both patients and field staff. An oral solution was developed, and PK Study 2 and Study 3 in fed dogs demonstrated approximately 70-80% dose-normalized bioavailability of the drug, supporting further investigation. See Example 3 above.

[0616] This open-label, single-center, phase 1, randomized, single-dose, crossover PK study of erraglusib administered as an oral solution and as an IV infusion in the fed and fasted states in healthy subjects was conducted in 18 subjects to compare the PK profile of erraglusib oral solution with that of erraglusib injection.

[0617] The primary objectives of the study were: (1) pharmacokinetics: to evaluate the plasma pharmacokinetics (PK) of a single dose of erraglusib administered as an intravenous (IV) infusion and as an oral solution in both fasted and fed states in healthy subjects; and (2) safety: to determine the tolerability of erraglusib administered as an IV infusion and as an oral solution.

[0618] Patient Populations: 18 subjects received at least one dose of erraglusib. These subjects are included in the safety population. 18 subjects had at least one blood sample that provided evaluable PK data for erraglusib and are included in the PK-evaluable population. 16 subjects had sufficient data to calculate at least one PK parameter of Cmax, AUC, or λz and are included in the PK analysis population for each of the treatments.

[0619] Inclusion Criteria: Subjects had to meet all of the following criteria to be eligible for testing: 1. Able to sign and submit the protocol's informed consent, which included compliance with the requirements and restrictions listed in the ICF. 2. Age was between 18 and 55 years (inclusive) at the time of signing the ICF. 3. Appeared to be in good health as determined by a medical evaluation including medical history, physical examination, eye examination (optometric and visual acuity tests), clinical tests, and electrocardiogram (ECG). 4. They had a systolic blood pressure (BP) of 95 to 140 mmHg, a diastolic BP of 45 to 90 mmHg, and a heart rate of 45 to 100 beats per minute (bpm). 5. Standard 12-lead ECG parameters were normal, unless the investigator considered the abnormal ECG tracings to be clinically irrelevant. QTc was ≤450 milliseconds (ms) in both men and women. 6. Laboratory parameters were within normal ranges, unless the investigator considered an abnormality clinically irrelevant in healthy participants. However, serum creatinine, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) should not exceed 1.25 times the upper limit of normal (ULN). Total bilirubin levels up to 1.5 times the ULN are acceptable with normal conjugated bilirubin levels (except for participants with a history of Gilbert's syndrome, in which case bilirubin levels up to 3.0 times the ULN are acceptable). 7. For men, body weight was between 50.0 and 100.0 kilograms (kg) inclusive; for women, it was between 40.0 and 90.0 kg inclusive, and body mass index (BMI) was between 18.0 and 32.0 inclusive. 8. Women must not be pregnant, lactating, or planning to become pregnant during the study period, and must have a negative urine pregnancy test within 24 hours prior to the start of the study. If menopausal, a documented serum follicle-stimulating hormone (FSH) level >40 mIU / mL must be present. a. Women of childbearing potential (WOCBP) and men with partners of childbearing potential must agree to use adequate contraception from the time of their first erraglusib dose until 4 months after their last erraglusib dose (except in same-sex partnerships). b. Hormonal contraception should be initiated at least one month prior to screening to ensure full contraceptive activity. c. Men with non-pregnant WOCBP partners had to agree to condom use and be informed about the risks of condom breakage or leakage during intercourse and the benefits of using a highly effective method of contraception with their WOCBP partners as per the protocol. 9. Men must agree to refrain from donating sperm for 4 months after their last dose of erraglusib.

[0620] Exclusion criteria: Subjects meeting any of the following criteria were ineligible for the study: 1. At screening, had a symptomatic, clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematologic, neurological, musculoskeletal, joint, psychiatric, systemic, ophthalmic, or gynecological (if female) medical history; infectious disease; or signs of acute illness. 2. Donated any amount of blood, including plasma, within 2 months prior to participation. 3. Had symptomatic hypotension. 4. Had a history of or a clinically significant drug hypersensitivity or allergic disease diagnosed and treated by a healthcare provider. Participants with known hypersensitivity to any component of the investigational product (IP) formulation were excluded. 5. Have a history of substance abuse within the past year. 6. A history of heavy [excessive] alcohol use within the past year [i.e., regular drinking 21 drinks / week for men and 14 drinks / week for women], which put them at risk of experiencing withdrawal symptoms during the study that could confound safety assessments. a. An alcoholic drink was defined as one 4-5 oz (113-142 g) glass of wine, one 12 oz (339 g) glass of beer, or one standard cocktail containing 1.5 oz (43 g) of alcohol. 7. Regularly smoked more than two cigarettes per day (or equivalently, vaped) and was unable to abstain during the study's confinement period. 8. Have used cannabinoids within 1 week prior to participation or have not agreed to discontinue cannabinoid use during the experiment. 9. Excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day) 10. Have taken any prescription or concomitant medications (other than contraceptives, inactive coronavirus disease (COVID) vaccines, or supplements (e.g., vitamins)) within 3 days prior to the first erraglusib dose. Occasional acetaminophen and ibuprofen are permitted. 11. Positive results for any of the following tests: hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus antibody (anti-HCVAb), or anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab) 12. Positive urine drug screen (amphetamine / methamphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, or opiates) a. Subjects may be included if their urine drug screen is positive for cannabinoids but they state that they have not used cannabinoids within one week prior to participation and agree to discontinue cannabinoid use during the study. 13. A urine alcohol test was positive. 14. Tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0621] Randomization Subjects will be randomly selected to receive one of six dosing sequences: 1. Oral Fed State - Oral Fasted State - IV 2. Oral (Fed State) - IV - Oral (Fasted State) 3. Oral fasting state - Oral fed state - IV 4. Oral fasting state - IV oral fed state 5. IV - Oral Fed State - Oral Fasted State 6. IV - Oral fasting state - Oral fed state

[0622] Randomization followed a permuted block size of 6. No stratification factors were introduced into the randomization schedule in this study. Subjects were randomized via a paper randomization schedule.

[0623] Dosage form: Erraglusib injection is a clear, light red to red solution of 10 mg / mL erraglusib in an inert co-solvent mixture of polyethylene glycol 400, ethanol, and Tween 80 (polysorbate 80) (PEG400:EtOH:Tween 80; 75:17:8). The route of administration is IV infusion after diluting erraglusib for injection with 0.9% sodium chloride injection.

[0624] Erraglusib oral solution is 50 mg / mL erraglusib in vehicle variant 7, a co-solvent mixture of PEG400:EtOH:Tween80 (94:5:1% / w / w). It is a clear, red solution free of visible particulate matter and is a low bioburden liquid dosage form that is self-preserving against microbial growth.

[0625] Dose Administration: Erraglusib will be administered on day 1 of each of three 2-week study periods.

[0626] Subjects received a single 3.3 mg / kg dose of each of the following in randomly assigned order, separated by 2-week periods:

[0627] Erraglusib oral solution (50 mg / mL) in the fed state: During a 30-minute period, fed subjects consumed a high-fat meal (breakfast). Erraglusib oral solution was also taken within this 30-minute period. During the experiment, the high-fat meal was administered over a period of 30 minutes or less (in almost all cases, 28 minutes). The erraglusib dose was administered within 1 minute of the end of the meal; in practice, the erraglusib oral dosage was administered within 20 minutes of the start of the high-fat meal.

[0628] Elraglusib oral solution (50 mg / mL) in the fasted state: Subjects fasted overnight (excluding water) for at least 8 hours prior to administration of the oral solution.

[0629] Notes for oral medications: Subjects were to refrain from eating a post-dose meal for at least 4 hours after taking erraglusib oral solution.

[0630] Subjects were not to drink or consume any liquids for 1 hour after taking the erraglusib oral solution, however, if subjects had any issues with the taste of the oral solution, they were allowed to consume a lozenge or hard candy or chew gum after dosing.

[0631] Elraglusib injection (10 mg / mL) was administered as an IV infusion over 60 minutes (concentration (mg / mL) and infusion rate (mL / kg / hr) may vary depending on subject weight).

[0632] Subjects fasted overnight (except for water) for at least 8 hours prior to administration of the IV infusion.

[0633] Subjects were instructed to abstain from post-dose food for at least 4 hours after the end of the infusion.

[0634] The 3.3 mg / kg dose was based on the subject's weight on Day 1 of Period 1 (rounded to the nearest 0.1 kg), unless the subject's weight changed by more than 10%, in which case the dose was recalculated using the subject's weight on Day 1 of Period 2 and / or 3 (rounded to the nearest 0.1 kg), as indicated.

[0635] result: Following each erraglusib dose, AUC, C were measured by standard non-compartmental analysis (NCA) methods. max , T max , and t 1 / 2 PK parameters were analyzed, including log-transformed C in subjects with adequate PK data after at least one of oral and IV dosing. max and AUC parameters were used to assess the relative bioavailability of oral dosing (fed and / or fasted states) compared to IV dosing.

[0636] Blood samples for erraglusib PK analysis were collected from all study subjects.

[0637] Best efforts were made to obtain PK samples at the nominal scheduled time for dosing. PK samples were assayed using a validated analytical method.

[0638] Drug dose and concentration Subjects were targeted to receive 3.3 mg / kg of erraglusib per protocol. One subject (106) received only approximately 3% of the target dose via IV infusion treatment after the infusion was discontinued due to an adverse event of flushing (grade 2) during period 2. This was assessed by the investigator as possibly related to the erraglusib injection. Oral dosing was administered as a pure oral solution containing 50 mg / mL erraglusib. Oral dosing ranged from 6 to 6.3 mL of oral solution depending on body weight. No additional oral intake of liquids was permitted for at least 1 hour; however, if the subject had a taste problem, they could consume a lozenge or hard candy or chew gum after dosing.

[0639] [Table 71]

[0640] Erraglusib mean PK profile by treatment Elraglusib plasma concentrations were collected for 96 hours post-dose for each of the three treatments. Figure 41 presents the mean concentration-time profiles for the three treatments using linear coordinates in the upper panel and semi-logarithmic coordinates in the lower panel.

[0641] Figure 41 shows that IV infusion produced the highest peak mean concentrations, while oral administration in the fasted state produced the lowest peak mean concentrations. The figure also shows that taking the drug concomitantly with a high-fat meal substantially increased exposure and delayed the time to peak mean concentrations by several hours compared with taking the drug in the fasted state. All three mean profiles showed similar rates of decline during the terminal washout phase. Twelve of the 15 subjects available for PK assessment for all three treatments had erraglusib plasma concentrations above the LLOQ for at least 96 hours. Plasma concentrations declined below the assay LLOQ (0.200 ng / mL) by 72 hours in one subject receiving the IV infusion treatment (118), one subject receiving oral fasting treatment (112), and two subjects receiving oral fasting treatment (112, 118), and by 48 hours post-dose in one subject receiving oral fasting treatment (118). Only one subject (118) had a C of less than 96 hours with all three treatments. last Quantifiable concentrations in other subjects at 96 hours post-dose ranged from 0.273 ng / mL (109, treated orally in a fasted state) to 7.18 ng / mL (111, treated by IV infusion).

[0642] There was substantial inter-subject variability in erraglusib plasma concentrations. With IV infusion, CVs were typically 35% to 45% over the first 24 hours after dosing, but ranged from 20% to 40% if data from a subject who received only 3% of the planned dose (106) were ignored. However, after oral treatment, CVs typically ranged from 60% to 100% when the drug was administered in the fasted state, or from 45% to 150% when administered in the fed state.

[0643] Erraglusib mean PK profile by treatment Erraglusib plasma PK parameters for erraglusib were determined over a 96-hour PK observation window for each of the three treatments. Table 5-2 summarizes the descriptive statistics after IV infusion, Table 5-3 summarizes the descriptive statistics after oral administration in the fasted state, and Table 5-4 summarizes the descriptive statistics after oral administration in the fed state. Subject 106 had a missed sample during the IV infusion, resulting in a C max Although evaluation of pharmacokinetic and AUC-related PK parameters was not possible, PK parameters related to the terminal elimination phase were calculable. Subject 114 was evaluable for PK parameters after IV infusion treatment but was discontinued after that treatment, and therefore does not provide comparative information for oral administration in the fasted or fed state. Both subjects were included in the descriptive statistics for treatment and PK parameters, which could be evaluated.

[0644] [Table 72]

[0645] [Table 73]

[0646] [Table 74]

[0647] These summary tables show the average C max The C values (arithmetic mean) were higher after IV infusion (1601 ng / mL) than after either oral administration, and the C values obtained by oral administration in the fed state were significantly higher. max (591.8ng / mL) was observed in the fasting state. max A similar pattern was observed for the partial and full AUC estimates, with the mean AUC ∞Values ranged from 8072 h·ng / mL after IV administration to 1811 h·ng / mL after oral administration in the fasted state, with an intermediate value of 5001 h·ng / mL after oral administration in the fed state. A 96-hour PK observation window was used to estimate the predicted AUC ∞ It was sufficient to obtain between 98% and 99% of the values.

[0648] Figure 42 provides a visual overview of how the various subjects participating in the study showed significant consistency in reduced plasma exposure when receiving IV infusion, oral dosing in the fed state, and oral dosing in the fasted state (C max and AUC ∞ The transition plots were performed in both the fed and fasted states at post-dose C max There was only one subject (118) who was similarly exposed, and the AUC ∞ The transition plot also shows that there was only one subject (also 118) who was similarly exposed. ∞ AUC of IV infusion exposure ∞ This indicates that there was only one subject (105) who was relatively close to exposure. A second patient (106) may also fall within this group, but this patient experienced a C of IV infusion due to missing data in the early infusion process and incomplete delivery of the target dose. max or AUC ∞ Exposure assessment was not possible.

[0649] The mean terminal elimination half-lives ranged from 16 to 21 hours for all three treatments. The longest terminal half-life (50.5 hours, 113) was observed after oral treatment in the fed state, and the shortest half-life (6.92 hours, 118) was observed after oral administration in the fasted state. In general, the terminal elimination half-life did not appear to be treatment-dependent, with the majority of subjects having half-lives between 15 and 25 hours for all three treatments. Subjects with short half-lives (<11 hours) on Treatment 1 showed a similar pattern across all three treatments. With the exception of a single case in one subject with a half-life of 50.5 hours, the longest half-lives ranged from 24 to 27 hours, did not differ significantly from the majority of subjects, and were not predominantly associated with any particular treatment.

[0650] The clearance of erraglusib averaged 0.4268 L / hr / kg or 31.14 L / hr among subjects receiving IV infusion. This clearance value is greater than the nominal adult glomerular filtration rate of 7.2 L / hr in humans, but less than the nominal renal blood flow (approximately 72 L / hr) or nominal hepatic blood flow (approximately 90 L / hr), consistent with renal and / or hepatic clearance mechanisms (Davies B and Morris T. Physiological Parameters in Laboratory Animals and Humans. Pharmaceutical Research 10(7), 1093-1095 (1993) DOI: 10.1023 / a:1018943613122).

[0651] The mean erraglusib apparent (oral) clearance was 2.608 L / h / kg or 185.7 L / h after dosing in the fasted state, but was lower than when administered in the fed state (0.9052 L / h / kg or 64.49 L / h), both consistent with incomplete absorption from the intestine. The difference in apparent clearance between the fasted and fed states, without any change in terminal elimination rate, indicates that a high-fat breakfast in the fed state enhances the extent of drug absorption from the intestine compared with oral administration in the fasted state.

[0652] When subjects received the IV infusion, the mean volume of distribution of erraglusib among subjects was 11.19 L / kg or 821.8 L. This volume was substantially greater than the total body volume, indicating distribution to body tissues, likely at concentrations greater than those observed in plasma in some, or even most, tissues. The mean apparent volume of distribution after oral administration was 2-5 times greater than the volume of distribution after IV administration, consistent with incomplete absorption of erraglusib from the intestine, as also noted for the apparent clearance. As can be seen from the apparent clearance values, the apparent volume of distribution indicates that less absorption from the intestine occurs after administration in the fasted state than after administration in the fed state.

[0653] Comparison of the relative bioavailability of erraglusib treatments The relative bioavailability of oral erraglusib administered in the fasted and fed states compared to the absolute (100%) bioavailability following IV infusion, as well as the relative bioavailability of oral erraglusib administered in the fed state compared to oral fasted state dosing, are summarized in Table 5-5. Erraglusib administered in the fasted state has a C of 100% compared to IV and oral fasted states. max It has an oral bioavailability of approximately 5-11% when calculated using the geometric mean of the AUC last or AUC ∞ Based on the geometric mean values, the oral bioavailability is 14-21%. Administration of erraglusib in the fed state results in increased oral bioavailability. Erraglusib administered in the fed state is significantly higher than the oral C values in the IV and fasted states. max When calculated using the geometric mean of the values, this results in oral bioavailability of approximately 19% to 38%, but the AUC last or AUC ∞ Based on the geometric mean of the C values, the C values observed in the fed state were 2.5 to 5 times those observed in the fasted state, and based on the AUC index, the C values observed in the fasted state were 2.4 to 3.6 times those observed in the fasted state. maxThis results in oral bioavailability based on

[0654] [Table 75]

[0655] Dose and relative bioavailability of erraglusib Erraglusib was dosed at 3.3 mg / kg in the study subjects, but subject weight varied approximately two-fold from 54.3 kg to 96.6 kg. Thus, the total dose of erraglusib administered ranged from approximately 180 mg to 316 mg (excluding the incomplete IV infusion dose of approximately 10.1 mg administered to subject 106). max or AUC ∞ The linear regressions of the relative bioavailability of erraglusib based on the ratio of β / β are provided in Figure 43 for IV infusion, Figure 44 for oral dosing in the fasted state, and Figure 45 for oral dosing in the fed state. Where the slope of the relationship in each case is approximately 0.0 (i.e., a nearly horizontal line), the bioavailability of erraglusib in that setting was approximately uniform across the two-fold dose range tested in this study. Given the limited number of data points available, confidence intervals (95% CI) are included in the plots to help estimate whether the regression line is statistically different from 0.0.

[0656] The fasted state / IV vs. dose bioavailability linear regression for erraglusib (Figure 43) suggests that bioavailability increases with increasing dose. max When bioavailability was assessed using the AUC ∞ This is not statistically different when compared using the F CmaxBased on the regression, oral bioavailability under fasting conditions is estimated to increase from approximately 4% to 16% as the dose increases from 180 mg to 320 mg, while F AUC∞ Base regressions estimate the increase to be approximately 14% to 24%.

[0657] The linear regression of fed state / IV vs. dose bioavailability (Figure 44) shows that C max shows a similar pattern with a statistically significant increase in bioavailability with dose, but AUC ∞ Not shown if based on F Cmax Based on the regression, oral bioavailability in the fed state was estimated to increase from approximately 16% to 52% as the dose increased from 180 mg to 320 mg, while F AUC∞ Based on regression, the increase is estimated to be approximately 41% to 71%. The oral bioavailability of erraglusib may increase due to a faster rate of drug absorption from the intestine in subjects receiving the higher dose, but the increase is slightly more pronounced in C than in AUC. max The slope shows that the effect of

[0658] When the two oral dosing treatments were compared using a linear regression of fed / fasted state versus dose (Figure 45), the slope of the regression was negative but not statistically different from 0.0. If this trend holds true, it would indicate that the difference in oral bioavailability in the fasted and fed states was greatest at the lower erraglusib doses and decreased at the higher erraglusib doses used in the study.

[0659] Dose and erraglusib clearance and volume of distribution Erraglusib clearance and apparent clearance were examined using linear regression for dependence on administered erraglusib dose. The slope of the regression relationship was not statistically different from 0.0 for any of the three treatments. However, there was a tendency for the slope to be slightly negative following both oral dosing treatments, which is consistent with C max and AUC ∞ This was consistent with previously observed bioavailability findings, with a regression relationship in which the apparent clearance increased with increasing dose. The regression line estimates that the apparent clearance after a 320 mg dose was one-third to one-half of the apparent clearance after a 180 mg dose.

[0660] Erraglusib volume of distribution and apparent volume of distribution were also examined using linear regression for their dependence on the administered erraglusib dose. The slope of the regression relationship was not statistically different from 0.0 for any of the three treatments. In addition, there was no apparent trend for the slope after oral dosing treatment to be always negative or always positive. There is little evidence that the volume of distribution or apparent volume of distribution is affected by the administered erraglusib dose.

[0661] This study investigated the plasma pharmacokinetics of erraglusib following drug administration as an IV infusion over an approximately 80-minute period, as an oral dose administered in the fasted state, and as an oral dose administered in the fed state (i.e., a high-fat, high-calorie breakfast). The pharmacokinetic objectives of the study included assessing the pharmacokinetics of erraglusib when administered IV and orally, and determining the relative bioavailability of erraglusib when administered orally in the fasted state or when administered orally in the fed state compared to its bioavailability when administered as an IV infusion. Additionally, the effect of administering the oral dose in the fed state was compared to administration in the fasted state.

[0662] The study enrolled 18 healthy adult subjects in a three-period, crossover study in which serial PK samples were collected for 96 hours after each single-dose treatment. All subjects were pharmacokinetically evaluable in the sense that PK samples were available after at least one dose, and all subjects had to demonstrate at least C for one or more of these three concentration-time profiles. max Only 16 subjects had sufficient data available to calculate the pharmacokinetic parameters of C and AUC. Fourteen of the patients had significant differences in drug exposure (i.e., C) during at least two of the three treatments. max There was sufficient pharmacokinetic information to perform a comparison of the pharmacokinetic (AUC) and AUC.

[0663] Concentration and Exposure Elraglusib plasma concentrations declined to near or below the assay LLOQ (0.200 ng / mL) by 96 hours post-dose for all three treatments, with the observed AUC last is the AUC averaged across all three treatments ∞ Concentration-time profiles showed clear differences between the amplitude and timing of mean peak concentrations, with the greatest exposure and most rapid increase in concentration associated with approximately 80-minute IV infusions. max and lower AUC) occurred when oral dosing was administered in the fasted state. Dosing in the fed state resulted in a significant increase in exposure compared to oral dosing in the fasted state, with the 95% CI indicating that oral dosing with food (i.e., fed state) exposure was 2.5 to 5 times that of oral dosing in the fasted state, but when the dose was taken with food, the C max The average time to reach the destination was delayed by three hours.

[0664] Terminal elimination half-lives appeared to be similar in most subjects, ranging from approximately 15 to 25 hours for all three treatments in most subjects. However, two or three of the 16 subjects with evaluable half-lives had elimination half-lives that were approximately one-third to one-half of the half-life of the majority of subjects, suggesting that the experimental population included several subjects with a rapid clearance phenotype. This subset of subjects had terminal elimination half-lives ranging from 7 to 11 hours, with C values after oral dosing in the fed or fasted state. max and AUC values tended to be lower. These subjects also had lower AUC values after IV infusion. ∞ Although the values were among the lowest, C after IV infusion max The values were intermediate for the population. The subset of subjects with a short half-life were those with the highest systemic clearance values and the lowest volume of distribution after IV infusion dosing, consistent with the observation of a shorter half-life.

[0665] Bioavailability assessment Relative bioavailability assessment among the three pairwise treatments revealed clear visual differences in their concentration-time profiles. The IV infusion treatment directly injects the drug into the systemic circulation, resulting in 100% bioavailability. The oral route of administration is expected to have lower bioavailability due to incomplete absorption from the intestine or clearance of the drug from the bloodstream via one or more first-pass effects before it can enter the general systemic circulation. The oral bioavailability of erraglusib when administered in the fasted state was significantly lower than when administered in the fed state, suggesting that erraglusib preferentially partitions into fatty or lipid materials, disperses more effectively, and migrates more easily across lipid interfaces when administered in the fed state. This interpretation of high lipophilicity is consistent with the observed large volume of distribution, i.e., approximately 11 L / kg, observed for erraglusib after administration as an IV infusion.

[0666] The relative bioavailability of erraglusib after oral dosing also showed some evidence of a dose-dependent relationship with the administered erraglusib, i.e., the relative bioavailability increased with increasing dose. This possibility suggests the existence of a saturable clearance pathway operating in parallel with a nonsaturable pathway somewhere along the chain of events between reaching the intestinal wall and the systemic circulation, e.g., in a saturable metabolic pathway. This possibility is supported by the fact that oral bioavailability at the lowest doses used in the study was only 3%-11% (C max Base or AUC ∞ This explains the observation that the relative bioavailability (based on the elimination of erraglusib) increased by approximately 13% at doses higher than the approximately 75% used in the study. However, these differences in relative bioavailability also occurred in different subjects, and it is possible that higher doses were administered by chance to individuals with a predisposition to better absorb erraglusib. This type of saturable drug elimination pathway is associated with a C value rather than an AUC value. max This is expected to have a large effect on the C value at the time when drug absorption occurs most rapidly (i.e., C max Before reaching and C max This is because it is the most prominent (within the time window).

[0667] The lower impact of this saturable drug elimination pathway on erraglusib when administered in the fed state may be related to its high lipophilicity allowing it to bypass this pathway, which may be due to location (subsequent T when administered with a high-fat meal). max means that more absorption occurs further along the intestine than when administered in the fasted state), or because of different uptake mechanisms that may occur for molecules dissolved in or carried with the fat particles.

[0668] Interestingly, relative bioavailability after oral dosing in the fed state reached 91% in one subject (105). This case highlights the point that while some saturable pathway may be at work to reduce oral bioavailability at low doses, the effect becomes less pronounced as oral dosing increases, ultimately having a nearly undetectable effect as the oral relative bioavailability approaches 100% (i.e., the dose provides essentially the same total exposure as if administered by IV infusion). While this study used 3.3 mg / kg IV infusion and oral dosing, previous early-phase studies in patient populations have used erraglusib administered by IV infusion at doses ranging from 1.0 to 15.0 mg / kg, approximately 3-5 times the dose utilized in this study, with only minor deviations from dose-proportionality (a 15-fold dose change resulted in a significant decrease in AUC 24 (This resulted in a 20-fold change in the saturable drug efflux pathway.) If the deviation is real, it is also consistent with the existence of a saturable drug efflux pathway operating in parallel with other nonsaturable pathways.

[0669] Drug accumulation due to repeated dosing Accumulation with repeated dosing was estimated by determining the extent of carryover from the first dosing interval (i.e., subsequent dosing intervals of 1 × τ, 2 × τ, etc., for the single dose used in this current experiment, up to n × τ hours, i.e., until carryover was less than 1%). max The concentration increase occurs rapidly, and once the infusion is completed, concentrations fall rapidly over the next approximately 10-12 hours due to a rapid distribution phase. Concentrations decline by more than 10-fold over that time interval. Accumulation using the planned twice-weekly dosing regimen is expected to be in the 1%-5% range, and even lower if the dosing interval employed is once-weekly. This increase in concentration between the first dose and steady state is similar to the precision of the current erraglusib assay and is therefore likely undetectable unless first-dose and steady-state data from a large number of patients are available.

[0670] Oral medications have a lower C maxAlthough erraglusib has a significant effect, absorption of erraglusib from the intestinal tract requires a longer time than is typically used for erraglusib infusion in this study. When taken with food, the terminal half-life prevails 18 to 24 hours after dosing, and 24 hours after administration of the first dose, concentrations are still C max Approximately 10%-20% of the values. Accumulation using the planned twice-weekly dosing regimen is expected to be in the range of 1%-10%, and lower if a once-weekly dosing interval is employed. Substantial accumulation (e.g., greater than 30%) with repeated dosing is not expected unless dosing intervals of 24 hours or less are utilized. Patients with long erraglusib half-lives (i.e., 20+ hours) generally show greater accumulation after steady state is reached than patients with shorter half-lives (i.e., 10 hours or less).

[0671] Pharmacokinetic Conclusions Erraglusib is systemically bioavailable when administered orally, and its oral bioavailability is enhanced 2.5-5-fold when administered in the fed state (i.e., with a high-fat breakfast). Doses above 3.3 mg / kg can demonstrate oral bioavailability greater than the approximately 5%-21% observed when administered in the fasted state and approximately 19%-63% when administered in the fed state.

[0672] Elraglusib pharmacokinetics shows substantial inter-subject variability when the dose is administered orally. Estimates of concentration and PK parameters are substantially less variable when the dose is administered by IV infusion.

[0673] Erraglusib pharmacokinetics, whether administered IV or orally, has a terminal elimination phase approximately 24 hours after dosing, with a half-life ranging from 15 to 25 hours in most individuals, although there may be a subset of individuals who eliminate the drug more rapidly and exhibit a terminal half-life ranging from 6 to 11 hours.

[0674] Erraglusib has a systemic clearance in healthy adults that exceeds the nominal glomerular filtration rate, consistent with either renally eliminated if an active secretory mechanism is present, or metabolically eliminated in the liver. The apparent clearance observed after oral dosing appears to be a combination of incomplete absorption and first-pass metabolism. Incomplete absorption likely plays a major role in the higher apparent clearance observed when the drug is administered in the fasted state.

[0675] Erraglusib has a volume distribution greater than approximately 11 times body weight, indicating extensive distribution to tissues, with concentrations in some tissues likely greatly exceeding plasma concentrations.

[0676] Significant accumulation of erraglusib with repeated dosing is not expected with weekly or twice-weekly dosing regimens, and significant accumulation likely occurs with dosing intervals of 24 hours or less from the first dose to steady state.

[0677] [Example 6] Preparation and evaluation of erraglusib ASD using four different polymers prepared by spray drying from acetone:water solvent Previous formulation development studies compared micronized erraglusib formulated in both dry- and wet-granulated tablets, as well as in a spray-dried dispersion (ASD) within a dry-granulated tablet. These formulations were dosed in a canine PK study 3. Based on that study, a 1:1 erraglusib:cellulose acetate phthalate (CAP) ASD composition dosed in a tablet was found to achieve approximately 68% oral bioavailability and was recommended as the lead for further development. The lead ASD-tablet composition is shown in Table 6-1.

[0678] [Table 76]

[0679] An erraglusib ASD optimization and tableting evaluation was performed to: (1) evaluate the feasibility of avoiding tetrahydrofuran (THF) as a spray-drying solvent by measuring active pharmaceutical ingredient (API) solubility in selected commercially available spray-drying solvents and confirming solubility in the presence of bioavailability-enhancing polymers; (2) manufacture ASD prototypes and characterize them for dissolution performance and physicochemical stability; and (3) evaluate the ASD prototypes in a lead tablet formulation.

[0680] To this end, a series of ASD prototypes were successfully prepared and characterized. Lead ASD formulations were selected based on initial biorelevant solubility and physical state characterization data. These lead ASD formulations were then advanced to tablet formulation evaluation and developmental stability studies.

[0681] material The materials used in the erraglusib ASD development experiments are summarized in Table 6-2 (raw materials) and Table 6-3 (analytical reagents). The equipment used in the erraglusib ASD development experiments is presented in Table 6-4.

[0682] [Table 77]

[0683] [Table 78]

[0684] [Table 79]

[0685] Manufacturing method Preparation of spray-dried dispersions (ASD) Four different erraglusib ASD formulations were prepared using four proprietary polymers (see Table 6-5). Erraglusib and polymer were weighed and dissolved in a 90:10 acetone:water mixture to produce a spray solution containing 4.0% weight / weight (w / w) total solids. The solution was stirred until complete dissolution of the solids was visually confirmed. A B-290 mini-spray dryer was set up as configured in Table 6-6. The equipment was heated, and the pump was calibrated with solvent to achieve a spray rate of 10-15 g / min (actual rates are listed in Table 6-6). Once the inlet temperature was reached, the outlet temperature was stabilized. The solvent was allowed to flow until a stable outlet temperature of 40-45°C was reached. Once steady-state conditions were achieved, spraying of the erraglusib / polymer solution was initiated using the calibrated pump flow rate and size 14 L / S tubing. After spray drying, the product was collected and oven-dried at 40°C for at least 20 hours (NLT). Complete processing parameters are provided in Tables 6-7.

[0686] [Table 80]

[0687] [Table 81]

[0688] [Table 82]

[0689] Granulation Microcrystalline cellulose (MCC), mannitol, and croscarmellose sodium (CCS) were sieved through a #20 mesh screen (0.85 mm). The sieved ingredients and erraglusib ASD material were transferred to a 500 mL polypropylene bottle and blended for 10 minutes at 25 revolutions per minute (rpm). Magnesium stearate was sieved through a #30 mesh (0.595 mm) and added to the mixture. The intragranular ingredients were blended for an additional 5 minutes at 25 rpm.

[0690] The preblend was compressed using an MCTM-1 manual compactor (roller compaction simulator) at a simulated roll force of 4-5 kN / cm and milled through a 1.25 mm screen. The blend was collected in a 250 mL polypropylene bottle and weighed to calculate the adjustment factor for the extragranular excipients. The extragranular CCS was added to the milled granules and blended for 5 minutes at 25 rpm. The extragranular silicon dioxide was sieved through a #20 mesh (0.85 mm) into the mixture, which was blended for 5 minutes at 25 rpm. The extragranular magnesium stearate was then sieved through a #30 mesh (0.595 mm) into the mixture, which was blended for 5 minutes at 25 rpm to produce the final blend.

[0691] Tableting Tablets were compressed using 9.5 x 21.0 mm smooth-faced modified oval tooling using MTCM-1.

[0692] Analysis method ID, Assay, and Related Substances by HPLC High performance liquid chromatography (HPLC) studies were performed using an Agilent 1100 series HPLC equipped with Chemstation data acquisition software or an Agilent 1260 series HPLC equipped with OpenLab data acquisition software.

[0693] Chromatographic separation was achieved using a Waters Atlantis T3, 4.6 x 150 mm, 3 μm column and the parameters provided in Tables 6-8. Testing was performed using an external standard prepared at 0.2 mg / mL erraglusib in diluent (Lot NB-Erraglusib (NG)-A-1). Test samples for the tablet prototype were prepared by serial dilution to a target concentration of 0.2 mg / mL erraglusib. All samples were diluted using volumetric flasks.

[0694] [Table 83]

[0695] Sink Dissolution Sink dissolution experiments were performed on a Sotax MD automated dissolution apparatus with in-line UV detection. Erraglusib standards were used to quantify percent dissolved using UV absorbance at 282 nm. Sink dissolution studies were performed using the parameters shown in Tables 6-9.

[0696] [Table 84]

[0697] Non-sink lysis Non-sink dissolution studies were performed in duplicate using manual sampling and the R&D HPLC method developed at Core Rx (Tables 6-10) with the same column as the assay and related materials methods (Tables 6-11). Approximately 15 mg of material was weighed into a scintillation vial equipped with a cross-shaped stir bar. To initiate the non-sink dissolution study, 15 mL of fasted-state (FaSSIF) or fed-state (FeSSIF) simulated intestinal fluid was then added to each vial while stirring at 125 rpm. 1.0 mL samples were taken at the time intervals indicated in Table 10. Aliquots were microcentrifuged at 15,800 x g for 2 minutes, and the supernatant was diluted using a 5x dilution factor and placed directly into an amber HPLC vial. At 10 and 90 min after microcentrifugation, additional samples of the supernatant were passed through a 0.2 μm microcentrifuge cut filter, aiming to extract unbound “free” drug from solubilized colloidal species without the use of an ultracentrifuge, using centrifugation parameters of 15800 × g for 2 min.

[0698] [Table 85]

[0699] [Table 86]

[0700] Karl Fischer water content Water content was determined by volumetric Karl Fischer (KF) titration using a Mettler Toledo V20S KF titrator. Titration standardization was performed using Hydranal Complex 2 and Check P solutions. 300 mg of sample was dissolved in CompoSolver E and used for KF water titration.

[0701] Bulk and tapped density To determine bulk density, the test article powder was dispensed into a 25 mL graduated cylinder and the test article weight was recorded. The mass of the powder in the measuring vessel was determined and divided by the volume of the test article.

[0702] To determine tap density, the graduated cylinder was tapped until the volume stopped changing. After tapping, the final powder volume was recorded. The tap density was calculated by dividing the initial mass by the final volume.

[0703] USP <616> The compression index and Hausner ratio were calculated as described in.

[0704] hardness USP <1062> Tablet hardness was determined using a Varian VK200 tablet hardness tester according to the method described above.

[0705] friability Using a friability tester (Sotax FT2), <1216> According to the method described above, friability was tested by tumbling 10 tablets for 4 minutes at 25 rpm (100 revolutions).

[0706] Compression Profile Compression profiles were generated for the prepared tablets using a Globe Pharma manual tablet compression machine model MTCM-1 equipped with 5 / 16-inch flat upper and lower TSM-B punches and dies.

[0707] Powder X-ray diffraction Powder X-ray diffraction (XRPD) was performed using a Rigaku Miniflex 6G benchtop X-ray diffractometer and a 2 mm deep aluminum cup. The sample was compressed and placed into the cup well using a glass slide. The X-ray source was operated at 40 kV and 15 mA. Sample data were collected from 3 to 40° with a 0.02° step size using an actuation rate of 10 degrees / min for erraglusib and 2.5 degrees / min for the ASD sample. Sample spinning was activated for all measurements.

[0708] Scanning electron microscopy Scanning electron microscopy (SEM) images were taken using a Phenom Pro in 10 kV high-resolution mode. Carbon paper was used as the conductive substrate. Samples were prepared by rolling a plastic spatula over a <100 mg sample and then carefully rolling the sample onto double-sided adhesive carbon paper on the stage. Rotating the sample holder counterclockwise 45° three times positioned the sample approximately 2 mm below the upper stage for imaging.

[0709] Differential scanning calorimetry A modulated differential scanning calorimeter was used in conjunction with a humidity chamber at <5% relative humidity (RH) to test the glass transition temperature. Samples were prepared in differential scanning calorimetry (DSC) pans and lids. Approximately 5-10 mg of sample was weighed into each pan, which was placed in an appropriate equilibration chamber for at least 10 hours. The samples were removed from the chamber, and the lid was crimped, if necessary, based on the experimental design. The samples were reweighed and placed on the DSC autosampler. The samples were then run using the method parameters listed in Tables 6-12.

[0710] [Table 87]

[0711] Acetone: Solubility of erraglusib in water and acetone The solubility of erraglusib API with and without the target polymer was evaluated in acetone. Erraglusib was soluble up to 4% w / w, but was observed to crystallize at room temperature when left under static conditions.

[0712] Tests conducted with 4% w / w erraglusib and 4% w / w polymer indicate that HPMCAS-MG, Eudragit® L100, and Eastman cellulose acetate phthalate (CAP) can be used for preparatory spray drying at a solids loading of 8% w / w if the solutions are used immediately. The HPMCAS-MG and Eastman CAP samples were visually observed to contain some undissolved solids, which are typically observed for these polymer types due to the presence of residual levels of insoluble high molecular weight fractions of the polymer.

[0713] Prior to ASD prototype fabrication, additional solvent and polymer combinations were evaluated to determine which mixtures should be targeted for further development and to find suitable erraglusib and polymer loading ranges that provided adequate solution stability for reasonable pre-spray solution hold times (NLT 24 hours). Samples were prepared according to Table 6-13.

[0714] [Table 88]

[0715] The samples were stirred and visually observed over a 24-hour period, with the observations summarized in Table 6-14. A 2-hour precipitation of a fine, bright orange powder was observed in both acetone (Sample 1) and 95:5 acetone:water (Sample 3), while erraglusib with HPMCAS-MG in acetone (Sample 4) took approximately 4 hours for precipitation to occur. Erraglusib in tetrahydrofuran (THF) remained dissolved over 24 hours when stored at 0°C, with no overnight crystallization occurring.

[0716] [Table 89]

[0717] Twenty-four hours after the solubility experiment was completed, the precipitated mixture was allowed to settle, an aliquot was taken, and centrifuged. The supernatant was then diluted and tested by HPLC to determine the solubility of erraglusib, as shown in Table 6-15.

[0718] [Table 90]

[0719] The measured solubility of erraglusib in acetone was 13.08 mg / mL. The THF solution measured 34.68 mg / mL of erraglusib. This closely matches the theoretical concentration based on the dispensed weights of erraglusib and THF (i.e., 37 mg / mL) and is consistent with product remaining in solution after 24 hours. The 1:1 erraglusib:HPMCAS-MG sample took longer for solids to precipitate, but the measured concentration is closer to that of the acetone sample after 24 hours.

[0720] In addition to analyzing the supernatant of the solubility experiment samples, the precipitate, where applicable, was collected and analyzed via XRPD. The spectrum indicated that form conversion of erraglusib to the acetone solvate form had occurred.

[0721] Additional experiments were performed to determine if increasing water content would prevent the formation of solvate precipitates, testing more dilute solutions for potential ASD treatments. Sample details are summarized in Tables 6-16.

[0722] [Table 91]

[0723] The samples were agitated and visually observed over a 24 hour period, and the observations are summarized in Tables 6-17.

[0724] [Table 92]

[0725] 95:5 acetone:water and 90:10 acetone:water mixtures with approximately 4% w / w solid loading both precipitated a bright orange solid after stirring for 2 and 3.5 hours, respectively. Erraglusib at 1.5-2.0% w / w in 95:5 acetone:water remained dissolved over 24 hours. These results support spray drying of 95:5 acetone:water solutions with drug substance loadings of 2.0% w / w or less.

[0726] The 90:10 acetone:water samples were sampled and centrifuged after 24 hours, and the erraglusib concentration was determined by HPLC, as summarized in Table 6-18. The measured concentrations alongside the initial 95:5 acetone:water sample indicate that the additional water did not result in improved solubility.

[0727] [Table 93]

[0728] To support formulation development, facilitate interpretation of in vitro solubility, and potentially model and interpret in vivo pharmacokinetic data, the solubility of erraglusib in simulated intestinal fluid containing different levels of SIF powder was measured. The resulting solubility data are presented in Table 6-19 and generally align with previously collected data for erraglusib. As expected for a compound with few readily ionizable sites, the equilibrium solubility is essentially independent of pH.

[0729] [Table 94]

[0730] Development of ASD manufacturing Four erraglusib / polymer mixture lots were successfully spray dried at 4% w / w total solids loading and a 90:10 acetone:water solvent. The lots used a variety of polymers and were completed without significant interruptions or deviations from the desired parameters. The spray drying parameters for these lots are presented in Tables 6-20 through 6-23. A summary of the manufacturing parameters for these lots is provided in Table 6-24.

[0731] [Table 95]

[0732] [Table 96]

[0733] [Table 97]

[0734] [Table 98]

[0735] [Table 99]

[0736] All lots had yields above 60%, which was expected for the scale and equipment used.

[0737] The ASD prototype was tested for assays and related substances as shown in Table 6-25. Assay values were within the expected range.

[0738] [Table 100]

[0739] As shown in Figures 46 and 47, the ASD prototypes were also characterized via SEM and XRPD to assess the ASD particle morphology and whether any crystallization could be detected.

[0740] All ASD lots were observed by SEM to have a mixed morphology of intact, collapsed, and shattered spheres. No surface crystallinity was observed, and particle size appeared to be fairly consistent across lots. See Figure 46.

[0741] The erraglusib ASD lots exhibited an amorphous halo with no detectable crystalline peaks. The observed differences in the amorphous halo were expected due to the inclusion of different polymers. The aluminum background holder used for the ASD material resulted in the observed peak at 37° 2-theta. See Figure 47.

[0742] Non-sink biorelevant dissolution of ASD prototypes was evaluated in both FaSSIF pH 6.5 (Figure 48) and FeSSIF pH 5.0 (Figure 49).

[0743] The ASD prototypes demonstrated approximately 10-fold greater solubility than the solubility of crystalline erraglusib measured in FaSSIF (5.7 μg / mL). The HPMCAS-M ASD sample exhibited the most rapid dissolution rate. However, the Eudragit® L100 and Eastman CAP ASDs sustained higher drug concentrations throughout the study. It was also observed that the 50:50 erraglusib:EL100, predissolved with 500 μg / mL HPMCAS-H, exhibited poor wettability, which may have contributed to suboptimal performance. Complete concentration data are provided in Table 6-26, with "free" indicating that the drug concentration remained colloidal after filtration of sizes >200 nm.

[0744] [Table 101]

[0745] The erraglusib:CAP and erraglusib:EL100 ASD prototypes showed similar performance in terms of solubilized and free drug species. HPMCAS-based formulations had lower total solubilized and free drug compared to the erraglusib:EL100 and erraglusib:CAP dispersions. Additionally, the addition of HPMCAS-H to erraglusib:EL100 ASD did not result in significant differences in solubility compared to erraglusib:EL100 ASD alone. Typically, HPMCAS-H can be added as a concentration-retaining polymer. Relevant data are provided in Table 6-27, where "free" indicates that the drug concentration remains as colloidal species after filtration of sizes >200 nm.

[0746] [Table 102]

[0747] Final characterization was performed to evaluate the glass transition temperature (Tg) of the ASD prototypes by DSC under dry conditions. The results of the DSC experiments are presented in Table 6-28.

[0748] [Table 103]

[0749] All ASD prototypes were observed to have a single Tg event, indicating a single amorphous phase and a uniform amorphous dispersion. Dry ASD Tg values ranged from 95 to 114°C. Among the different ASD formulations, erraglusib:CAP ASD had the highest Tg, and erraglusib:EL100 ASD had a Tg of 106°C. Higher Tg values tend to indicate a lower risk of a change in physical state related to stability.

[0750] Stability testing After packaging with desiccant and exposure to 40°C / 75% RH for 3 months, erraglusib ASD showed no evidence of significant changes to its physical appearance, physical state, or chemical state. There was no reduction in performance when evaluated under non-sink dissolution conditions.

[0751] Assays for ASD formulations tended to be approximately 1% lower than previous time points. No change in phthalate content was observed for CAP-based ASDs after 3 months of sealing with desiccant at 40°C / 75% RH.

[0752] conclusion The production of four ASD prototypes was successfully completed with overall yields ranging from 63.5 to 68.7% and assay values ranging from 99.2 to 100.5%. XRPD confirmed the amorphous nature of the final products, and SEM imaging showed a mixed morphology typical of the ASD process. All ASD prototypes demonstrated significant solubility enhancement in SIF compared to crystalline erraglusib. The erraglusib:CAP and erraglusib:EL100 ASD prototypes were selected for further development into tablet prototypes.

[0753] Granulation and Blending Erragulusib:CAP and erragulusib:EL100 ASD were granulated and blended according to the formulation presented in Table 6-29.

[0754] [Table 104]

[0755] The final blends of erraglusib:CAP and erraglusib:EL100 ASD were weighed and characterized. A final blend yield of 96.3% was obtained for the Eastman CAP formulation and 96.0% for the Eudragit® L100 formulation. The yields of both blends are within the expected range. An 8 mm round, flat-faced tool was used to measure the compression profiles for both formulations, and the data are presented in Tables 6-30 and 6-31. As shown in Figure 50, the erraglusib:EL100 formulation exhibited a significant increase in compressibility compared to the erraglusib:CAP formulation, which is likely inherent to the polymer structure.

[0756] [Table 105]

[0757] [Table 106]

[0758] The erraglusib:EL100 bulk blends were also tested for bulk and tapped density in triplicate, as shown in Table 6-32. The CI and HR values indicate that the final blends should have good flow properties.

[0759] [Table 107]

[0760] Tableting Tablets were manufactured using an MCTM-1 tablet press according to the previously defined tablet formulation to compare formulation performance. Compression of unit doses targeted at a compression pressure of 4,000 psi was performed using 9.5 x 21.0 mm smooth-faced modified oval tooling.

[0761] Physical characterization tests were performed on the tablet prototypes, and the tablet characterization results are shown in Table 6-33.

[0762] [Table 108]

[0763] Visually, core tablets compressed with 9.5 x 21.0 mm tooling exhibited acceptable side band and cup depth (approximately 24% of total thickness), as shown in Figure 51.

[0764] At equivalent compaction pressures (4000 psi), the erraglusib:EL100 formulation had a tensile strength of approximately 1.9 MPa. The erraglusib:CAP formulation had a tensile strength of approximately 1.4 MPa, but was more friable, which could cause problems during coating.

[0765] Tablets were also evaluated for appearance, moisture content, assay, and related substances as summarized in Table 6-34.

[0766] [Table 109]

[0767] As shown in Figure 52, dissolution rates were measured for both ASD formulation lots and compared to the previous erraglusib:CAP prototype. The tablet erraglusib:CAP prototype (35044-052-CAP-B) was comparable to previous data generated for the larger CAP tablet lot 35044-033. However, the erraglusib:EL100 tablet prototype (35044-052-L100-B) exhibited slower dissolution release than the CAP tablet prototype. By T = 15 minutes, the CAP prototype was >80% dissolved, whereas the erraglusib:EL100 tablet prototype dissolved more slowly (>80% at T = 60 minutes). The slower release profile observed for the erraglusib:EL100 tablet prototype may be related to the higher tensile strength of these tablets (1.9 MPa) compared to the tensile strength of the erraglusib:CAP tablet prototype (1.4 MPa).

[0768] conclusion The solubility of erraglusib in commercially viable spray-drying solvents was successfully evaluated with and without the inclusion of various polymers. Although switching the solvent from THF to acetone decreased drug substance solubility, erraglusib remained soluble in the presence of dispersion polymers at commercially relevant spray solution weight percentages in acetone:water mixtures.

[0769] Micellar partition coefficients were experimentally determined for erraglusib to inform in vitro non-sink biorelevant dissolution studies and in vivo performance. This preformulation knowledge was utilized to prepare spray-dried dispersions of erraglusib for subsequent characterization.

[0770] Two ASD prototypes were identified as leads—50:50 erraglusib:CAP and 50:50 erraglusib:EL100. These were successfully dry granulated, final blended, and compressed into 250 mg strength tablets. Tablet characterization was performed. The erraglusib:CAP ASD tablets demonstrated performance consistent with previous tablet prototypes. The erraglusib:CAP tablets exhibited more rapid dissolution than the erraglusib:EL100 tablet prototype, which may be related to the lower tensile strength of the erraglusib:CAP tablets compared to the erraglusib:EL100 tablets.

[0771] Stability testing This protocol describes a stability study of packaged non-GMP lots of erraglusib ASD tablets: 35044-052-CAP-B (250 mg) and 35044-052-L100-B (250 mg). The stability study evaluates changes in product quality over time under the following conditions: storage (25°C / 60% RH) and accelerated storage (40°C / 75% RH).

[0772] Erraglusib ASD tablets, 250 mg, were packaged in a 5-pack configuration. The 5-pack configuration consisted of a 60 cc, white HDPE plastic round packer bottle (33 / 400) sealed with a 33 mm white child-resistant polypropylene cap with a foil inner foam liner that activated the heat induction seal, and a 1 gram desiccant sachet. The packaged active tablet product was stored at 25°C / 60% RH and 40°C / 75% RH.

[0773] Three-month tablet samples were pulled and analyzed for appearance, assay and related substances, and sink dissolution.

[0774] At 3 months, appearance remained unchanged for both formulations and in all conditions.

[0775] Sink dissolution at 3 months was slower than the initial dissolution profile for both formulations when compared to profiles normalized to final percent dissolution. Normalized results are presented based on the initial and 1-month time points where percent dissolved was greater than 100%.

[0776] Sink dissolution at the 3-month time point was analyzed using HPLC rather than the previously used in-line UV analysis. Additionally, samples were analyzed using a standard prepared in 6% CTAB and a separate standard prepared in ACN. This was done to evaluate the hypothesis that the API standard in CTAB did not completely dissolve and was at least partially responsible for the greater than 100% dissolution results collected at the early and 1-month time points. The CTAB standard had a lower response compared to the ACN standard and was observed to precipitate over time. This was closely monitored during the 3-month analysis and was injected immediately after preparation to ensure it dissolved during analysis. The data presented here are based on the CTAB standard, which closely agreed with the ACN standard and did not result in greater than 100% dissolution as observed at previous time points.

[0777] Three-month assay and related substance results for Eastman CAP tablets were comparable to the initial results. Three-month results for Eudragit® L100 tablets were comparable to the initial results (97%).

[0778] The impurity profiles of both tablet samples stored at 25°C / 60% RH and 40°C / 75% RH for 3 months were consistent with historical data generated at T=0.

[0779] Sample preparation for tablets was updated to include shaking in water for 30 minutes to promote complete disintegration of the tablets. Samples were also placed on a shaker and sonicated after adding diluent until approximately 75% full. These updates to sample preparation appear to be more robust for stability samples and are recommended for future testing.

[0780] Tablet formulation optimization Prototype tablet manufacturing Prototype tablets were manufactured based on the formulation compositions contained in Table 6-35. The previous formulation is included for reference. The goal of tablet optimization was to minimize tablet weight while increasing processing robustness. Two composition tables are included for each prototype, the first by weight % and the second by mg / tablet.

[0781] [Table 110]

[0782] A Turbula T2 F blender was used to facilitate the blending-deagglomeration-blending procedure on the pre-granulated blend, and this process is shown in Figure 58 with additional details.

[0783] Slugging and Grinding Compression profiles were generated on an MTCM-1 hydraulic single station press equipped with a 0.9735" (2.5 cm) round flat face fixture. A summary of this data is presented in Figure 59. All formulations had very good compressibility at reasonable pressures.

[0784] Slugging was performed in an MTCM-1 hydraulic single station press equipped with a 0.9735" (2.5 cm) round flat-face fixture. Slugs were produced to a target 0.5 MPa tensile strength. Summary data is included in Table 6-36.

[0785] [Table 111]

[0786] The slugs were milled using a small Gerteis mill with a 1.00 mm square wire mesh screen and a 1.0 mm gap. Representative images of the granules show that there is no evidence of material being extruded through the screen, resulting in high aspect ratio granules.

[0787] Final Blend The final blend was prepared in a Turbula T2 F blender. Additional details are included in Figure 60.

[0788] compression Tablets were compressed on an MTCM-1 hydraulic tablet press equipped with 9.5 x 21.5 mm modified oval tooling (1000 mg) and 8.5 x 19.0 mm modified oval tooling (900 and 850 mg). Tablets were manufactured to a target tensile strength of approximately 2.0 MPa to ensure robust tablet integrity for potential future coating operations. Summary data from tablet manufacture can be found below in Table 6-37.

[0789] [Table 112]

[0790] Disintegration of the prototype tablet formulations was performed in 0.01N HCl pH 2.0. Summary data is included in Table 6-38 below; all formulations disintegrated in less than 10 minutes.

[0791] [Table 113]

[0792] For Prototype 1 tablets, it was observed that the tablet dimensions were relatively large compared to the tubes used for disintegration, which may have contributed to variability in endpoint determinations by disintegration device and higher than expected variability in results.

[0793] Non-sink dissolution was performed on the three tablet formulations compared to the input ASD formulation (conditions: USP Type II, 1 L container, large paddle, 50 RPM, pH 4.0 HCl 1000 μg / mL to pH 5.0 FeSSIF 500 μg / mL). The tablets were significantly slower than the ASD as shown in Figure 61 and Table 6-39.

[0794] [Table 114]

[0795] It was noted that coning and unstirred material was present in all formulations during the solubility experiments.

[0796] Drug Product Performance Survey Based on the slower dissolution of Prototype 1-3 tablets compared to the ASD formulation, a second round of dissolution studies was conducted to better understand the potential sources of slow solubility in non-sink biorelevant studies.

[0797] In this experiment, Prototype 1 tablets were compared to the final blend to determine if the formulation rapidly dissolves after granulation / final blending and before compression. See Table 6-40. The final blend dissolved to a higher maximum concentration and had a higher concentration at each time point compared to the tablet formulation. This indicates that the compression step of the process reduces solubility and range during non-sink biorelevant testing. See Figure 62 (Conditions: USP Type II, 1 L container, large paddle, 75 RPM, pH 4.0 HCl 1000 μg / mL to pH 5.0 FeSSIF 500 μg / mL).

[0798] [Table 115]

[0799] The experiment also compared Prototype 1 tablets and the final blend to an in vivo dosed CAP tablet formulation with acceptable performance. The Prototype 1 final blend matched the CAP tablet formulation quite well, with Prototype 1 tablets dissolving slower and exhibiting a lower maximum dissolved concentration.

[0800] One note about the comparison is that the CAP tablet formulation only compressed to a tensile strength of 1.4 MPa, while the Prototype 1 tablets compressed to a tensile strength of 2.1 MPa. Tablet tensile strength is an important attribute for downstream processing when cosmetic coatings are applied.

[0801] Drug Product Formulation and Performance Optimization Based on the findings from the Prototype 1-3 tablet performance study, a second round of tablet formulations was manufactured. The goal of the second round was to increase the disintegrant to improve dissolution performance and evaluate different disintegrants to provide a more robust formulation with less sensitivity to hardness / tensile strength, ensuring acceptable properties for downstream processing in a pan coating operation.

[0802] Tablet prototype 4-7 formulations manufactured as part of the second round of prototyping are summarized below in Table 6-41. Manufacturing data are summarized in Table 6-42.

[0803] [Table 116]

[0804] [Table 117]

[0805] Prototype 6 included an additional manufacturing step of mixing ASD with PVP XL10 to see if a small particle size disintegrant could be used to more effectively break down the granules into small particles with rapid solubility.

[0806] Tablet formulations were tested for disintegration and the results are presented in Table 6-43. Prototype 4 tablets had the fastest disintegration time and good reproducibility.

[0807] [Table 118]

[0808] Based on the size of the device used for 1g tablets, they did not fit into the disintegration device as designed. The tablets were too large and did not fall flat to the bottom of the test tube, resulting in the tablets not agitating in the device as designed. The tablets all settled at the bottom of the test tube and did not rise or fall with agitation as expected for this device.

[0809] The tablet formulations were tested for friability and the results are presented in Table 6-44.

[0810] [Table 119]

[0811] A single tablet friability test was used as an in-process check to provide confidence in proceeding with the manufacture of 10-20 tablets at a tensile strength of approximately 1.8 MPa. All formulations compressed to 1.7-1.8 MPa had low friability and were predicted to be acceptable for downstream processing.

[0812] Based on the poor disintegration of Prototype 6, 3% extragranular disintegrant was added to the formulation for solubility evaluation (Prototype 7 - composition presented in Table 6-41 above). The intent of this evaluation was to add the disintegrant, break up the tablets, and determine if the incorporation of the disintegrant by the ASD had a positive impact on solubility. This formulation was also purposely manufactured at a tensile strength of 1.5 MPa to collect friability data and evaluate performance.

[0813] Prototype 7 formulations were tested for friability and disintegration, and this data, along with manufacturing data, is included in Table 6-45 below.

[0814] [Table 120]

[0815] Dissolution under non-sink biorelevant conditions was performed on prototype formulations 4, 5, and 7. (Conditions: USP Type II, 1 L container, large paddle, 75 RPM, pH 4.0 HCl 1000 μg / mL to pH 5.0 FeSSIF 500 μg / mL) The data are presented below in Figure 63 and Table 6-50.

[0816] [Table 121]

[0817] The solubility of the prototype 4 formulation compressed to a tensile strength of 1.71 MPa closely matched previously tested CAP formulations that had good in vivo performance. The prototype 7 formulation performed like the first round of prototype formulations, while prototype 5 was slow to dissolve.

[0818] It is noteworthy that prototype formulations 4, 5, and 7 all floated during dissolution testing. Sinkers should be evaluated and used, if necessary, to avoid repeated floating of these formulations during dissolution.

[0819] [Example 7] Scaled-up preparation of Elra:EL100 ASD by spray drying Supply of lead ASD for tablet manufacturing To aid in stability and analytical method development, the lead ASD formulation was manufactured to provide a larger tablet batch. The target batch size for the batch was 720 g, which was split into five equal sub-batches due to limitations in the tank size utilized to support manufacturing. The batch utilized an SD40 spray dryer.

[0820] Spray drying parameters were maintained within reasonable limits of target for all five batches. The atomization pressure was increased from the target of 130 Psig to approximately 145 Psig to help mitigate atomizer buildup. Some nozzle contamination was observed in each sub-batch, and the time required to clean the nozzle improved with higher atomization pressures. This issue is expected to be scale-dependent and should become less of an issue with scale-up as higher atomization pressures and available nozzle geometries become available.

[0821] [Table 122]

[0822] [Table 123]

[0823] Five subblots of ASD were analyzed by SEM and PXRD to confirm morphology, and the initial physical state was similar across all lots. SEM images are presented below in Figure 53. PXRD testing resulted in an amorphous halo with no evidence of crystallinity (Figure 54). All subblots were deemed similar by SEM and PXRD and were combined by bag blending to produce a single lot, BBS0002-028, for further characterization and downstream processing.

[0824] The composite ASD (lot BBS0002-028) had a Tg of 112.3±0.1° C. with no signs of phase separation or crystallization. This Tg is slightly higher than the Tg measured for BBS0002-005 at 107.4° C. (test reference BBS0002-017), indicating that the acetone was probably dried more completely in this lot than in previous batches that were shown to contain significant amounts of residual acetone.

[0825] A non-sink biorelevant (conditions: 50 mL beaker, 30 mL FaSSIF pH=6.5) dissolution was performed to assess the concentration versus time profile for the lead ASD. The data in Figure 55 and Table 7-3 show that the complex ASD preforms similarly to previously manufactured formulations.

[0826] [Table 124]

[0827] Non-sink dissolution was performed at slightly different volumes compared to previous studies to aid in the wettability of the ASD when tested at a smaller scale.

[0828] Ultracentrifugation data continued to be variable for the lead elragulusib ASD formulation. The reference formulation (BBS0002-018) had higher ultra values in the past, so the variability is not expected to have any effect and is shown to be related to sampling and analytical variability.

[0829] 50:50 Elra:Eudragit® L100 ASD (BBS0002-028) showed no significant signs of degradation in the form of relevant peaks. 50:50 Elra:Eudragit® L100 (BBS0002-028) was found to be 48.7% 9-ING-41 and had an average impurity of 1.13 area %. Assay and related substances data are presented in Table 7-4 below.

[0830] [Table 125]

[0831] [Example 8] Scaled-up preparation of Elra:EL100 tablets. Blending and dry granulation were performed in a batch size of 1131.52 g to provide a 50% ASD (25% erraglusib) filled final blend. A blend-sieve-blend process was used during intragranular blending to remove clumps of components and eliminate any potential adventitious contaminants (i.e., HDPE) that may have been inadvertently left in the excipient bag. The intragranular blend was sticky. Gentle tapping of the 8 qt (7.5 liter) tote was required to release the blend. The intragranular blend was approximately 50% filled within the 8 qt tote. A 50 g sample of the IG blend was taken for subsequent FloDex, bulk / tapped density, and...

Claims

1. A solid dispersion comprising amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer.

2. The solid dispersion according to claim 1, wherein the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyvinylpyrrolidone, poly(methyl methacrylate-co-methacrylic acid), or a miscible mixture thereof.

3. The solid dispersion according to claim 2, wherein the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone).

4. The solid dispersion according to claim 2, wherein the stabilizing polymer is cellulose phthalate acetate.

5. The solid dispersion according to claim 2, wherein the stabilizing polymer is hydroxypropylmethylcellulose phthalate.

6. The solid dispersion according to claim 2, wherein the stabilizing polymer is hydroxypropyl methylcellulose acetate succinate.

7. The solid dispersion according to claim 2, wherein the stabilizing polymer is polyvinyl acetate phthalate.

8. The solid dispersion according to claim 2, wherein the stabilizing polymer is polyvinylpyrrolidone.

9. The solid dispersion according to claim 1, wherein the stabilizing polymer is poly(methyl methacrylate-co-methacrylic acid).

10. The solid dispersion according to claim 1, wherein the stabilizing polymer is poly(methyl methacrylate-co-methacrylic acid) (1:1).

11. The solid dispersion according to claim 1, wherein the stabilizing polymer is Eudragit® L100 polymer ("EL100").

12. The solid dispersion according to claim 1, wherein the stabilizing polymer is Eudragit® L100-55 polymer.

13. The solid dispersion according to claim 1, wherein the stabilizing polymer is soluble at a pH higher than pH 5.

14. The solid dispersion according to claim 1, wherein the stabilizing polymer is soluble at a pH higher than 5.

5.

15. The solid dispersion according to claim 1, wherein the stabilizing polymer is soluble at a pH higher than pH 6.

16. The solid dispersion according to claim 1, wherein the 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 10% to about 70% by weight relative to the weight of the stabilizing polymer.

17. The solid dispersion according to claim 1, wherein the 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 20% to about 60% by weight relative to the weight of the stabilizing polymer.

18. The solid dispersion according to claim 1, wherein the 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 25% to about 50% by weight relative to the weight of the stabilizing polymer.

19. The solid dispersion according to claim 1, wherein the weight ratio of amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione to the stabilizing polymer is in the range of about 30:70 to about 50:

50.

20. The solid dispersion according to claim 1, having a single glass transition temperature.

21. The solid dispersion according to claim 1, which is stable for at least 48 hours at 60°C and 75% relative humidity.

22. The solid dispersion according to claim 1, which is stable for at least four weeks at 40°C and 75% relative humidity.

23. The solid dispersion according to claim 1, which is stable for at least 12 weeks at 40°C and 75% relative humidity.

24. The solid dispersion according to claim 1, wherein oral administration of the solid dispersion to a patient results in erraglucib AUC∞ which is at least 40% of the erraglucib AUC∞ obtained from an equivalent dose (on a mg / kg basis) of erraglucib administered IV to the patient.

25. The solid dispersion according to claim 24, wherein oral administration of the solid dispersion to a patient results in erraglucib AUC∞ which is at least 68% of the erraglucib AUC∞ obtained from an equivalent dose (on a mg / kg basis) of erraglucib administered IV to the patient.

26. The solid dispersion according to claim 24, wherein oral administration of the solid dispersion to a patient results in erraglucib AUC∞ which is at least 97% of the erraglucib AUC∞ obtained from an equivalent dose (on a mg / kg basis) of erraglucib administered IV to the patient.

27. A pharmaceutical composition comprising a therapeutically effective amount of a solid dispersion according to any one of claims 1 to 26 and a pharmaceutically acceptable excipient.

28. A method for preparing a solid dispersion according to any one of claims 1 to 23, comprising the steps of: a) dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione and a stabilizing polymer in a solvent to form a solution; and b) removing the solvent by evaporation to form the solid dispersion.

29. The method according to claim 28, wherein the solvent is dichloromethane, tetrahydrofuran, aqueous tetrahydrofuran, acetone, aqueous acetone, methanol, ethanol, ethyl acetate, and mixtures thereof.

30. The method according to claim 28, wherein the solvent is evaporated by spray drying.

31. The method according to claim 28, wherein the solvent is evaporated under reduced pressure.

32. The method according to claim 28, wherein the solvent is evaporated using an inert gas.

33. A liquid solution comprising: 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione (erlaglucib); emulsifiers which are polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglycerides, diglycerides, polysorbates, stearoyl lactylate, sorbitan esters, polyglycerol esters, or sucrose esters; pharmaceutically acceptable alcohols; and surfactants which are sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, sodium docusate, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers.

34. Approximately 4.0–6.0% by weight of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)-1H-pyrrole-2,5-dione (erlaglucib); approximately 75–95% by weight of an emulsifier, which is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglycerides, diglycerides, polysorbates, stearoyl lactylate, sorbitan esters, polyglycerol esters, or sucrose esters; approximately 2–17% by weight of a pharmaceutically acceptable alcohol; and The liquid solution according to claim 33, comprising about 0.5 to 10% by weight of surfactants, wherein the surfactants are sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, sodium docusate, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether.

35. The liquid solution according to claim 33 or claim 34, wherein the emulsifier is polyethylene glycol (PEG).

36. The liquid solution according to claim 35, wherein the polyethylene glycol has a molecular weight of 100 to 1000 Da.

37. The liquid solution according to claim 35, wherein the emulsifier is PEG400.

38. The liquid solution according to claim 33 or 34, wherein the pharmaceutically acceptable alcohol is ethanol.

39. The liquid solution according to claim 33 or 34, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

40. The liquid solution according to claim 33 or 34, comprising approximately 4.3 to 5.5% by weight of erlaglucib.

41. The liquid solution according to claim 33 or 34, wherein the concentration of erlaglucib in the solution is at least 45 mg / mL.

42. The liquid solution according to claim 33 or 34, wherein the concentration of erlaglucib in the solution is at least 50 mg / mL.

43. The solution according to claim 33 or 34, wherein the purity of the erlaglucib is greater than 97% when measured by HPLC area percentage.

44. The solution according to claim 43, wherein the purity of the erlaglucib is greater than 98% when measured by HPLC area percentage.

45. The solution according to claim 44, wherein the purity of the erlaglucib is greater than 99% when measured by HPLC area percentage.

46. The solution according to claim 33 or 34, wherein the solution contains less than 2% of impurities, which, when measured by HPLC area percentage, have a relative retention time of 0.97 or 0.96 with respect to the retention time of the erlaglucib.

47. The solution according to claim 33 or 34, wherein the solution contains less than 1% of impurities, which, when measured by HPLC area percentage, have a relative retention time of 0.97 or 0.96 with respect to the retention time of the erlaglucib.

48. The solution according to claim 33 or 34, wherein oral administration of the solution to a patient results in an erraglucib AUC∞ that is at least 40% of the erraglucib AUC∞ obtained from an IV administration of an equivalent dose (on a mg / kg basis) of erraglucib to the patient.

49. The solution according to claim 48, wherein oral administration of the solution to a patient results in an erraglucib AUC∞ that is at least 80% of the erraglucib AUC∞ obtained from an IV administration of an equivalent dose (on a mg / kg basis) of erraglucib to the patient.

50. The solution according to claim 33 or 34, wherein oral administration of the oral solution to a patient in a feeding state results in an erlaglucib AUC∞ that is at least 2.4 times the erlaglucib AUC∞ obtained from administration of the solution to a patient in a fasting state.

51. The solution according to claim 33 or 34, wherein oral administration of the solution to a subject results in plasma erlaglucib Cmax (feeding state) being at least 250% of the corresponding plasma erlaglucib Cmax (fasting state).

52. The solution according to claim 33 or 34, wherein oral administration of the solution to a subject results in plasma erlaglucib AUC∞ (feeding state) which is at least 240% of the corresponding plasma erlaglucib AUC∞ (fasting state).

53. Liquid suspension comprising: erlaglucib; emulsifiers which are polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglycerides, diglycerides, polysorbates, stearoyl lactylate, sorbitan esters, polyglycerol esters, or sucrose esters; pharmaceutically acceptable alcohols; surfactants which are sodium stearate, 4-(5-dodecyl)benzenesulfonate, sodium lauryl sulfate, sodium docusate, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene nonylphenol ethers; and pharmaceutically acceptable diluents.

54. Approximately 0.04–0.6% by weight of an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is an emulsifier, which is a emulsifier, which is an The liquid suspension according to claim 53, comprising about 0.009 to 1% by weight of surfactants, which are lium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 15-hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether, and polyoxyethylene nonylphenol ether; and about 87 to 98% by weight of a pharmaceutically acceptable diluent.

55. The liquid suspension according to claim 53 or 54, wherein the emulsifier is polyethylene glycol (PEG).

56. The liquid suspension according to claim 55, wherein the polyethylene glycol has a molecular weight of 100 to 1000 Da.

57. The liquid suspension according to claim 55, wherein the emulsifier is PEG400.

58. The liquid suspension according to claim 53 or 54, wherein the pharmaceutically acceptable alcohol is ethanol.

59. The liquid suspension according to claim 53 or 54, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

60. The liquid suspension according to claim 53 or 54, comprising approximately 0.04% by weight of erlaglucib.

61. The liquid suspension according to claim 53 or 54, comprising approximately 0.1% by weight of erlaglucib.

62. A liquid suspension according to claim 53 or 54, comprising approximately 0.2% by weight of erlaglucib.

63. The liquid suspension according to claim 53 or 54, comprising approximately 0.5% by weight of erlaglucib.

64. The suspension according to claim 53 or 54, wherein the concentration of erlaglucib in the suspension is at least 0.4 mg / mL.

65. The suspension according to claim 53 or 54, wherein the concentration of erlaglucib in the suspension is at least 0.5 mg / mL.

66. The liquid suspension according to claim 53 or 54, wherein the pharmaceutically acceptable diluent is water, physiological saline, an electrolyte solution, a sugar solution, or a flavoring solution.

67. The liquid suspension according to claim 66, wherein the pharmaceutically acceptable diluent is 5% glucose in water (D5W).

68. The suspension according to claim 53 or 54, wherein the purity of the erlaglucib is greater than 97% when measured by HPLC area percentage.

69. The suspension according to claim 53 or 54, wherein the purity of the erlaglucib is greater than 98% when measured by HPLC area percentage.

70. The suspension according to claim 53 or 54, wherein the purity of the erlaglucib is greater than 99% when measured by HPLC area percentage.

71. The suspension according to claim 53 or 54, wherein, as measured by HPLC area%, the suspension contains less than 2% impurities having a relative retention time of 0.97 or 0.96 with respect to the retention time of the erlaglucib.

72. The suspension according to claim 53 or 54, wherein, as measured by HPLC area%, the suspension contains less than 1% of impurities having a relative retention time of 0.97 or 0.96 with respect to the retention time of the erlaglucib.

73. The suspension according to claim 53 or 54, wherein oral administration of the suspension to a subject results in plasma erlaglucib Cmax (feeding state) being at least 250% of the corresponding plasma erlaglucib Cmax (fasting state).

74. The suspension according to claim 53 or 54, wherein oral administration of the suspension to a subject results in plasma erlaglucib AUC∞ (feeding state) which is at least 240% of the corresponding plasma erlaglucib AUC∞ (fasting state).

75. A tablet for oral administration, (i) ASDs containing erlaglucib and stabilizing polymers; (ii) Binder; (iii) Filler; (iv) Disintegrant; and (v) Lubricants Tablets containing [this ingredient].

76. (i) About 40-60% by weight of ASD containing erlaglucib and stabilizing polymer; (ii) Approximately 19-27% by weight of a binder; (iii) Approximately 10-25% by weight of filler; (iv) Approximately 4-9% by weight of a disintegrant; and (v) Approximately 1-3% lubricant A tablet according to claim 75, comprising:

77. (i) About 50% by weight of ASD containing erlaglucib and stabilizing polymer; (ii) Approximately 19.5% by weight of a binder; (iii) Approximately 19.5% by weight of filler; (iv) about 9% by weight of a disintegrant; and (v) Approximately 2% lubricant A tablet according to claim 76, comprising:

78. The tablet according to any one of claims 75 to 77, wherein the stabilizing polymer is poly(methyl methacrylate-co-methacrylic acid).

79. The tablet according to any one of claims 75 to 77, wherein the ASD comprises about 50% by weight of erlaglucib and about 50% by weight of poly(methyl methacrylate-co-methacrylic acid).

80. The tablet according to any one of claims 75 to 77, wherein the stabilizing polymer is CAP.

81. The tablet according to any one of claims 75 to 77, wherein the ASD comprises about 50% by weight of erlaglucib and about 50% by weight of CAP.

82. The tablet according to any one of claims 75 to 77, wherein the binder is microcrystalline cellulose.

83. The tablet according to any one of claims 75 to 77, wherein the filler is mannitol.

84. The tablet according to any one of claims 75 to 77, wherein the disintegrant is croscarmellose sodium or polyvinylpyrrolidone.

85. The tablet according to any one of claims 75 to 77, wherein the disintegrant is croscarmellose sodium.

86. The tablet according to any one of claims 75 to 77, wherein the lubricant is one or more of silicon dioxide or magnesium stearate.

87. The tablet according to any one of claims 75 to 77, wherein the lubricant comprises silicon dioxide and magnesium stearate.

88. (i) ASD containing approximately 50% by weight of erlaglucib and approximately 50% by weight of poly(methyl methacrylate-co-methacrylic acid); (ii) Microcrystalline cellulose; (iii) Mannitol; (iv) Croscarmellose sodium; (v) silicon dioxide; and (vi) Magnesium stearate A tablet according to claim 75, comprising:

89. (i) Approximately 50% by weight of ASD, comprising approximately 50% by weight of erlaglucib and approximately 50% by weight of poly(methyl methacrylate-co-methacrylic acid); (ii) Approximately 19.5% by weight of microcrystalline cellulose; (iii) Approximately 19.5% by weight of mannitol; (iv) Approximately 9% by weight of croscarmellose sodium; (v) about 1% by weight of silicon dioxide; and (vi) Approximately 1% by weight of magnesium stearate A tablet according to claim 88, comprising:

90. The tablet according to any one of claims 75 to 77, wherein oral administration of the tablet to a subject results in plasma erlaglucib Cmax (feeding state) being at least 250% of the corresponding plasma erlaglucib Cmax (fasting state).

91. The tablet according to any one of claims 75 to 77, wherein oral administration of the tablet to a subject results in plasma erlaglucib AUC∞ (feeding state) which is at least 240% of the corresponding plasma erlaglucib AUC∞ (fasting state).

92. The tablet according to any one of claims 75 to 77, wherein oral administration of the tablet to a subject results in an erraglucib AUC∞ that is at least 40% of the erraglucib AUC∞ obtained from an IV administration of an equivalent dose (on a mg / kg basis) of erraglucib to the subject.

93. The tablet according to claim 92, wherein oral administration of the tablet to a subject results in erraglucib AUC∞ which is at least 68% of the erraglucib AUC∞ obtained from IV administration of an equivalent dose (on a mg / kg basis) of erraglucib to the subject.

94. (i) ASD comprising erlaglucib and stabilizing polymer; and (ii) One or more pharmaceutically acceptable excipients A capsule formulation for oral administration, containing the above.

95. A solid dispersion, liquid solution, liquid suspension, or pharmaceutical composition of the present disclosure for achieving an elaglucib plasma concentration in the range of 1,000 to 10,000 ng / mL in humans, wherein the solid dispersion, liquid solution, liquid suspension, or pharmaceutical composition is for oral administration.

96. A solid dispersion according to any one of claims 1 to 26, a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion according to any one of claims 1 to 26 and a pharmaceutically acceptable excipient, a solution according to claim 33 or 34, a suspension according to claim 53 or 54, a tablet according to any one of claims 75 to 77, or a capsule according to claim 94, for oral administration to the subject.

97. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 96, wherein the disease or disorder is cancer.

98. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 97, wherein the cancer is a brain tumor, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, pancreatic cancer, or glioblastoma.

99. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 97, wherein the cancer is glioblastoma.

100. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 96, wherein the disease or disorder is a lymphoproliferative disorder.

101. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 100, wherein the lymphoproliferative disorder is malignant lymphoproliferative disorder.

102. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 101, wherein the malignant lymphoproliferative disorder is malignant B-cell lymphoproliferative disorder.

103. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 102, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma, acute lymphoblastic leukemia, chronic myeloid leukemia in the acute transformation phase of lymphoblastic leukemia, chronic lymphocytic leukemia / small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, mantle cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, splenic marginal zone B-cell lymphoma, Waldenström macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, plasma cell cachexia, plasma cell neoplasm, primary mediastinal B-cell lymphoma, Hodgkin's disease, or Castleman disease.

104. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 103, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma.

105. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 104, wherein the diffuse large B-cell lymphoma is a double-hit lymphoma.

106. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 101, wherein the lymphoproliferative disorder is malignant T-cell lymphoproliferative disorder.

107. The aforementioned malignant T-cell lymphoproliferative disorders include T-cell leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, intestinal disease-type T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell T / null cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell macrogranule lymphocytic leukemia, chronic myeloid leukemia in the lymphoblastic acute transformation phase, post-transplant lymphoproliferative syndrome, and human T-cell leukemia virus type 1-positive (HTLV-1). ＋ The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 106, wherein the patient is adult T-cell leukemia / lymphoma (ATL), T-cell prelymphocytic leukemia (T-PLL), or an unspecified T-cell lymphoma.

108. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 96, wherein the disease or disorder is traumatic brain injury.

109. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 96, wherein the disease or disorder is idiopathic pulmonary fibrosis.

110. The solid dispersion, pharmaceutical composition, solution, suspension, tablet, or capsule according to claim 96, wherein the disease or disorder is pleural fibrosis.

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