Oral dosage forms of Elglausib

Abstract

The present invention relates to a solid dispersion comprising an amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1, 3] dioxametallo [4, 5-f] indol-7-yl)-1H-pyrrole-2, 5-dione and a stabilizing polymer, and to a method for preparing the same. Comprising a liquid solution of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1, 3] dioxametallo [4, 5-f] indole-7-yl)-1H-pyrrole-2, 5-diketone, and a liquid solution of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1, 3] dioxametallo [4 Comprising a liquid suspension of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1, 3] dioxametallo [4, 5-f] indole-7-yl)-1H-pyrrole-2, 5-dione, and a liquid suspension of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1, 3] dioxametallo [4 Pharmaceutical compositions containing these components and their use in the treatment of diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 355,718, filed on June 27, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application relates to an oral dosage form 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 elraglusib). Background Art

[0004] 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolano[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, also referred to herein as 9-ING-41 or elraglusib, is a 22 H 13 N2O5F, a small molecule with the following chemical structure:

[0005]

[0006] The structure, properties and / or biological activity of elraglusib 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.

[0007] Elraglusib is a glycogen synthase kinase-3β (GSK-3β) inhibitor that is being studied as a single agent and in combination with other chemotherapies for patients with refractory hematological malignancies or solid tumors. GSK-3β is a constitutively active serine-threonine kinase. Increased expression and dysfunction of GSK-3β have been implicated in the biology of multiple diseases, including cancer, inflammation, fibrosis, and neurodegeneration.

[0008] Elraglusib has extremely low water solubility, which limits its use in clinical practice and can only be administered by slow intravenous infusion. The intravenous infusion of elraglusib consists of a 10 mg / mL solution of elraglusib API in a co-solvent vehicle, which is subsequently added to a sterile intravenous diluent, such as 5% w / v dextrose injection. This infusion regimen is burdensome to both caregivers and patients, requiring once or twice weekly dosing and long (≥4 hours) infusion times. Therefore, there is a need for a liquid or solid oral dosage form of elraglusib that can be administered. Summary of the invention

[0009] The present application provides novel solid amorphous dispersions, liquid solutions and liquid suspensions of elraglusib suitable for oral administration.

[0010] The present application also provides novel amorphous solid dispersions ("ASD"), tablets, liquid solutions and liquid suspensions of elraglusib suitable for oral administration.

[0011] In some aspects, the present application 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.

[0012] In some aspects, the present application provides an ASD incorporated into a tablet dosage form.

[0013] In some aspects, the present application provides a liquid solution, which includes 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolane[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (elraglusib), an emulsifier, a pharmaceutically acceptable alcohol, and a surfactant; the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, lactylate), sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene-15-hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitol fatty acid ester, polyoxyethylene alkyl ether and polyoxyethylene nonylphenol ether.

[0014] In other aspects, the present application provides a liquid suspension, which includes: elraglusib, an emulsifier, a pharmaceutically acceptable alcohol, a surfactant, and a pharmaceutically acceptable diluent; the emulsifier is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium dodecyl 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.

[0015] The present application also provides methods of producing these new ASDs, tablets, liquid solutions and liquid suspensions of elraglusib, and methods of using these new ASDs, tablets, liquid solutions and liquid suspensions of elraglusib for treating diseases.

[0016] The present application also provides methods of using the disclosed new ASDs, tablets, liquid solutions, and liquid suspensions of elraglusib. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Shown is the X-ray powder diffraction (XRPD) pattern of amorphous elraglusib solid dispersion (ASD) after dissolution in simulated gastric fluid (SGF).

[0018] Figure 2Shown is the XRPD of ASD after dissolution in fasting state simulated intestinal fluid (FaSSIF).

[0019] Figure 3 Shown is the XRPD of ASD after dissolution in fed state simulated intestinal fluid (FeSSIF).

[0020] Figure 4 Shown is an XRPD overlay of various ASDs after exposure to 40°C, 33% RH for 2 weeks.

[0021] Figure 5 Shown is an XRPD overlay of various ASDs after exposure to 40°C, 75% RH for 3 weeks.

[0022] Figure 6 Shown is an XRPD overlay of an ASD stability sample after 9 weeks exposure at 40°C / 33% RH.

[0023] Figure 7 Shown is an XRPD overlay of an ASD stability sample after 9 weeks exposure at 40°C / 75% RH.

[0024] Figure 8 XRPD showing "Elra:PVAP," a specific ASD made of Phthalavin (polyvinyl acetate phthalate or PVAP) with 50% w / w elraglusib drug load and prepared by spray drying from tetrahydrofuran (THF) solvent.

[0025] Fig. 9 Polarized light microscopy (PLM) images of Elra:PVAP prepared by THF spray drying are shown.

[0026] Fig.10 Shown is the TGA / DSC curve of Elra:PVAP prepared by THF spray drying (no pinhole in the DSC pan).

[0027] Fig.11A and Fig. 11B Shown are TGA and mDSC of Elra:PVAP prepared by THF spray drying after additional drying; (A) no pinholes in the DSC pan, and (B) with pinholes in the DSC pan.

[0028] Fig.12 Shown is the HPLC chromatogram of Elra:PVAP prepared by THF spray drying.

[0029] Figure 13A-13C Shown are particle size distribution (PSD) analysis of Elra:PVAP - (A) Run 1, (B) Run 2, (C) Run 3.

[0030] Fig.14 Showing the XRPD of "Elra:CAP", a specific ASD made of cellulose acetate phthalate (CAP) with 50% w / w elraglusib drug load and prepared by spray drying from THF solvent.

[0031] Fig.15 PLM image showing Elra:CAP spray dried using THF.

[0032] Fig.16 Shown is the TGA / DSC curve of Elra:CAP prepared by THF spray drying.

[0033] Fig.17A and Fig. 17B Shown are TGA and mDSC of Elra:CAP prepared by THF spray drying after additional drying; (A) without pinholes in the DSC pan, and (B) with pinholes in the DSC pan.

[0034] Fig.18 Shown is the HPLC chromatogram of Elra:CAP prepared by THF spray drying.

[0035] Figure 19A-Figure 19C Shown are PSD analysis of Elra:CAP spray dried by THF - (A) Run 1, (B) Run 2, (C) Run 3.

[0036] Fig. 20 Shown are the XRPDs of solids recovered after kinetic solubility analysis of Elra:PVAP and Elra:CAP prepared by THF spray drying.

[0037] Fig.21A and Fig. 21B Shown are the XRPDs of Elra:CAP prepared by THF spray drying after (A) 6 weeks and (B) 12 weeks under different storage conditions.

[0038] Fig. 22 Shows TGA and mDSC of Elra:PVAP after exposure to (A) 5°C sample for 6 weeks, (B) 40°C 33% RH sample for 6 weeks, (C) 40°C 75% RH sample for 6 weeks, (D) 5°C sample for 12 weeks, (E) 40°C 33% RH sample for 12 weeks, and (F) 40°C 75% RH sample for 12 weeks. There are no pinholes in the DSC pan.

[0039] Fig.23Shows TGA and mDSC of Elra:CAP after exposure to (A) 5°C sample for 6 weeks, (B) 40°C 33% RH sample for 6 weeks, (C) 40°C 75% RH sample for 6 weeks, (D) 5°C sample for 12 weeks, (E) 40°C 33% RH sample for 12 weeks, and (F) 40°C 75% RH sample for 12 weeks. There are no pinholes in the DSC pan.

[0040] Fig.24 Shown is an overlay of the ssNMR profiles of the API control, Phthalavin, and CAP, with emphasis on the baseline resolved peak of the API at 91.5 ppm.

[0041] Fig.25 Shown is an overlay of ssNMR spectra of API control, Phthalavin, and CAP, with the first derivative applied to each spectrum.

[0042] Fig.26 ssNMR overlay showing first derivative spectra of 6014415-13-A5 5°C 12 weeks, API control and Phthalavin.

[0043] Fig. 27 Shown is an ssNMR overlay of the first derivative spectra of 6014415-13-A5 40°C / 75% RH 12 weeks, API control, and Phthalavin.

[0044] Fig.28 ssNMR overlay showing first derivative spectra of 6014415-14-A1 5°C 12 weeks, API control, and CAP.

[0045] Fig.29 ssNMR overlay showing first derivative spectra of 6014415-14-A1 40°C / 75% RH 12 weeks, API control, and CAP.

[0046] Fig.30 The elraglusib plasma concentration versus time curves for the pharmacokinetic study outlined in Example 3 are shown.

[0047] Fig.31 XRPD showing Elra:CAP prepared by spray drying of THF ASD material batch 35044-004 shows a monomodal distribution characteristic of an amorphous material. See Example 2B.

[0048] Fig.32 SEM images of ASD material are shown, showing hollow sphere, collapsed sphere and broken sphere morphologies (Batch 35044-004). See Example 2B.

[0049] Fig.33SEM images of elraglusib particles before (upper panel) and after (lower panel) grinding are shown. See Example 2B.

[0050] Fig.34 The change in the PSD distribution of elraglusib before (left panel) and after (right panel) grinding is shown, see Example 2B.

[0051] Fig.35 The XRPD curves of elraglusib before (upper panel) and after (lower panel) milling are consistent. See Example 2B.

[0052] Fig.36 The dissolution profile of elraglusib dosage form in 6% w / w CTAB (cetyltrimethylammonium bromide) in 0.7M sodium chloride is shown, with paddle speeds of 75 rpm vs 100 rpm showing different final dissolution rates. See Example 2B.

[0053] Fig.37 The dissolution profiles of 1% and 6% w / w CTAB in 0.7M sodium chloride are shown, indicating an improved dissolution profile for the ASD material. See Example 2B.

[0054] Fig.38 The elraglusib plasma concentration versus time curves are shown for the pharmacokinetic study outlined in Example 3. The intravenous and oral solution curves represent the average of Studies 2 and 3.

[0055] Fig.39 Shown is DSC of elraglusib API. A TA-Q2000 differential scanning calorimeter was used for DSC.

[0056] Fig.40 Shown is the TGA of elraglusib API. A TA-Q500 thermogravimetric analyzer was used for TGA.

[0057] Fig.41 Plasma concentrations of Elraglusib following intravenous infusion, oral administration with food, and oral administration with food are shown. See Example 5.

[0058] Fig.42 The relationship between the elraglusib exposure metrics Cmax (upper graph) and AUC∞ (lower graph) for the three treatments in individual subjects (PK evaluable population) is shown. See Example 5.

[0059] Fig.43The relative oral bioavailability of elraglusib based on Cmax and AUC∞ of elraglusib is shown as a function of elraglusib dose in the fasted state compared to intravenous infusion (PK evaluable population). See Example 5.

[0060] Fig.44 The relative oral bioavailability of elraglusib based on Cmax and AUC∞ of elraglusib is shown as a function of elraglusib dose in the fed state compared to intravenous infusion (PK evaluable population). See Example 5.

[0061] Fig.45 The relative oral bioavailability of elraglusib based on Cmax and AUC∞ of elraglusib in the fed state compared to the fasted state is shown as a function of elraglusib dose (PK evaluable population). See Example 5.

[0062] Fig.46 SEM images of ASD prototypes are shown, showing a mixed morphology of intact, collapsed and broken spheres. See Example 6.

[0063] Fig.47 XRPD showing ASD batch compared to native elraglusib, showing no detectable crystalline peaks in the dispersion. See Example 6.

[0064] Fig.48 The biorelevant dissolution of Elraglusib ASD prototype in FaSSIF pH 6.5 is shown. (Note: X indicates "free" drug concentration), see Example 6.

[0065] Fig.49 The biorelevant dissolution profile of the elraglusib ASD prototype in FeSSIF pH 5.0 is shown (Note: X indicates “free” drug concentration). See Example 6.

[0066] Fig.50 Compression curves for elraglusib:CAP and elraglusib:EL100 ASD formulations are shown, demonstrating increased compressibility of the elraglusib:EL100 formulation. See Example 6.

[0067] Fig.51 A visual comparison of elraglusib:EL100 and elraglusib:CAP ASD tablets is shown. See Example 6.

[0068] Fig.52Dissolution overlays are shown for tablet formulations (Note: because the percent dissolved exceeded 110% and the variability between vessels was high (>4.2% RSD), the data shown are normalized to the percent dissolved at 120 minutes). See Example 6.

[0069] Fig.53 SEM images of the 5 ASD sub-batches described in Example 7 are shown.

[0070] Fig.54 Shown are PXRD tests of the five ASD sublots described in Example 7. Each sublot exhibited an amorphous halo with no evidence of crystallinity.

[0071] Fig.55 Shown is the dissolution profile of the composite batch of lead ASD described in Example 7 compared to the previous batch of ASD (non-settling biorelevant; conditions: 50 mL beaker, 30 mL FaSSIF pH=6.5).

[0072] Fig.56 Sieve size analysis of Elraglusib lead tablet formulation granules is shown (data reference: BBS0002-062). See Example 8.

[0073] Fig.57 Shown are the results of non-settling dissolution testing performed on the lead tablet formulation compared to the incoming ASD. See Example 8.

[0074] Fig.58 Shows the mixing-delumping-mixing process of an intragranular blend (reference: BBS0002-019). See Example 6.

[0075] Fig.59 The compactability of the elraglusib pregranulation blend used in the prototype formulation (reference: BBS0002-019) is shown. See Example 6.

[0076] Fig.60 The process for final blending of the elraglusib prototype formulation (reference: BBS0002-019) is shown. See Example 6.

[0077] Fig.61 Non-sedimenting dissolution of elraglusib prototype formulation compared to incoming ASD (Ref: BBS0002-024). See Example 6.

[0078] Fig.62 Non-sedimenting dissolution of elraglusib prototype formulation compared to incoming ASD is shown. See Example 6.

[0079] Fig.63 Non-sedimenting dissolution of elraglusib prototype formulation compared to incoming ASD (Ref: BBS0002-044). See Example 6. DETAILED DESCRIPTION

[0080] By reference to the following description, including the following definitions and examples, the application can be more fully understood. Some features of the disclosed compositions and methods described herein in the context of the individual aspects may also be provided in combination in a single aspect. In addition, for simplicity, the various features of the disclosed compositions and methods described in the context of the individual aspects may also be provided individually or in any sub-combination.

[0081] Unless otherwise defined herein, scientific and technical terms related to this application shall have the meanings commonly understood by those of ordinary skill in the art. In addition, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0082] As used above and throughout the disclosure, the following terms and abbreviations shall be understood to have the following meanings unless otherwise indicated.

[0083] The term "solid dispersion" when applied to a material comprising an active ingredient in an amorphous form is referred to herein as an amorphous solid dispersion, or "ASD."

[0084] The term "SDD" refers to a spray-dried dispersion, i.e. a solid dispersion made by spray drying. ASD made by spray drying is a type of SDD.

[0085] As used in the specification, including the appended claims, the singular forms "a," "an," and "the" include plural referents and a reference to a particular value includes at least that particular value unless the context clearly dictates otherwise.

[0086] When representing the range of values, exemplary embodiments include from one specific value and / or to another specific value. All ranges are inclusive and combinable. In addition, reference to the value described in the range includes each value in the range. When numerical values ​​are expressed as approximate values ​​by using the preposition "about", it should be understood that the specific value forms another embodiment. When referring to a measurable value (such as quantity, length of time, etc.), the term "about" as used herein refers to a reasonable change including the value, for example, ± 10% of the specified value. For example, the phrase "about 50%" can include ± 10% of 50%, or from 45% to 55%, including 50%.

[0087] It should be understood that, for clarity, certain features of the present application described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for simplicity, various features of the present application described in the context of a single embodiment may also be provided separately or in any sub-combination.

[0088] As used herein, "pharmaceutically acceptable," whether by itself or in combination with another term or terms, means that the specified entity, such as a pharmaceutically acceptable excipient, is generally chemically and / or physically compatible with the other ingredients of the composition, and / or is generally physiologically compatible with the recipient thereof.

[0089] As used herein, "subject", "individual" and "patient", whether by themselves or in combination with one or more other terms, refer to mammals, including humans. The term "human" refers to and includes human children, adolescents or adults.

[0090] As used herein, the phrases "method of treating" and "method of treatment," whether by themselves or in combination with another term or terms, should be understood to be used interchangeably with the phrase "for treating" a particular disease.

[0091] As used herein, "treats," "treating," "treated," and "treatment," whether by themselves or in combination with one or more other terms, refer to and include amelioration, alleviation, and / or therapeutic uses and results, or any combination thereof. In other embodiments, the methods described herein may be used prophylactically, i.e., preventatively. It should be understood that "prevention" or preventive uses or results do not refer to or require absolute or complete prevention (i.e., 100% preventive or protective uses or results). As used herein, prevention or prophylactic (preventative) uses or results refer to the administration of a compound or composition that reduces or decreases the severity of a specific condition, symptom, disorder, or disease described herein; reduces or decreases the likelihood of experiencing a specific condition, symptom, disorder, or disease described herein; or delays the onset or recurrence (recurrence) of a specific condition, symptom, disorder, or disease described herein; or any combination of the above uses and results.

[0092] As used herein, "therapeutic" and "therapeutically effective amount", whether by themselves or in combination with one or more other terms, refer to an amount of a compound or composition that (a) treats a specific condition, symptom, disorder, or disease described herein; (b) alleviates, 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; (d) prevents the onset of a specific condition, symptom, disorder, or disease described herein. It should be understood that the terms "therapeutic" and "therapeutically effective" include any of the above-mentioned (a)-(d) effects, alone or in combination with any other (a)-(d).

[0093] "Pharmaceutically acceptable salts" refer to salts of the compounds disclosed in the present application, which are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or with organic acids (e.g., 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- (i) when the acidic protons in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions or aluminum ions), or when the acidic protons in the parent compound are coordinated with organic bases (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Salts also include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochlorides, hydrobromides, tartrates, methanesulfonates, acetates, maleates, oxalates, etc.

[0094] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance, that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate drug administration and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Pharmaceutically acceptable excipients will be known to those skilled in the art and include, for example, in, for example, Paul J. Sheskey et al. (eds), Handbook of Pharmaceutical Excipients, Pharmaceutical Press; Ninth revised edition (October 20, 2020).

[0095] "Solvate" refers to a physical association of a compound of the present application with one or more solvent molecules.

[0096] As used herein, the term "isomers" refers to compounds that have identical chemical structure, but differ with regard to the arrangement of the atoms or groups in space, for example, enantiomers, diastereomers, tautomers.

[0097] The term "administering" refers to directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog that will form an equivalent amount of the active compound or substance in vivo.

[0098] The terms "glycogen synthase kinase-3β" and "GSK-3β" are used interchangeably and according to their common ordinary meaning, refer to proteins with the same or similar names and their functional fragments and homologs. The term includes any recombinant or native form or variant thereof that maintains GSK-3β activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% activity compared to GSK-3β).

[0099] Amorphous solid dispersion of Elraglusib

[0100] In certain aspects, the present application relates 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 (ie, Elraglusib) and a stabilizing polymer.

[0101] As used herein, the term "solid dispersion" refers to a solid material in which an active pharmaceutical ingredient is dispersed in another material. In some embodiments, the solid dispersion is homogeneous, such that amorphous elraglusib is uniformly dispersed throughout the polymer.

[0102] In some embodiments, the dispersion itself has a single glass transition temperature (Tg), which indicates that the dispersion is homogeneous.

[0103] As used herein, Tg refers to the characteristic temperature at which a glassy material undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glassy state to a fluid state after gradual heating. The Tg of an amorphous material (e.g., a polymer, a drug, or a dispersion) can be measured by a variety of techniques, including a dynamic mechanical analyzer (DMA), a dilatometer, a dielectric analyzer, and by a differential scanning calorimeter (DSC). The exact values ​​measured by each technique will vary somewhat, but are generally within 10°C to 30°C of each other. Regardless of the technique used, when an amorphous dispersion exhibits a single Tg, this indicates that the dispersion is substantially uniform.

[0104] As used herein, "stable 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 (ie, Elraglusib) in an amorphous form.

[0105] In some embodiments, the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (Hypromellose): hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate: hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (Phthalavin or PVAP), polyvinyl pyrrolidone, poly (methyl methacrylate-co-methacrylic acid) or a miscible mixture thereof. A miscible mixture of these polymers refers to a mixture in which the mixture of polymers forms a single phase.

[0106] In some embodiments, the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone).

[0107] In some embodiments, the stabilizing polymer is cellulose acetate phthalate (CAP).

[0108] In some embodiments, the stabilizing polymer is hydroxypropyl methylcellulose phthalate.

[0109] In some embodiments, the stabilizing polymer is hydroxypropylmethylcellulose acetate succinate.

[0110] In some embodiments, the stabilizing polymer is polyvinyl acetate phthalate (Phthalavin or PVAP).

[0111] In some embodiments, the stabilizing polymer is polyvinylpyrrolidone.

[0112] In some embodiments, the stabilizing polymer is hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyvinyl pyrrolidone, or mixtures thereof.

[0113] In some embodiments, the stabilizing polymer is a methacrylic acid polymer.

[0114] In some embodiments, the stabilizing polymer is a methacrylic acid copolymer with an alkyl methacrylate.

[0115] 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, L100 polymer ("EL100" or "L100" herein).

[0116] In some embodiments, the stabilizing polymer is poly(methyl methacrylate-co-methacrylic acid) (1:1).

[0117] In some embodiments, the stabilizing polymer is L100.

[0118] In some embodiments, the stabilizing polymer is L100-55 polymer.

[0119] In some embodiments, the stabilizing polymer is soluble at a pH above 5.

[0120] In some embodiments, the stabilizing polymer is soluble at a pH above 5.5.

[0121] In some embodiments, the stabilizing polymer is soluble at a pH above 6.

[0122] In some aspects, 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 from about 10 wt % to about 70 wt % relative to the weight of the stabilizing polymer.

[0123] In some aspects, 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 from about 10 wt % to about 60 wt % relative to the weight of the stabilizing polymer.

[0124] In some aspects, 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 from about 10 wt % to about 50 wt % relative to the weight of the stabilizing polymer.

[0125] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 20 wt % to about 60 wt %, or about 25 wt % to about 50 wt %, relative to the weight of the stabilizing polymer.

[0126] 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 weight percent relative to the weight of the stabilizing polymer.

[0127] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-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, for example, about 20%, about 21%, about 22%, about 23%, about 24%, 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 10 Any of 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%, or about 60%.

[0128] In some embodiments, 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount from about 25% to about 50% by weight relative to the weight of the stabilizing polymer, for example, any of 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%, or about 50% by weight relative to the weight of the stabilizing polymer.

[0129] In some embodiments, the weight ratio of amorphous 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolano[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione to the stabilizing polymer is from about 30:70 to about 50:50, for example, any of 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.

[0130] In some embodiments, the ASD comprises about 40-50 wt % elraglusib and about 50-60 wt % cellulose acetate phthalate (CAP).

[0131] In some embodiments, the ASD comprises about 50 wt % elraglusib and about 50 wt % cellulose acetate phthalate (CAP).

[0132] In some embodiments, the ASD comprises about 40-50 wt % elraglusib and about 50-60 wt % poly(methyl methacrylate-co-methacrylic acid).

[0133] In some embodiments, the ASD comprises about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid).

[0134] In some embodiments, the ASD comprises about 40-50 wt % elraglusib and about 50-60 wt % L00.

[0135] In some embodiments, the ASD comprises about 50% by weight elraglusib and about 50% by weight L00.

[0136] In some embodiments, the solid dispersion has a single glass transition temperature.

[0137] In some embodiments, the solid dispersion is stable when exposed to 60° C. and 75% relative humidity for at least 48 hours, e.g., 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 elraglusib in the solid dispersion remains amorphous as measured by XRPD or other analytical techniques.

[0138] In other embodiments, the solid dispersion is stable when exposed to 40°C and 75% relative humidity for at least 4 weeks, eg, at least 4 weeks, at least 8 weeks, or at least 12 weeks.

[0139] In other embodiments, the solid dispersion is stable for at least 12 weeks when exposed to 40°C and 75% relative humidity.

[0140] In some aspects, oral administration of the solid dispersion of the present application to a patient produces an AUC∞ of elraglusib that is 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 %, 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%.

[0141] Oral administration of the solid dispersion of the present application to a patient produces an elraglusib AUC∞ that is at least 68% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

[0142] Oral administration of the solid dispersion of the present application to a patient produces an elraglusib AUC∞ that is at least 97% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

[0143] In some aspects, the invention relates to methods for preparing the solid dispersions of the invention.

[0144] In some embodiments, the dispersion is formed by "solvent treatment", in which elraglusib and polymer are dissolved in a common solvent. "Common" here means that the solvent, which can be a mixture of compounds, will dissolve the drug and polymer at the same time. After elraglusib and polymer are dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. An exemplary method is spray drying and precipitation by rapidly mixing the polymer and drug solution with CO2, water or some other non-solvent. In some embodiments, the removal of the solvent produces a uniform solid dispersion. As previously described, in this uniform dispersion, elraglusib is uniformly dispersed throughout the polymer and can be considered to be a solid solution of elraglusib in the polymer.

[0145] The solvent can be removed by a spray drying process. The term spraying is used conventionally and broadly to refer to the process of breaking up a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a vessel (the spray drying apparatus) wherein there is a strong driving force for evaporation of the solvent from the droplets. The strong driving force for solvent evaporation is typically provided by maintaining the solvent partial pressure in the spray drying apparatus well below the solvent vapor pressure at the temperature of the drying droplets. This is accomplished by (1) maintaining the pressure in the spray drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2) mixing the droplets with a warm drying gas; or (3) both. In addition, at least a portion of the heat required for solvent evaporation can be provided by heating the spray solution.

[0146] Solvents suitable for spray drying can be any organic compound in which elraglusib and the polymer are mutually soluble, so that the total dissolved solids are at least 8% by weight of the solution. In some embodiments, the solvent is also volatile, with a boiling point of 150°C or less. In addition, the solvent should have relatively low toxicity and be removed from the dispersion to an acceptable level according to the guidelines of the International Committee for Harmonization (ICH). Removing the solvent to this level may require a treatment 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, dichloromethane, toluene, and 1,1,1-trichloroethane. Low volatility solvents such as dimethylacetamide or dimethyl sulfoxide may also be used. Solvent mixtures may also be used, such as 50% methanol and 50% acetone, and may also be a mixture with water, as long as the polymer and elraglusib are sufficiently soluble and chemically stable to make the spray drying process feasible. Typically, due to the hydrophobic nature of elraglusib, a non-aqueous solvent or a mixture of a non-aqueous solvent and water is used. In some embodiments, the non-aqueous solvent contains less than or equal to about 10 wt.% water. In other embodiments, the non-aqueous solvent includes less than about 10 wt.% water; in some embodiments, less than 1 wt.% water.

[0147] In some embodiments, the solvent used to spray dry the elraglusib / polymer solution is THF, acetone, ethanol, methanol, mixtures thereof, or mixtures with water.

[0148] In some embodiments, the solvent used to spray dry the elraglusib / CAP solution is an acetone / water mixture.

[0149] In some embodiments, the solvent used to spray dry the elraglusib / CAP solution is a mixture of 90-95 wt % acetone and 5-10 wt % water.

[0150] In some embodiments, the solvent used to spray dry the elraglusib / CAP solution is a mixture of 90 wt % acetone and 10 wt % water.

[0151] In some embodiments, the solvent used to spray dry the elraglusib / CAP solution is a mixture of 95 wt % acetone and 5 wt % water.

[0152] In some embodiments, the solvent used for spray drying the elraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of acetone and water.

[0153] In some embodiments, the solvent used to spray dry the elraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of 90-95 wt % acetone and 5-10 wt % water.

[0154] In some embodiments, the solvent used to spray dry the elraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of 90 wt % acetone and 10 wt % water.

[0155] In some embodiments, the solvent used to spray dry the elraglusib / poly(methyl methacrylate-co-methacrylic acid) solution is a mixture of 95 wt % acetone and 5 wt % water.

[0156] In some embodiments, the solvent used to spray dry the elraglusib / EL100 solution is a mixture of acetone and water.

[0157] In some embodiments, the solvent used to spray dry the elraglusib / EL100 solution is a mixture of 90-95 wt % acetone and 5-10 wt % water.

[0158] In some embodiments, the solvent used to spray dry the elraglusib / EL100 solution is a mixture of 90 wt % acetone and 10 wt % water.

[0159] In some embodiments, the solvent used to spray dry the elraglusib / EL100 solution is a mixture of 95 wt % acetone and 5 wt % water.

[0160] Usually, the temperature and flow rate of the drying gas are selected so that the polymer / drug solution droplets are sufficiently dry when they arrive at the device wall, so that they are substantially solid, and so that they form a fine powder and do not adhere to the device wall. The actual time length to reach this degree of dryness depends on the size of the droplets. The large surface volume ratio of the droplets and the large driving force for solvent evaporation cause the actual drying time to be several seconds or shorter, more generally less than 0.1 second. This fast drying is usually most important for particles to maintain a consistent, uniform dispersion rather than being separated into a phase rich in drug and rich in polymer.

[0161] Spray drying methods 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, pp. 2054 to 2057. For more details on spray drying methods and equipment, see Marshall "Atomization and Spray-Drying." 50 Chem. Eng. Prog. Monogr. Series 2 (1954).

[0162] In some embodiments, the method for preparing a solid dispersion comprises the following steps: (a) dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[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.

[0163] In the method of the present application, suitable solvents for dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione and stabilizing the polymer include dichloromethane, tetrahydrofuran, aqueous tetrahydrofuran solution, acetone, aqueous acetone solution, methanol, ethanol, ethyl acetate and mixtures thereof.

[0164] In some embodiments, a suitable solvent for dissolving elraglusib and stabilizing the polymer in the methods of the present application is aqueous acetone.

[0165] In some embodiments, a suitable solvent for dissolving elraglusib and the stabilizing polymer in the methods of the present application is an acetone-water solution comprising about 90 weight percent acetone and about 10 weight percent water.

[0166] In some embodiments, a suitable solvent for dissolving elraglusib and the stabilizing polymer in the methods of the present application is an acetone-water solution comprising about 95 weight percent acetone and about 5 weight percent water.

[0167] In some embodiments, the stabilizing polymer suitable for preparing the method for the solid dispersion of the present application includes N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copolyvidone), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (Phthalavin), polyvinyl pyrrolidone or its miscible mixture. The miscible mixture of these polymers is a mixture in which the mixture of polymers forms a single phase.

[0168] In some embodiments, stabilizing polymers suitable for use in the method for preparing the solid dispersion of the present application include N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (Phthalavin), polyvinyl pyrrolidone, poly(methyl methacrylate-co-methacrylic acid), for example. L100 polymer ("EL100"), or a miscible mixture thereof. A miscible mixture of these polymers is a mixture in which the mixture of polymers forms a single phase.

[0169] In some embodiments, a stabilizing polymer suitable for use in the methods of preparing the solid dispersions of the present application is poly(methyl methacrylate-co-methacrylic acid).

[0170] In some embodiments, the stabilizing polymer suitable for use in the method for preparing the solid dispersion of the present application is L100 polymer ("EL100").

[0171] In some embodiments, a stabilizing polymer suitable for use in the methods of preparing the solid dispersions of the present application is cellulose acetate phthalate (CAP).

[0172] In some embodiments of the disclosed method, the solvent is removed by evaporation. The solvent can be removed by any evaporation technique to prepare the solid dispersion of the present application, that is, the solid dispersion containing amorphous elraglusib.

[0173] In some embodiments, the solvent is evaporated by spray drying.

[0174] In some embodiments, the solvent is evaporated under reduced pressure, eg, a partial vacuum.

[0175] In some embodiments, the solvent is evaporated using an inert gas. For example, in some aspects, the solution is passed through an evaporating solvent under an inert gas flow. In some embodiments, the inert gas comprises nitrogen. In other embodiments, the inert gas comprises argon.

[0176] Elraglusib oral liquid suspension and liquid solution

[0177] Oral liquid solution

[0178] In other aspects, the present application provides a liquid solution, which includes 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolane[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (elraglusib), an emulsifier, a pharmaceutically acceptable alcohol, and a surfactant; the emulsifier is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride The surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

[0179] In some embodiments, the present application provides a liquid solution, the liquid solution comprising about 4.0-6.0wt.% 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolane[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione; about 75-95wt.% emulsifier (emulsifier is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester , polyglycerol ester or sucrose ester); about 2-17%wt.% of a pharmaceutically acceptable alcohol; about 0.5-10%wt.% of a surfactant (the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium lauryl sulfate, sodium docusate, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene-15-hydroxystearate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan fatty acid ester, polyoxyethylene alkyl ether and polyoxyethylene nonylphenol ether).

[0180] In some aspects, the liquid solution includes about 4.0-6.0 wt.% of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, for example, 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%.

[0181] In some embodiments, the emulsifier is polyethylene glycol (PEG).

[0182] In some embodiments, the emulsifier is polyethylene glycol having a molecular weight of 100-1000 Da.

[0183] In some embodiments, the emulsifier is PEG 400.

[0184] In some embodiments, the emulsifier is mustard lecithin.

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

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

[0187] In some embodiments, the emulsifier is a monoglyceride.

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

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

[0190] In some embodiments, the emulsifier is stearoyl lactylate.

[0191] In some embodiments, the emulsifier is a sorbitan ester.

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

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

[0194] In some aspects, the emulsifier is present in an amount of about 75-95 wt.%, for example, one of about 75 wt.%, about 76 wt.%, about 77 wt.%, about 78 wt.%, about 79 wt.%, about 80 wt.%, about 81 wt.%, about 82 wt.%, about 83 wt.%, about 84 wt.%, about 85 wt.%, about 86 wt.%, about 87 wt.%, about 88 wt.%, about 89 wt.%, about 90 wt.%, about 91 wt.%, about 92 wt.%, about 93 wt.%, about 94 wt.%, or about 95 wt.%.

[0195] Pharmaceutically acceptable alcohols are alcohols that are non-toxic when administered orally to humans in the amounts present in the composition. Non-toxic alcohols are those that are considered "generally recognized as safe" ("GRAS") by the U.S. Food and Drug Administration. An exemplary pharmaceutically acceptable alcohol is ethanol.

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

[0197] In some aspects, the pharmaceutically acceptable alcohol is present in an amount of about 2-17% wt.%, for example, one of about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, or about 17 wt.%.

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

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

[0200] In some embodiments, the surfactant is sodium dodecyl 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 polyoxyethylene nonylphenol ether.

[0212] In some aspects, the surfactant is present in an amount of about 0.5-10% wt.%, for example, one of about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1.0 wt.%, about 1.5 wt.%, about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.%, about 5 wt.%, about 5.5 wt.%, about 6 wt.%, about 6.5 wt.%, about 7 wt.%, about 7.5 wt.%, about 8 wt.%, about 8.5 wt.%, about 9 wt.%, about 9.5 wt.%, or about 10 wt.%.

[0213] In some embodiments, the present application is directed to a liquid solution comprising about 4.3-5.5 wt.% of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, about 75-95 wt.% of polyethylene glycol 400, about 1-16 wt.% of ethanol, about 0.5-8.5 wt.% of polysorbate 80, and about 0-5 wt.% of water.

[0214] In some embodiments, the present application is directed to a liquid solution comprising about 4.5-5.5 wt.% of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, about 75-95 wt.% of polyethylene glycol 400, about 1-16 wt.% of ethanol, about 0.5-8.5 wt.% of polysorbate 80, and about 0-5 wt.% of water.

[0215] In some embodiments, the liquid solution comprises about 4.7-4.8 wt. % elraglusib, about 76-91 wt. % polyethylene glycol 400, about 4.7-14.3 wt. % ethanol, and about 0.5-1 wt. % polysorbate 80.

[0216] In some embodiments, the liquid solution comprises about 4.7-4.8 wt. % elraglusib, about 89-90 wt. % polyethylene glycol 400, about 4.7-4.8 wt. % ethanol, and about 0.9-1 wt. % polysorbate 80.

[0217] In some embodiments, the liquid solution comprises about 4.2-4.4 wt.% elraglusib, about 89-90 wt.% polyethylene glycol 400, about 4.7-4.8 wt.% ethanol, and about 0.9-1 wt.% polysorbate 80.

[0218] In some embodiments, the concentration of elraglusib 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.

[0219] In some embodiments, the concentration of elraglusib in the liquid solution is about 50 mg / mL.

[0220] In some embodiments, the concentration of elraglusib in the liquid solution is at least 50 mg / mL.

[0221] In some embodiments, the liquid solution contains less than 3% total related substances as determined by high performance liquid chromatography (HPLC) area %.As used herein, the term "related substances" refers to compounds that are structurally related to elraglusib and that exist as impurities.

[0222] As used herein, HPLC Area % is determined using the HPLC method listed in Table 5 herein.

[0223] In some embodiments, the solution contains less than 2% total related substances as determined by HPLC area %.

[0224] In some embodiments, the solution contains less than 1% total related substances as determined by HPLC area %.

[0225] In some embodiments, the elraglusib in the solution has a purity greater than 97% as determined by HPLC area %.

[0226] In some embodiments, the elraglusib in the solution has a purity greater than 98% as determined by HPLC area %.

[0227] In some embodiments, the elraglusib in the solution has a purity greater than 99% as determined by HPLC area %.

[0228] In some embodiments, the solution contains less than 2% of related species having a relative retention time of 0.96 or 0.97 relative to the retention time of elraglusib as determined by HPLC area %.

[0229] In some embodiments, the solution contains less than 1% of a related species having a relative retention time of 0.96 or 0.97 relative to the retention time of elraglusib.

[0230] In some embodiments, the solution contains less than 0.5% of a related species having a relative retention time of 0.96 or 0.97 relative to the retention time of elraglusib.

[0231] In some embodiments, the solution contains less than 0.2% of a related species having a relative retention time of 0.96 or 0.97 relative to the retention time of elraglusib as determined by high performance liquid chromatography (HPLC) area %.

[0232] In some embodiments, the substance of interest is one of the following compounds:

[0233]

[0234] In some aspects, administration of the oral solution of the present application to a patient produces an AUC∞ of elraglusib that is 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%, 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 %, 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%.

[0235] In some embodiments, administration of the oral solution of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 13% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0236] In some embodiments, administration of the oral solution of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 17% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0237] In some embodiments, administration of the oral solution of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 20% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0238] In some embodiments, administration of the oral solution of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 40% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0239] In some embodiments, administration of the oral solution of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 60% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0240] In some embodiments, administration of the oral solution of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 80% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0241] In some aspects of the present application, administration of the oral solution of the present application to a fed patient produces an elraglusib AUC∞ that is at least 2.4 times, at least 2.5 times, at least 2.6 times, at least 2.7 times, at least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, or at least 3.8 times greater than the elraglusib AUC∞ produced by administration of the oral solution of the present application to a fasted patient.

[0242] Oral liquid suspension

[0243] In some aspects, the present application provides a liquid suspension comprising elraglusib, an emulsifier, a pharmaceutically acceptable alcohol, a surfactant and a pharmaceutically acceptable diluent; the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium dodecyl 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.

[0244] In some embodiments, the present application relates to a liquid suspension comprising about 0.04-0.6wt.% elraglusib; about 0.8-10wt.% emulsifier (the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester); about 0.04-1.7wt.% pharmaceutically acceptable alcohol; about 0.0 09-1wt.% of a surfactant (the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium dodecyl 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 about 87-99wt.% of a pharmaceutically acceptable diluent.

[0245] In some aspects, the present application relates to a liquid suspension comprising about 0.08-0.6 wt.% elraglusib; about 1.5-10 wt.% of an emulsifier (the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester); about 0.08-1.7 wt.% of a pharmaceutically acceptable alcohol; about 0.01 -1wt.% of a surfactant (the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium dodecyl 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 about 87-99wt% of a pharmaceutically acceptable diluent.

[0246] In some aspects, the present application relates to a liquid suspension comprising about 0.15-0.6 wt.% elraglusib; about 3-10 wt.% of an emulsifier (the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester); about 0.15-1.7 wt.% of a pharmaceutically acceptable alcohol; about 0.03- 1wt.% of a surfactant (the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium dodecyl 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 about 87-99wt% of a pharmaceutically acceptable diluent.

[0247] In some aspects, the present application relates to a liquid suspension comprising about 0.1-0.6 wt.% elraglusib; about 1.5-10 wt.% of an emulsifier (the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester); about 0.1-1.7 wt.% of a pharmaceutically acceptable alcohol; about 0.01- 1wt.% of a surfactant (the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium dodecyl 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 about 87-98wt% of a pharmaceutically acceptable diluent.

[0248] In some aspects, the liquid suspension includes about 0.4-0.6 wt.% of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione, such as about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, 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%, or about 0.6%.

[0249] In some embodiments of liquid suspensions, the emulsifier is polyethylene glycol (PEG).

[0250] In some embodiments of liquid suspensions, the emulsifier is polyethylene glycol with a molecular weight of 100-1000 Da.

[0251] In some embodiments of liquid suspensions, the emulsifier is PEG 400.

[0252] In some embodiments, the emulsifier is mustard lecithin.

[0253] In some embodiments, the emulsifier is soy lecithin.

[0254] In some embodiments, the emulsifier is egg lecithin.

[0255] In some embodiments, the emulsifier is a monoglyceride.

[0256] In some embodiments, the emulsifier is a diglyceride.

[0257] In some embodiments, the emulsifier is a polysorbate.

[0258] In some embodiments, the emulsifier is stearoyl lactylate.

[0259] In some embodiments, the emulsifier is a sorbitan ester.

[0260] In some embodiments, the emulsifier is a polyglycerol ester.

[0261] In some embodiments, the emulsifier is a sucrose ester.

[0262] In some aspects, the emulsifier is present in an amount of about 0.8-10 wt.%, for example, one of about 0.8 wt.%, about 0.9 wt.%, about 1.0 wt.%, about 1.1 wt.%, about 1.2 wt.%, about 1.3 wt.%, about 1.4 wt.%, about 1.5 wt.%, about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.%, about 5 wt.%, about 5.5 wt.%, about 6 wt.%, about 6.5 wt.%, about 7 wt.%, about 7.5 wt.%, about 8 wt.%, about 8.5 wt.%, about 9 wt.%, about 9.5 wt.%, or about 10 wt.%.

[0263] In some embodiments of the liquid suspension, the pharmaceutically acceptable alcohol is ethanol.

[0264] In some aspects, the pharmaceutically acceptable alcohol is present in an amount of about 0.04-1.7 wt.%, for example, one of about 0.04 wt.%, about 0.05 wt.%, about 0.06 wt.%, about 0.07 wt.%, about 0.08 wt.%, about 0.09 wt.%, about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt.%, about 1.1 wt.%, about 1.2 wt.%, about 1.3 wt.%, about 1.4 wt.%, about 1.5 wt.%, about 1.6 wt.%, or about 1.7 wt.%.

[0265] In some embodiments, the surfactant in the liquid suspension is sodium stearate.

[0266] In some embodiments, the surfactant is 4-(5-dodecyl)benzenesulfonic acid.

[0267] In some embodiments, the surfactant is sodium dodecyl sulfate.

[0268] In some embodiments, the surfactant is docusate sodium.

[0269] In some embodiments, the surfactant is phosphatidylcholine.

[0270] In some embodiments, the surfactant is benzalkonium chloride.

[0271] In some embodiments, the surfactant is a polyoxyethylene sorbitan fatty acid ester.

[0272] In some embodiments, the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

[0273] In some embodiments, the surfactant is polyoxyethylene-15-hydroxystearate.

[0274] In some embodiments, the surfactant is a polyoxyethylene castor oil derivative.

[0275] In some embodiments, the surfactant is polyoxyethylene stearate.

[0276] In some embodiments, the surfactant is a sorbitan fatty acid ester.

[0277] In some embodiments, the surfactant is a polyoxyethylene alkyl ether.

[0278] In some embodiments, the surfactant is polyoxyethylene nonylphenol ether.

[0279] In some aspects, the surfactant is present in an amount of about 0.009-1%wt.%, for example, one of about 0.009wt.%, about 0.01wt.%, about 0.05wt.%, about 0.1wt.%, about 0.15wt.%, about 0.2wt.%, about 0.25wt.%, about 0.3wt.%, about 0.35wt.%, about 0.4wt.%, about 0.45wt.%, about 0.5wt.%, about 0.55wt.%, about 0.6wt.%, about 0.65wt.%, about 0.7wt.%, about 0.75wt.%, about 0.8wt.%, about 0.85wt.%, about 0.9wt.%, about 0.95wt.%, or about 1wt.%.

[0280] In some aspects, the oral suspension of the present application includes about 87-99wt% of a pharmaceutically acceptable diluent, such as one of 87wt%, 88wt%, 89wt%, 90wt%, 91wt%, 92wt%, 93wt%, 94wt%, 95wt%, 96wt%, 97wt%, 98wt% or 99wt%. As used herein, a pharmaceutically acceptable diluent is a liquid that can be safely ingested by a person. Examples of pharmaceutically acceptable diluents include water and aqueous solutions, such as physiological saline, electrolyte solutions, sugar solutions, flavoring solutions, etc.

[0281] In some embodiments, the pharmaceutically acceptable diluent is water.

[0282] In other embodiments, the pharmaceutically acceptable diluent is dextrose (5%) in water (also known as D5W).

[0283] In some embodiments, the present application relates to a suspension comprising: about 0.04-0.05 wt.% elraglusib, about 0.8-1.0 wt.% polyethylene glycol 400, about 0.04-0.05 wt.% ethanol, about 0.009-0.05 wt.% polysorbate 80, and about 98-99 wt.% glucose (5%) aqueous solution.

[0284] In some embodiments, the present application relates to a suspension comprising: about 0.08-0.1 wt.% elraglusib, about 1.5-2.0 wt.% polyethylene glycol 400, about 0.08-0.1 wt.% ethanol, about 0.018-0.1 wt.% polysorbate 80, and about 97-99 wt.% glucose (5%) aqueous solution.

[0285] In some embodiments, the present application relates to a suspension comprising: about 0.15-0.2 wt.% elraglusib, about 3-4 wt.% polyethylene glycol 400, about 0.15-0.2 wt.% ethanol, about 0.03-0.2 wt.% polysorbate 80, and about 96-97 wt.% D5W.

[0286] In some embodiments, the present application relates to a suspension comprising: about 0.1-0.4 wt.% elraglusib, about 2-8 wt.% polyethylene glycol 400, about 0.1-0.5 wt.% ethanol, about 0.01-0.05 wt.% polysorbate 80, and about 98 wt.% D5W.

[0287] In some embodiments, the suspension comprises: about 0.1-0.5 wt.% elraglusib, about 2.6-9.4 wt.% polyethylene glycol 400, about 0.1-0.5 wt.% ethanol, about 0.03-0.1 wt.% polysorbate 80, and about 97 wt.% glucose (5%) aqueous solution.

[0288] In some embodiments, the suspension comprises: about 0.15-0.6 wt.% elraglusib, about 2.7-9.5 wt.% polyethylene glycol 400, about 0.5-1.7 wt.% ethanol, about 0.01 wt.% polysorbate 80, and about 96 wt.% D5W.

[0289] In some embodiments, the concentration of elraglusib in the suspension is at least 0.5 mg / mL.

[0290] In some embodiments, the concentration of elraglusib in the suspension is at least 1 mg / mL.

[0291] In some embodiments, the concentration of elraglusib in the suspension is at least 2 mg / mL.

[0292] In some aspects, the liquid suspension has particles with diameters ranging from 100-1000 nm.

[0293] In some aspects, oral administration of a liquid solution or liquid suspension of the present application to a subject produces an elraglusib plasma concentration ranging from 1000 ng / mL to 10000 ng / mL.

[0294] In some aspects, administration of the oral suspension of the present application to a patient produces an AUC∞ of elraglusib that is 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%, 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 %, 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%.

[0295] In some embodiments, administration of the oral suspension of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 13% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0296] In some embodiments, administration of the oral suspension of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 17% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0297] In some embodiments, administration of the oral suspension of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 20% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0298] In some embodiments, administration of the oral suspension of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 40% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0299] In some embodiments, administration of the oral suspension of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 60% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0300] In some embodiments, administration of the oral suspension of the present disclosure to a patient produces an elraglusib AUC∞ that is at least 80% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to the patient.

[0301] In some aspects of the application, administration of the oral suspension of the application to fed patients produces an elraglusib AUC∞ that is at least 2.4 times, at least 2.5 times, at least 2.6 times, at least 2.7 times, at least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, or at least 3.8 times greater than the elraglusib AUC∞ produced by administration of the oral solution of the application to fasted patients.

[0302] Pharmaceutical compositions for oral administration

[0303] The pharmaceutical compositions of the present application are generally formulated to provide a therapeutically effective amount of elraglusib as an active ingredient. In some embodiments, the pharmaceutical composition contains elraglusib 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, penetration enhancers, solubilizers, adjuvants, surfactants, etc.

[0304] In some aspects, the present application provides a pharmaceutical composition for oral administration, comprising an elraglusib solid dispersion disclosed herein, an elraglusib liquid suspension disclosed herein, or a liquid solution disclosed herein.

[0305] In some aspects, the present application provides a pharmaceutical composition for oral administration, comprising an elraglusib ASD disclosed herein, an elraglusib liquid suspension disclosed herein, or an elraglusib liquid solution disclosed herein.

[0306] In some embodiments, the pharmaceutical composition consists of an elraglusib amorphous solid dispersion disclosed herein, an elraglusib liquid solution disclosed herein, or an elraglusib liquid suspension disclosed herein.

[0307] In some aspects, the pharmaceutical composition of the present application can be administered alone or in combination with one or more other agents (usually also administered in the form of a pharmaceutical composition). When necessary, elraglusib and other agents can be mixed into a preparation, or the two components can be formulated into separate preparations, so that they can be used alone or in combination at the same time.

[0308] In some embodiments, the present application provides a solid pharmaceutical composition for oral administration, which contains: (i) an effective amount of elraglusib; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third agent.

[0309] In some aspects, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of the amorphous solid dispersion of the present application and a pharmaceutically acceptable excipient.

[0310] In some embodiments, the pharmaceutical composition is in a form suitable for oral (e.g., peroral) administration, such as tablets, capsules, caplets, reconstitutable powders, elixirs, liquids, colloids or other types of suspensions, beads, beadlets, granules, microparticles, nanoparticles, and combinations thereof.

[0311] In some embodiments, the pharmaceutical composition is a tablet.

[0312] In other embodiments, the pharmaceutical composition is a capsule.

[0313] In some embodiments, the amount of elraglusib in the pharmaceutical composition is equal to or less than 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. 0.002g, or 0.0001g (or a number in a range defined by or including any two of the foregoing numbers).

[0314] In some embodiments, the amount of elraglusib is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g. , 0.004g, 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, 0.045 g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1 g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.7 5g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or a number in the range defined by any two of the above numbers and a number in the range including any two of the above numbers).

[0315] In some embodiments, the amount of elraglusib ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0316] In some embodiments of adult treatment, dosages of 0.01 mg to 1000 mg, 0.5 mg to 100 mg, and 1 mg to 50 mg per day are examples of dosages that may be used. The exact dosage will depend on the administration form of the compound, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0317] In some respects, the liquid solution or liquid suspension of the present application is for oral administration. In such an embodiment, the liquid solution or liquid suspension may further include a sweetener or flavoring agent, a coloring agent or dye, an emulsifying and / or suspending agent, and a diluent of water, ethanol, propylene glycol, glycerol, polysorbate, and a combination thereof.

[0318] In other aspects, the solid dispersion of the present application is administered orally.

[0319] Pharmaceutical compositions comprising the solid dispersions of the present application can be formulated into discrete dosage forms, such as capsules, cachets, or tablets, liquid or aerosol sprays, each containing a predetermined amount of elraglusib as a powder or granules; or a suspension in water or a non-aqueous liquid, an oil-in-water emulsion or an oil-in-water liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method. In general, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier 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 auxiliary ingredients. Compressed tablets can be prepared by mixing the active ingredient in a free-flowing form (e.g., powder or granules), optionally with an excipient (e.g., but not limited to, a binder, a lubricant, an inert diluent and / or a surfactant or dispersant) in a suitable machine, and tableting. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0320] capsule

[0321] In some aspects, the present application relates to a pharmaceutical dosage form comprising a capsule of the elraglusib ASD of the present application.

[0322] In some embodiments, the present application relates to a pharmaceutical dosage form comprising a capsule of the elraglusib ASD of the present application.

[0323] In some embodiments, the capsule includes the elraglusib ASD of the present application and one or more pharmaceutically acceptable excipients.

[0324] In some embodiments, the capsule includes the elraglusib ASD of the present application and one or more pharmaceutically acceptable excipients, wherein the weight ratio of the ASD to the pharmaceutically acceptable excipient is about 19:1.

[0325] In some embodiments, the capsule includes elraglusib ASD of the present application and croscarmellose sodium.

[0326] In some embodiments, the capsule comprises the elraglusib ASD of the present application and silicon dioxide.

[0327] In some embodiments, the capsule includes elraglusib ASD of the present application and a blend of croscarmellose sodium and silicon dioxide.

[0328] In some embodiments, the capsule includes elraglusib ASD of the present application, and a blend of croscarmellose sodium and silicon dioxide in a weight ratio of croscarmellose sodium:silicon dioxide (90:10).

[0329] In some embodiments, the capsule comprises elraglusib ASD of the present application and a blend of croscarmellose sodium and silicon dioxide, wherein the weight ratio of ASD to the blend of croscarmellose sodium and silicon dioxide is about 19:1.

[0330] In some embodiments, the ASD in the capsule of the present application is Elra:PVAP.

[0331] In some embodiments, the ASD in the capsules of the present application is Elra:CAP.

[0332] In some embodiments, the ASD in the capsules of the present application is Elra: poly(methyl methacrylate-co-methacrylic acid) (ie, amorphous elraglusib with poly(methyl methacrylate-co-methacrylic acid)).

[0333] In some embodiments, the ASD in the capsule of the present application is Elra:EL100 (i.e., having EL100 polymer of amorphous elraglusib).

[0334] In some embodiments, the capsules of the present application comprise hard gelatin capsules.

[0335] In other embodiments, the capsules of the present application include soft gelatin capsules.

[0336] tablet

[0337] In some aspects, the present application relates to a pharmaceutical dosage form comprising a tablet of the elraglusib ASD of the present application.

[0338] In some embodiments, the tablet of the present application comprises:

[0339] (i) an ASD comprising elraglusib and a stabilizing polymer;

[0340] (ii) adhesives;

[0341] (iii) fillers;

[0342] (iv) a disintegrant; and

[0343] (v) Lubricants.

[0344] In some embodiments, the tablet of the present application comprises:

[0345] (i) about 40-60 wt % ASD, the ASD comprising elraglusib and a stabilizing polymer;

[0346] (ii) about 19-27% by weight of a binder;

[0347] (iii) about 10-25% by weight of a filler;

[0348] (iv) about 4-9% by weight of a disintegrant; and

[0349] (v) about 1-3% lubricant.

[0350] In some embodiments, the tablet of the present application comprises:

[0351] (i) about 50 wt % ASD, the ASD comprising elraglusib and a stabilizing polymer;

[0352] (ii) about 19.5% by weight of a binder;

[0353] (iii) about 19.5% by weight of a filler;

[0354] (iv) about 9% by weight of a disintegrant; and

[0355] (v) about 2% lubricant.

[0356] In some embodiments of the tablet of the present application, the ASD comprises elraglusib and poly(methyl methacrylate-co-methacrylic acid).

[0357] In some embodiments of the tablets of the present application, the ASD comprises about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid).

[0358] In some embodiments of the tablet of the present application, the ASD comprises elraglusib and EL100.

[0359] In some embodiments of the tablet of the present application, the ASD comprises about 50 wt % of elraglusib and about 50 wt % of EL100.

[0360] In some embodiments of the tablet of the present application, the ASD comprises elraglusib and CAP.

[0361] In some embodiments of the tablets of the present application, the ASD comprises about 50 wt % elraglusib and about 50 wt % CAP.

[0362] In some embodiments of the tablet of the present application, the binder is microcrystalline cellulose.

[0363] In some embodiments of the tablet of the present application, the filler is mannitol.

[0364] In some embodiments of the tablet of the present application, the disintegrant is cross-linked sodium carboxymethylcellulose or polyvinyl pyrrolidone.

[0365] In some embodiments of the tablet of the present application, the disintegrant is croscarmellose sodium.

[0366] In some embodiments of the tablet of the present application, the lubricant is one or more of syloid silicon dioxide or magnesium stearate.

[0367] In some embodiments of the tablet of the present application, the lubricant includes syloid silicon dioxide and magnesium stearate.

[0368] In some embodiments, the tablet of the present application comprises:

[0369] (i) an ASD comprising about 50 wt% elraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid);

[0370] (ii) microcrystalline cellulose;

[0371] (iii) mannitol;

[0372] (iv) croscarmellose sodium;

[0373] (v) silicon dioxide; and

[0374] (vi) Magnesium stearate.

[0375] In some embodiments, the tablet of the present application comprises:

[0376] (i) about 50 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid);

[0377] (ii) about 19.5% by weight of microcrystalline cellulose;

[0378] (iii) about 19.5% by weight mannitol;

[0379] (iv) about 9 weight percent croscarmellose sodium;

[0380] (v) about 1 weight percent silicon dioxide; and

[0381] (vi) about 1% magnesium stearate.

[0382] In some embodiments, the tablet of the present application comprises:

[0383] (i) 50 wt% ASD, the ASD comprising about 50 wt% elraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid);

[0384] (ii) 19.5% by weight of microcrystalline cellulose;

[0385] (iii) 19.5% by weight of mannitol;

[0386] (iv) 9% by weight of croscarmellose sodium;

[0387] (v) 1 wt % silicon dioxide; and

[0388] (vi) 1% magnesium stearate.

[0389] In some embodiments, the tablet of the present application comprises:

[0390] (i) an ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0391] (ii) microcrystalline cellulose;

[0392] (iii) mannitol;

[0393] (iv) croscarmellose sodium;

[0394] (v) silicon dioxide; and

[0395] (vi) Magnesium stearate.

[0396] In some embodiments, the tablet of the present application comprises:

[0397] (i) about 50 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0398] (ii) about 19.5% by weight of microcrystalline cellulose;

[0399] (iii) about 19.5% by weight mannitol;

[0400] (iv) about 9 weight percent croscarmellose sodium;

[0401] (v) about 1 weight percent silicon dioxide; and

[0402] (vi) about 1% magnesium stearate.

[0403] In some embodiments, the tablet of the present application comprises:

[0404] (i) 50 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0405] (ii) 19.5% by weight of microcrystalline cellulose;

[0406] (iii) 19.5% by weight of mannitol;

[0407] (iv) 9% by weight of croscarmellose sodium;

[0408] (v) 1 wt % silicon dioxide; and

[0409] (vi) 1% magnesium stearate.

[0410] In some embodiments, the tablet of the present application comprises:

[0411] (i) approximately 42% of an ASD comprising elraglusib and a stabilizing polymer;

[0412] (ii) about 27% binder;

[0413] (iii) about 25% filler;

[0414] (iv) about 4% of a disintegrant; and

[0415] (v) about 2% lubricant.

[0416] In some embodiments, the tablet of the present application comprises:

[0417] (i) an ASD comprising about 50 wt% elraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid);

[0418] (ii) microcrystalline cellulose;

[0419] (iii) mannitol;

[0420] (iv) croscarmellose sodium;

[0421] (v) silicon dioxide; and

[0422] (vi) Magnesium stearate.

[0423] In some embodiments, the tablet of the present application comprises:

[0424] (i) about 42 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid);

[0425] (ii) about 27% by weight of microcrystalline cellulose;

[0426] (iii) about 25% by weight mannitol;

[0427] (iv) about 4% by weight of croscarmellose sodium;

[0428] (v) about 0.5 weight percent silicon dioxide; and

[0429] (vi) about 1.5% magnesium stearate.

[0430] In some embodiments, the tablet of the present application comprises:

[0431] (i) an ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0432] (ii) microcrystalline cellulose;

[0433] (iii) mannitol;

[0434] (iv) croscarmellose sodium;

[0435] (v) silicon dioxide; and

[0436] (vi) Magnesium stearate.

[0437] In some embodiments, the tablet of the present application comprises:

[0438] (i) about 42 wt % ASD, wherein the ASD comprises about 50 wt % elraglusib and about 50 wt % EL100; (ii) about 27 wt % microcrystalline cellulose;

[0439] (iii) about 25% by weight mannitol;

[0440] (iv) about 4% by weight of croscarmellose sodium;

[0441] (v) about 0.5 weight percent silicon dioxide; and

[0442] (vi) about 1.5% magnesium stearate.

[0443] In some embodiments, the tablet of the present application comprises:

[0444] (i) an ASD comprising about 50% by weight elraglusib and about 50% by weight CAP;

[0445] (ii) microcrystalline cellulose;

[0446] (iii) mannitol;

[0447] (iv) croscarmellose sodium;

[0448] (v) silicon dioxide; and

[0449] (vi) Magnesium stearate.

[0450] In some embodiments, the tablet of the present application comprises:

[0451] (i) about 42 wt % ASD, wherein the ASD comprises about 50 wt % elraglusib and about 50 wt % CAP; (ii) about 27 wt % microcrystalline cellulose;

[0452] (iii) about 25% by weight mannitol;

[0453] (iv) about 4% by weight of croscarmellose sodium;

[0454] (v) about 0.5 weight percent silicon dioxide; and

[0455] (vi) about 1.5% magnesium stearate.

[0456] In some embodiments, the tablet of the present application comprises:

[0457] (i) about 50 wt % ASD, the ASD comprising elraglusib and a stabilizing polymer;

[0458] (ii) about 22% by weight of a binder;

[0459] (iii) about 22% by weight of a filler;

[0460] (iv) about 5% by weight of a disintegrant; and

[0461] (v) about 2% lubricant.

[0462] In some embodiments, the tablet of the present application comprises:

[0463] (i) about 50 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0464] (ii) about 21.5% by weight of microcrystalline cellulose;

[0465] (iii) about 21.5% by weight mannitol;

[0466] (iv) about 5% by weight of croscarmellose sodium;

[0467] (v) about 1 weight percent silicon dioxide; and

[0468] (vi) about 1% by weight of magnesium stearate.

[0469] In some embodiments, the tablet of the present application comprises:

[0470] (i) about 50 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid);

[0471] (ii) about 21.5% by weight of microcrystalline cellulose;

[0472] (iii) about 21.5% by weight mannitol;

[0473] (iv) about 5% by weight of croscarmellose sodium;

[0474] (v) about 1 weight percent silicon dioxide; and

[0475] (vi) about 1% by weight of magnesium stearate.

[0476] In some embodiments, the tablet of the present application comprises:

[0477] (i) about 55.6 wt % ASD, wherein the ASD comprises elraglusib and a stabilizing polymer;

[0478] (ii) about 24.9 weight percent of a binder;

[0479] (iii) about 12.5% ​​by weight of a filler;

[0480] (iv) about 5% by weight of a disintegrant; and

[0481] (v) about 2% lubricant.

[0482] In some embodiments, the tablet of the present application comprises:

[0483] (i) about 55.6 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid);

[0484] (ii) about 21.5% by weight of microcrystalline cellulose;

[0485] (iii) about 12.5% ​​by weight mannitol;

[0486] (iv) about 5% by weight of croscarmellose sodium;

[0487] (v) about 1 weight percent silicon dioxide; and

[0488] (vi) about 1% by weight of magnesium stearate.

[0489] In some embodiments, the tablet of the present application comprises:

[0490] (i) about 55.6 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0491] (ii) about 21.5% by weight of microcrystalline cellulose;

[0492] (iii) about 12.5% ​​by weight mannitol;

[0493] (iv) about 5% by weight of croscarmellose sodium;

[0494] (v) about 1 weight percent silicon dioxide; and

[0495] (vi) about 1% by weight of magnesium stearate.

[0496] In some embodiments, the tablet of the present application comprises:

[0497] (i) about 58.8 wt % ASD, the ASD comprising elraglusib and a stabilizing polymer;

[0498] (ii) about 20.8 weight percent of a binder;

[0499] (iii) about 10.4% by weight of a filler;

[0500] (iv) about 8% by weight of a disintegrant; and

[0501] (v) about 2% lubricant.

[0502] In some embodiments, the tablet of the present application comprises:

[0503] (i) about 58.8 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % poly(methyl methacrylate-co-methacrylic acid);

[0504] (ii) about 20.8% by weight of microcrystalline cellulose;

[0505] (iii) about 10.4% by weight mannitol;

[0506] (iv) about 8 weight percent croscarmellose sodium;

[0507] (v) about 1 weight percent silicon dioxide; and

[0508] (vi) about 1% by weight of magnesium stearate.

[0509] In some embodiments, the tablet of the present application comprises:

[0510] (i) about 58.8 wt % ASD, the ASD comprising about 50 wt % elraglusib and about 50 wt % EL100;

[0511] (ii) about 20.8% by weight of microcrystalline cellulose;

[0512] (iii) about 10.4% by weight mannitol;

[0513] (iv) about 8 weight percent croscarmellose sodium;

[0514] (v) about 1 weight percent silicon dioxide; and

[0515] (vi) about 1% by weight of magnesium stearate.

[0516] In some aspects, oral administration of the tablet of the present application to a patient produces an elraglusib AUC∞ that is an elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (based on mg / kg) to a patient. %, 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% of the AUC∞.

[0517] In some aspects, oral administration of the solid dispersion of the present application to a patient produces an elraglusib AUC∞ that is at least 68% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

[0518] In some embodiments, the pharmaceutical composition of the present application is anhydrous. The anhydrous pharmaceutical composition of the present application can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions can be packaged using known materials to prevent exposure to water so that they can be included in suitable formula packages. Examples of suitable packaging include, but are not limited to, sealed foil, plastic or the like, unit dose containers, blister packs, and strip packs.

[0519] According to conventional pharmaceutical formulation techniques, Elraglusib can be combined with a pharmaceutical carrier in a close mixture. The carrier can take a variety of forms, depending on the dosage form required for administration. When preparing a composition for oral dosage forms, any commonly used pharmaceutical medium can be used as a carrier, for example, in the case of oral liquid preparations (e.g., suspensions and solutions) or aerosols, such as water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, colorants, etc.; or, in the case of oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, polymers and disintegrants can be used, and in some embodiments, lactose is not used. For example, suitable carriers for solid oral preparations include powders, capsules and tablets. If necessary, tablets can be coated with standard water or non-aqueous technology.

[0520] Binders suitable for use in the pharmaceutical compositions of the present application 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, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinylpolypyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), microcrystalline cellulose, and mixtures thereof.

[0521] Examples of suitable fillers for use in the pharmaceutical compositions disclosed herein include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0522] Disintegrants can be used in pharmaceutical compositions to provide tablets that disintegrate when exposed to an aqueous environment. The amount of the disintegrant used can vary according to the type and mode of administration of the preparation, and can be easily distinguished by those of ordinary skill in the art. In some embodiments, a disintegrant of about 0.5 to about 15 weight percent, or a disintegrant of about 1 to about 5 weight percent can be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical composition of the present application include but are not limited to agar, alginic acid, calcium carbonate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, polycrilin potassium, sodium carboxymethyl starch, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other alginates (algins), other celluloses, glue, or mixtures thereof.

[0523] Lubricants that can be used to form the pharmaceutical composition of the present application include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other ethylene 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. Other lubricants include, for example, colloidal silica gel, a condensed aerosol of synthetic silica, or mixtures thereof. Lubricants can be optionally added in an amount, for example, less than about 1 weight percent of the pharmaceutical composition.

[0524] Tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. The preparation for oral administration can also be a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin); or as a soft gelatin capsule in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0525] Surfactants that can be used to form the pharmaceutical composition of the present application include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, that is, a mixture of hydrophilic surfactants, a mixture of lipophilic surfactants, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0526] 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 than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophile-lipophile balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0527] 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 equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to achieve industrial, pharmaceutical, and cosmetic emulsion formulations.

[0528] The hydrophilic surfactant may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of monoglycerides / diglycerides; succinyl mono- and diglycerides; citric acid esters of monoglycerides / diglycerides; and mixtures thereof.

[0529] Among the above groups, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylate; mono- and diacetylated tartaric acid esters of monoglycerides / diglycerides; succinyl mono- and diglycerides; citric acid esters of monoglycerides / diglycerides; and mixtures thereof.

[0530] The ionic surfactant can be lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactates, stearoyl-2-lactyloyl lactylate, stearoyl lactylate, succinyl monoglyceride, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linolenate, stearate, dodecyl sulfate, teracecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristyl carnitine, and salts and mixtures thereof.

[0531] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glycosides; alkyl maltosides; alkyl thioglycosides; lauroyl polyoxyethylene 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 .... ester), such as polyethylene glycol sorbitan fatty acid ester; hydrophilic transesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols and their derivatives and analogs; polyoxyethylene vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid ester, hydrophilic transesterification products of polyols and 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 saccharide.

[0532] Other hydrophilic nonionic surfactants include, but are not limited to, 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, PEG-20 dilaurate, PEG-25 triolein, 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, P EG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 glyceryl caprylate / caprate, PEG-8 glyceryl caprylate / caprate, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 behenate Sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10-oleate, Tween 40, Tween 60, Tween 80, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0533] Suitable lipophilic surfactants include, by way of example only: 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; polyoxyethylene sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides 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. In this group, 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.

[0534] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers 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-caprolactone, 2-hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, cyclodextrins and cyclodextrin derivatives; amines, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, 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 solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether and water.

[0535] Mixtures of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, tetraethylene glycol ether, carbitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, tetraethylene glycol ether, and propylene glycol.

[0536] The amount of the solubilizing agent that can be included has no particular restrictions.The amount of a given solubilizing agent can be limited to a bioacceptable amount, which can be easily determined by those skilled in the art.In some cases, it may be advantageous to include the amount of a solubilizing agent that far exceeds a bioacceptable amount, for example, in order to maximize drug concentration, conventional techniques (for example, distillation or evaporation) are used to remove excess solubilizing agent before providing compositions to the subject.Therefore, if present, based on the combined weight of medicine and other excipients, by weight, solubilizing agent can be 10%, 25%, 50%, 100% or up to about 200% weight ratio.If desired, a very small amount of solubilizing agent can also be used, for example 5%, 2%, 1% or even less.Usually, by weight, solubilizing agent can exist with about 1% to about 100%, more typically about 5% to about 25% amount.

[0537] The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, colorants, odorants, opacifiers, suspending agents, adhesives, fillers, plasticizers, lubricants, and mixtures thereof.

[0538] In addition, acids or bases can be added to the composition to facilitate handling, enhance 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, aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS) and the like. Also suitable for use as bases are salts of pharmaceutically acceptable acids (e.g., acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, 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, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.). Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation may be any convenient and pharmaceutically acceptable cation such as ammonium, alkali metals, alkaline earth metals, etc. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0539] 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, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0540] In some embodiments, the elraglusib composition is administered in multiple doses. The dosage can be about once a day, twice, three times, four times, five times, six times or more than six times. The dosage can be about once a month, once every two weeks, once a week, twice a week, or once every other day. In another embodiment, the elraglusib composition and another drug are administered together from about once a day to about 6 times a day. In another embodiment, the administration of the elraglusib composition and the drug continues for less than about 7 days. In another embodiment, the administration continues for more than about 6, 10, 14, 28 days, two months, six months or one year. In some cases, continuous administration can be achieved and maintained for the necessary duration.

[0541] Administration of the elraglusib composition can continue for as long as necessary. In some embodiments, the elraglusib composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the elraglusib composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the elraglusib composition is administered for more than 1, 2, 3, 4, 5, 6, 12, 18, or 24 months. In some embodiments, the elraglusib composition is administered chronically on an ongoing basis for as long as necessary, for example, for the treatment of a chronic disease or disorder.

[0542] An effective amount of the elraglusib composition may be administered in single or multiple doses by any of the recognized modes of administration for similarly effective drugs, including rectal, oral, intranasal and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhalant.

[0543] In some aspects, the plasma concentrations of elraglusib produced by the methods of the present application exhibit a food effect. As used herein, the term "food effect" refers to the extent and / or rate of drug absorption depending on whether the subject is fed or fasting at the time of administration.

[0544] The term "eating" as used herein means that the subject has consumed food immediately before and / or immediately after ingesting elraglusib or a pharmaceutically acceptable salt thereof. For example, in some embodiments, "eating" means that the subject has consumed food 30 minutes or less before ingesting elraglusib or a pharmaceutically acceptable salt thereof.

[0545] The term "fasting" as used herein means that the subject has not consumed food within 8 hours immediately before or within 4 hours immediately after ingestion of elraglusib or a pharmaceutically acceptable salt thereof.

[0546] In some embodiments, oral administration of an elraglusib pharmaceutical composition of the present application to a subject produces a ratio of plasma elraglusib Cmax (fed): Cmax (fasted) of about 2.5-5, for example, 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.

[0547] In some embodiments, oral administration of an elraglusib pharmaceutical composition of the present application to a subject produces a plasma elraglusib Cmax (fed): Cmax (fasted) ratio of 2.5 or greater, e.g., 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.

[0548] In some embodiments, oral administration of the elraglusib pharmaceutical composition of the present application to a subject produces a plasma elraglusib Cmax (fed) of at least 250%, for example, 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 elraglusib Cmax (fasting).

[0549] As used herein, the term "Cmax (fasting)" refers to the peak concentration in plasma after oral administration of the elraglusib pharmaceutical composition of the present application to a fasting subject. As used herein, the term "Cmax (fed)" refers to the peak concentration in plasma after oral administration of the elraglusib pharmaceutical composition of the present application to a fed subject. The peak concentration of elraglusib in the subject's plasma sample can be determined using an appropriate pharmacokinetic model, which is applied to the plasma concentration versus time curve determined using a standard analytical method. Appropriate pharmacokinetic models for determining Cmax are known to those of ordinary skill in the art.

[0550] In some embodiments of the disclosed methods, the ratio of Cmax(fed):Cmax(fasting) is calculated using the arithmetic mean of the individual Cmax(fed) values ​​calculated in the subject population and the arithmetic mean of the individual Cmax(fasted) values ​​calculated in the subject population.

[0551] In some embodiments of the disclosed methods, the ratio of Cmax(fed):Cmax(fasting) is calculated using the geometric mean of the individual Cmax(fed) values ​​calculated in the subject population and the geometric mean of the individual Cmax(fasted) values ​​calculated in the subject population.

[0552] In some embodiments, oral administration of the elraglusib pharmaceutical composition of the present application to a subject produces a ratio of plasma elraglusib AUC∞(fed):AUC∞(fasted) of about 2.4 to 3.6, for example, 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.

[0553] In some embodiments, oral administration of the elraglusib pharmaceutical composition of the present application to a subject produces a ratio of plasma elraglusib AUC∞(fed):AUC∞(fasted) of 2.4 or greater, for example, 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.

[0554] In some embodiments, oral administration of the elraglusib pharmaceutical composition of the present application to a subject produces a plasma elraglusib AUC∞(fed) of 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 elraglusib AUC∞(fasting).

[0555] As used herein, the term "AUC∞(fasting)" refers to the area under the plasma concentration-time curve extrapolated from AUCo to AUC∞ after oral administration of the elraglusib pharmaceutical composition of the present application to fasted subjects. As used herein, the term "AUC∞(fed)" refers to the area under the plasma concentration-time curve extrapolated from AUCo to AUC∞ after oral administration of the elraglusib pharmaceutical composition of the present application to fed subjects. Methods for determining concentration-time curves and AUC are known to those of ordinary skill in the art.

[0556] In some embodiments of the disclosed methods, the ratio of AUC∞(fed):AUC∞(fasting) is calculated using the arithmetic mean of the individual AUC∞(fed) values ​​calculated in the subject population and the arithmetic mean of the individual AUC∞(fasted) values ​​calculated in the subject population.

[0557] In some embodiments of the disclosed methods, the ratio of AUC∞(fed):AUC∞(fasting) is calculated using the geometric mean of the individual AUC∞(fed) values ​​calculated in the subject population and the geometric mean of the individual AUC∞(fasted) values ​​calculated in the subject population.

[0558] How to use

[0559] In some aspects, the present application relates 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 according to any embodiment disclosed herein or a liquid solution or liquid suspension according to any embodiment disclosed herein.

[0560] In some embodiments, the present application relates to a method for treating a disease or disorder in a subject in need thereof, the method comprising orally administering the solid dispersion of the present application to the subject.

[0561] In some embodiments, the present application relates to a method for treating a disease or disorder in a subject in need thereof, the method comprising orally administering to the subject a solution or suspension of the present application.

[0562] In some embodiments of these methods, the solution or suspension is administered orally as a pharmaceutical composition.

[0563] In other embodiments of these methods, the solid dispersion is administered orally as a pharmaceutical composition.

[0564] In some embodiments, the effective amount of elraglusib for the treatment method of the present application is based on the patient's weight and condition and the disease to be treated. In some embodiments, the effective amount of elraglusib is about 0.1 mg / kg to 20 mg / kg, for example, 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.

[0565] In some embodiments, the disease or disorder is cancer.

[0566] In some embodiments, the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, pancreatic cancer, sarcoma, or glioblastoma.

[0567] In some embodiments, the cancer is glioblastoma.

[0568] In other embodiments, the disease or disorder is a lymphoproliferative disease.

[0569] 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 with lymphoblastic 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 disorder, plasma cell neoplasm, primary mediastinal B-cell lymphoma, Hodgkin's disease, or Castelman's disease.

[0570] In some embodiments, the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma.

[0571] In other embodiments, the Diffuse Large B Cell Lymphoma is Double Hit Lymphoma.

[0572] 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, enteropathy-type T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large T / naked cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, lymphoblastic 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-prolymphocytic leukemia (T-PLL), or unspecified T-cell lymphoma.

[0573] In other embodiments, the disease or disorder is traumatic brain injury.

[0574] In other embodiments, the disease or disorder is idiopathic pulmonary fibrosis.

[0575] In other embodiments, the disease or disorder is pleural fibrosis.

[0576] This application also involves the following aspects:

[0577] Aspect 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.

[0578] Aspect 2. A solid dispersion according to 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, polyvinyl pyrrolidone or a miscible mixture thereof.

[0579] Aspect 3. The solid dispersion according to aspect 2, wherein the stabilizing polymer is N-vinyl-2-pyrrolidone-vinyl acetate copolymer (copovidone).

[0580] Aspect 4. The solid dispersion according to aspect 2, wherein the stabilizing polymer is cellulose acetate phthalate.

[0581] Aspect 5. The solid dispersion according to aspect 2, wherein the stabilizing polymer is hydroxypropyl methylcellulose phthalate.

[0582] Aspect 6. The solid dispersion according to aspect 2, wherein the stabilizing polymer is hydroxypropylmethylcellulose acetate succinate.

[0583] Aspect 7. The solid dispersion according to aspect 2, wherein the stabilizing polymer is polyvinyl acetate phthalate.

[0584] Aspect 8. The solid dispersion according to aspect 2, wherein the stabilizing polymer is polyvinyl pyrrolidone.

[0585] Aspect 9. A solid dispersion according to any of the preceding aspects, wherein 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolano[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 10 wt % to about 70 wt % relative to the weight of the stabilizing polymer.

[0586] Aspect 10. A solid dispersion according to any of the preceding aspects, wherein 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolano[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 20 wt % to about 60 wt % relative to the weight of the stabilizing polymer.

[0587] Aspect 11. A solid dispersion according to any of the preceding aspects, wherein 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione is present in an amount of about 25 wt % to about 50 wt % relative to the weight of the stabilizing polymer.

[0588] Aspect 12. A solid dispersion according to any of the preceding aspects, 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 the stabilizing polymer is from about 30:70 to about 50:50.

[0589] Aspect 13. The solid dispersion according to any of the preceding aspects, wherein the solid dispersion has a single glass transition temperature.

[0590] Aspect 14. The solid dispersion according to any of the preceding aspects, wherein the solid dispersion is stable at 60° C. and 75% relative humidity for at least 48 hours.

[0591] Aspect 15. The solid dispersion according to any of the preceding aspects, wherein the solid dispersion is stable at 40° C. and 75% relative humidity for at least 4 weeks.

[0592] Aspect 16. The solid dispersion according to any of the preceding aspects, wherein the solid dispersion is stable at 40° C. and 75% relative humidity for at least 12 weeks.

[0593] Aspect 17. A pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion according to any one of the preceding aspects and a pharmaceutically acceptable excipient.

[0594] Aspect 18. A method for preparing a solid dispersion according to any one of Aspects 1 to 17, comprising the following steps: a) dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[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 a solid dispersion.

[0595] Aspect 19. The method according to aspect 18, wherein the solvent is dichloromethane, tetrahydrofuran, aqueous tetrahydrofuran solution, acetone, aqueous acetone solution, methanol, ethanol, ethyl acetate and a mixture thereof.

[0596] Aspect 20. The method according to any one of aspects 18-19, wherein the solvent is evaporated by spray drying.

[0597] Aspect 21. The method according to any one of aspects 18-19, wherein the solvent is evaporated under reduced pressure.

[0598] Aspect 22. The method according to any one of aspects 18-19, wherein the solvent is evaporated using an inert gas.

[0599] Aspect 23. A liquid solution comprising 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolane[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (elraglusib), an emulsifier, a pharmaceutically acceptable alcohol, and a surfactant; the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate 60, or a combination thereof. Sorbitol ester, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

[0600] Aspect 24. A liquid solution according to aspect 23, comprising about 4.0-6.0 wt.% of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolato[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (elraglusib), about 75-95 wt.% of an emulsifier, about 2-17% wt.% of a pharmaceutically acceptable alcohol, and about 0.5-10% wt.% of a surfactant; the emulsifier is polyethylene glycol, mustard egg Lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

[0601] Aspect 25. The liquid solution according to aspect 23 or aspect 24, wherein the emulsifier is polyethylene glycol (PEG).

[0602] Aspect 26. The liquid solution according to aspect 25, wherein the polyethylene glycol has a molecular weight of 100-1000 Da.

[0603] Aspect 27. The liquid solution according to aspect 25 or aspect 26, wherein the emulsifier is PEG 400.

[0604] Aspect 28. The liquid solution according to any one of aspects 23 to 27, wherein the pharmaceutically acceptable alcohol is ethanol.

[0605] Aspect 29. The liquid solution according to any one of aspects 23 to 28, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

[0606] Aspect 30. The liquid solution according to any one of aspects 23-29, comprising about 4.3-5.5 wt.% elraglusib.

[0607] Aspect 31. The liquid solution according to any one of aspects 23-30, wherein the concentration of elraglusib in the solution is at least 45 mg / mL.

[0608] Aspect 32. The liquid solution according to any one of aspects 23-30, wherein the concentration of elraglusib in the solution is at least 50 mg / mL.

[0609] Aspect 33. The solution according to any one of aspects 23-32, wherein the purity of elraglusib is greater than 97% as determined by HPLC area %.

[0610] Aspect 34. The solution according to Aspect 33, wherein the purity of elraglusib is greater than 98% as determined by HPLC area %.

[0611] Aspect 35. The solution according to Aspect 34, wherein the purity of elraglusib is greater than 99% as determined by HPLC area %.

[0612] Aspect 36. The solution according to any one of aspects 23-35, 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 elraglusib as determined by HPLC area %.

[0613] Aspect 37. The solution according to any one of aspects 23-36, 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 elraglusib as determined by HPLC area %.

[0614] Aspect 38. A liquid suspension comprising elraglusib, an emulsifier, a pharmaceutically acceptable alcohol, a surfactant, and a pharmaceutically acceptable diluent; the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitan ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

[0615] Aspect 39. The liquid suspension according to aspect 38, comprising: about 0.04-0.6 wt.% elraglusib, about 0.8-10 wt.% emulsifier, about 0.04-1.7 wt.% pharmaceutically acceptable alcohol, about 0.009-1 wt.% surfactant, and about 87-99 wt.% pharmaceutically acceptable diluent; the emulsifier is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, Diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

[0616] Aspect 40. The liquid suspension according to aspect 38 or aspect 39, wherein the emulsifier is polyethylene glycol (PEG).

[0617] Aspect 41. The liquid suspension according to aspect 40, wherein the polyethylene glycol has a molecular weight of 100-1000 Da.

[0618] Aspect 42. The liquid suspension according to aspect 40 or aspect 41, wherein the emulsifier is PEG 400.

[0619] Aspect 43. The liquid suspension according to any one of aspects 38 to 42, wherein the pharmaceutically acceptable alcohol is ethanol.

[0620] Aspect 44. The liquid suspension according to any one of aspects 38 to 43, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

[0621] Aspect 45. The liquid suspension according to any one of aspects 38-44, comprising about 0.04 wt.% elraglusib.

[0622] Aspect 46. The liquid suspension according to any one of aspects 38-44, comprising about 0.1 wt.% elraglusib.

[0623] Aspect 47. The liquid suspension according to any one of aspects 38-44, comprising about 0.2 wt.% elraglusib.

[0624] Aspect 48. The liquid suspension according to any one of aspects 38-44, comprising about 0.5 wt.% elraglusib.

[0625] Aspect 49. The solution or suspension according to any one of aspects 38 to 48, wherein the concentration of elraglusib in the suspension is at least 0.4 mg / mL.

[0626] Aspect 50. The solution or suspension according to any one of aspects 38 to 48, wherein the concentration of elraglusib in the suspension is at least 0.5 mg / mL.

[0627] 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 solution.

[0628] Aspect 52. The liquid suspension according to aspect 51, wherein the pharmaceutically acceptable diluent is dextrose (5%) in water (D5W).

[0629] Aspect 53. The suspension according to any one of aspects 38-52, wherein the purity of elraglusib is greater than 97% as determined by HPLC area %.

[0630] Aspect 54. The suspension according to any one of aspects 38-52, wherein the purity of elraglusib is greater than 98% as determined by HPLC area %.

[0631] Aspect 55. The suspension according to any one of aspects 38-52, wherein the purity of elraglusib is greater than 99% as determined by HPLC area %.

[0632] Aspect 56. The suspension according to any one of aspects 38-52, 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 elraglusib as determined by HPLC area %.

[0633] Aspect 57. The suspension according to any one of aspects 38-52, 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 elraglusib as determined by HPLC area %.

[0634] Aspect 58. A method for achieving an elraglusib plasma concentration in the range of 1000-10000 ng / mL in a human, the method comprising orally administering to the human the solid dispersion, liquid solution, liquid suspension or pharmaceutical composition of the present application.

[0635] Aspect 59. A method of treating a disease or disorder in a subject in need thereof, the method comprising orally administering to the subject the solid dispersion of any one of Aspects 1-16, the pharmaceutical composition of Aspect 17, the solution of any one of Aspects 23-37, or the suspension of any one of Aspects 38-57.

[0636] Aspect 60. The method according to Aspect 59, wherein the disease or disorder is cancer.

[0637] Aspect 61. The method according to Aspect 60, wherein the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, pancreatic cancer or glioblastoma.

[0638] Aspect 62. The method according to Aspect 60, wherein the cancer is glioblastoma.

[0639] Aspect 63. The method according to Aspect 59, wherein the disease or disorder is a lymphoproliferative disease.

[0640] Aspect 64. The method according to Aspect 63, wherein the lymphoproliferative disorder is a malignant lymphoproliferative disorder.

[0641] Aspect 65. The method according to Aspect 64, wherein the malignant lymphoproliferative disorder is a malignant B-cell lymphoproliferative disorder.

[0642] Aspect 66. The method according to aspect 65, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma, acute lymphocytic leukemia, chronic myeloid leukemia in the lymphoblastic stage, 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 disorder, plasma cell neoplasm, primary mediastinal B-cell lymphoma, Hodgkin's disease or Castleman's disease.

[0643] Aspect 67. The method according to Aspect 66, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma.

[0644] Aspect 68. The method according to Aspect 67, wherein the diffuse large B-cell lymphoma is double hit lymphoma.

[0645] Aspect 69. The method according to Aspect 63, wherein the lymphoproliferative disorder is a malignant T-cell lymphoproliferative disorder.

[0646] Aspect 70. The method according to aspect 69, wherein the malignant T-cell lymphoproliferative disorder is 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 / naked cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, lymphoblastic stage chronic myeloid leukemia, post-transplant lymphoproliferative syndrome, human T-cell leukemia virus type 1 positive (HTLV-1 + ) Adult T-cell leukemia / lymphoma (ATL), T-prolymphocytic leukemia (T-PLL), or unspecified T-cell lymphoma.

[0647] Aspect 71. The method according to Aspect 59, wherein the disease or disorder is traumatic brain injury.

[0648] Aspect 72. The method according to Aspect 59, wherein the disease or disorder is idiopathic pulmonary fibrosis.

[0649] Aspect 73. The method according to Aspect 59, wherein the disease or disorder is pleural fibrosis.

[0650] Having described the present application with reference to certain preferred embodiments, other embodiments will become apparent to those skilled in the art by considering this specification. The present application will be further illustrated by reference to the following examples. It will be apparent to those skilled in the art that many modifications to materials and methods may be implemented without departing from the scope of the present application.

[0651] Example

[0652] Example 1 - Preparation of oral liquid

[0653] Liquid dosage forms of elraglusib were prepared that could be administered directly by oral ingestion or that could be diluted into 5% dextrose in water to form a liquid suspension suitable for oral administration. Table 1-1 shows the batch formulations.

[0654] Table 1-1. Batch formulation for 5L scale

[0655]

[0656] *Total weight of elraglusib (247.0 g) multiplied by the assay value of the elraglusib batch (0.98) = 0.2421 kg

[0657] Day 1: Weigh 5.040 kg of PEG400 into a 6L flask in the batching room. Cover the solution and transfer it to the biosafety cabinet. Weigh Elraglusib powder four times in the batching room: 64.42 g, 69.89 g, 76.76 g, and 35.97 g. The total weight is 247.04 g. Transfer each portion to the biosafety cabinet, add it to the flask containing PEG400 in sequence, and stir overnight in the dark.

[0658] Day 2: There is a layer of elraglusib on the bottom of the flask. Use a combination of a shaker plate and a stir plate to loosen the bottom layer of the flask. Then place the flask on the shaker plate and mix overnight in the dark.

[0659] Day 3: Elraglusib appeared in solution. 57 mL of polysorbate 80 (Tween 80) was added to the solution using a serological pipette and placed on a vibrating plate for 60 minutes. After 60 minutes, 270.05 g of dehydrated ethanol was added to the solution and placed on a vibrating plate for another 60 minutes of mixing.

[0660] Pre-filtration of bulk samples: Use new serological pipettes to draw 20 mL samples from the top, middle, and bottom of the pre-filtered bulk samples on day 3. Store samples in 20 mL amber vials in a cardboard box at room temperature, protected from light.

[0661] Filtration of bulk solution: The solution was transferred to a laminar flow hood and filtered using a 4-inch 0.2 μm Opticap XL4 Durapore clarification filter via a peristaltic pump into a clean, dry 6 L flask.

[0662] Vial Filling of Filtered Bulk Solution: In a laminar flow hood, 20 mL amber vials (molded glass) were filled with 11 ± 0.1 mL of filtered bulk solution using a calibrated repeating pipette (with a 50 mL tip). The vials were sealed with FluroTec rubber stoppers and metal crimps with white cuff seals. The vials were stored in cardboard boxes under ambient conditions protected from light.

[0663] Tables 1-2 summarize the properties of the 50 mg / mL solution of the oral suspension batches.

[0664] Table 1-2. Elraglusib solution, 50 mg / mL batch analysis

[0665]

[0666] preparation

[0667] The starting point for the development of the elraglusib oral solution formulation is the 10 mg / mL intravenous drug product of elraglusib, which includes 10 mg / mL elraglusib dissolved in a PEG400:EtOH:Tween 80 (75:17:8% w / w) vehicle. The objectives of developing the elraglusib oral solution drug product are to:

[0668] Increasing elraglusib concentrations (thereby reducing the required dose volume);

[0669] Maintain the same excipients as the elraglusib 10 mg / mL injection drug product;

[0670] Reducing EtOH concentrations (thus reducing the dose of ethanol given to patients);

[0671] Reducing the concentration of Tween 80 (thereby reducing the dose of Tween 80 given to the patient);

[0672] • Oral administration has a bioavailability of >50% compared to intravenous (IV) administration.

[0673] A preliminary study prepared 50 mg / mL elraglusib solutions in 12 vector variants. Tables 1-3 show the components of the vector variants.

[0674] Table 1-3. Vector variants evaluated for 9-ING-41 oral formulation development

[0675]

[0676] Each vector variant was formulated with elraglusib at 50 mg / mL and tested (with or without syringe filtration) for the following: (1) elraglusib main peak area%, (2) related material RRT 0.96 area%, (3) related material area% RRT 0.97. RRT is the HPLC relative retention time, i.e., the retention time of a material relative to the retention time of elraglusib.

[0677] Elraglusib remained soluble at 50 mg / mL with no precipitation or turbidity and no visible particulates.

[0678] • The concentration of elraglusib in all unfiltered vector variants averaged 99.0 ± 2.9% of 50 mg / mL.

[0679] • The concentration of elraglusib in all syringe-filtered vector variants averaged 98.6 ± 2.7% of 50 mg / mL.

[0680] - Variants 7 to 12 (Tables 1-3) were made within 24 hours of mixing the API into PEG400 and showed more consistent values ​​for area% values ​​of the main peak (ie, elraglusib peak) = 99% and recoveries ranging from 97-102%.

[0681] - The related substances RRT 0.96 area % values ​​of variants 1 to 6 (>1.2%) are higher than those of variants 7 to 12 (<0.5%).

[0682] - Related substance RRT 0.96 levels appear to increase with increasing EtOH% or Tween 80% (or both) in the vector variants.

[0683] To evaluate the use of the 12 carrier variants to formulate 50 mg / mL elraglusib for the manufacture of a liquid oral suspension drug product, two in vitro studies were conducted. In one study, each of the 12 carrier variants was diluted to 0.50 mg / mL, 1.0 mg / mL, and 2.0 mg / mL elraglusib in two potential oral solution diluents (i.e., 5% dextrose injection (D5W) and After PED, the solubility of elraglusib at room temperature was determined.

[0684] All 12 carrier variants that made 50 mg / mL elraglusib produced precipitation when diluted to 0.50 mg / mL, 1.0 mg / mL, and 2.0 mg / mL concentrations in PED. When diluted to D5W, carrier variants 1 to 5 produced obvious precipitation, but carrier variants 6 to 12 produced turbid, fine dispersions that lasted for at least 4 hours after dilution. For 50 mg / mL elraglusib diluted to 2 mg / mL in D5W in carrier variant 7, dynamic light scattering (DLS) analysis showed an average particle size value of approximately 200 nm. HPLC analysis using the methods shown in Tables 1-5 showed a potential correlation between high carrier variant EtOH and / or Tween 80 content and the formation of elevated levels of related substances RRT 0.97.

[0685] Another study determined the concentration of soluble and soluble elraglusib microparticles in each of three biorelevant dissolution media (FaSSGF, FaSSIF, and FeSSIF) after the addition of 1.0 mg / mL and 2.0 mg / mL dilutions in D5W from a 50 mg / mL carrier variant 7 formulation. When a 1.0 mg / mL (700 mL) or 2.0 mg / mL (350 mL) suspension in D5W was mixed with a biorelevant dissolution medium to a total volume of 900 mL, a suspension containing both soluble elraglusib and elraglusib microparticles was obtained. The concentration of soluble elraglusib in FeSSIF medium (~50% of theoretical [9-ING-41]) was slightly higher than that in FaSSGF medium (~20% of theoretical [9-ING-41]) or FaSSIF medium (~10% of theoretical [9-ING-41]).

[0686] Elraglusib at 50 mg / mL in carrier variant 7 (PEG400:EtOH:Tween 80 94:5:1% w / w) was further developed as an oral solution dosage form. The strengths of the 50 mg / mL oral solution are summarized in Tables 1-4.

[0687] Table 1-4.9-ING-41 50mg / mL oral solution specifications

[0688]

[0689]

[0690] HPLC was used to detect identification, purity and related substances. Tables 1-5 show the chromatographic operating parameters of the HPLC method.

[0691] Table 1-5. Chromatographic operating parameters of HPLC method

[0692]

[0693] Characterization of Impurities in Drug Products

[0694] Two related substances were detected by HPLC, namely:

[0695] Related substances eluted at a relative retention time RRT 0.96, and

[0696] The elraglusib anhydride analog eluted at a relative retention time RRT 1.21.

[0697] Example 2A - Preparation of Amorphous Solid Dispersion (ASD)

[0698] Characterization of elraglusib starting material

[0699] The starting elraglusib 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 graph showed a weight loss of 0.91%, indicating that the material was anhydrous in nature, while the DSC graph showed an endothermic peak corresponding to a melting point (onset) of 227.1°C. These data graphs indicate that elraglusib is a crystalline solid in Form I. Methods for preparing elraglusib Form I are known in the art. See U.S. Patent No. 11,136,334.

[0700] Elraglusib has a Tg of ˜111° C. (384.15 K) and a Tm of ˜228° C. (501.15 K), giving it a Tm(K) / Tg(K) ratio of ˜1.3; a cLogP value of ˜4.3. In order to keep the API in an amorphous state, the Tg of the ASD is preferably above 80° C. Both elraglusib:CAP ASD and elraglusib:EL100 ASD are characterized by a Tg of ˜106° C.

[0701] The HPLC reference standard was a 0.2 mg / mL elraglusib acetonitrile stock solution. The method acquisition included 438 nm detection. The HPLC analysis simultaneously detected the API and related substance peaks at a relative retention time RRT = 0.97.

[0702] Amorphous Solid Dispersion (ASD) Screening and Characterization

[0703] Solubility analysis of elraglusib and polymers

[0704] The approximate solubility of elraglusib (Table 2A-1) and the target stabilizing polymer (Table 2A-2) in solvents commonly used for spray drying was studied separately. In addition, more quantitative solubility values ​​of elraglusib were obtained by high performance liquid chromatography (HPLC) in the presence of organic solvents with or without surfactants (Table 2A-3). Tetrahydrofuran (THF) or solvent mixtures containing THF showed the highest solubility for elraglusib among the organic solvents tested. XRPD analysis of solids recovered at 24 hours from some of the solubility experiments showed that samples containing THF solvent converted to THF solvate, while samples with only water and surfactant did not show any morphological changes. Approximate solubility checks were performed on the polymer to ensure that sufficient amounts could be dissolved to produce 50% w / w drug loading based on the solubility of the API in the specific solvent. The results of the study showed that, except for hydroxypropyl methylcellulose 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).

[0705] Table 2A-1. Approximate solubility determination of API in various solvents

[0706] API (elraglusib) Solvents Approximate solubility range (mg / mL) API Tetrahydrofuran (THF) S>64.0 API acetone 28.3<S<85.0 API Dichloromethane (DCM) 6.2<S<20.7 API DCM:Methanol (MeOH) 4.2<S<14.0 API DCM:Ethanol (EtOH) 11.0<S<33.0 API DCM:Acetone 18.0<S<54.0 API Ethyl acetate 9.7<S<29.0 API THF: Water (85:15) S>98.0 API Acetone:water (85:15) 18.0<S<54.0

[0707] Table 2A-2. Approximate solubility determination of various polymers in the presence of different solvents

[0708]

[0709]

[0710]

[0711] Table 2A-3. Quantitative solubility determination of API in the presence of organic solvents and surfactants (by HPLC)

[0712]

[0713] Table 2A-4. Visual solubilization of polymers at maximum concentration of API in organic solvents

[0714]

[0715] ASD Screening

[0716] ASD screening was performed using elraglusib starting material and various polymers. A total of 24 screening experiments were performed to prepare ASD, of which 5 experiments were performed by solvent air drying at 50% w / w drug loading, 4 experiments were performed by rotary evaporation at 25% w / w drug loading, and 15 experiments were performed by rotary evaporation at 50% w / w drug loading. Initially, ASD was obtained by rapid solvent evaporation, which was achieved by air drying. In these experiments, solutions containing 150 mg of API and 150 mg of polymer were prepared in 4 ml of the desired solvent to achieve 50% w / w drug loading. The solution was sonicated for 5 min and then visually analyzed to ensure it was clear, and then the solution was exposed to a gas stream for rapid evaporation. The resulting solid was analyzed by XRPD.

[0717] Tables 2A-5 summarize the characterization results.

[0718] Table 2A-5. ASD screening by air drying at 50% w / w drug loading

[0719]

[0720] The results showed that only the Plasdone S-630 polymer produced an amorphous material, while the others all produced crystalline acetone solvates.

[0721] In order to successfully obtain more amorphous results, rotary evaporation was used only at 25% drug loading. To prepare ASD by rotary evaporation, a solution of API and polymer (containing 25% API) was prepared in the desired solvent. The solution was sonicated for 5 min and then visually analyzed to ensure its clarity, and then the solution was kept in a rotary evaporator under 50 mbar vacuum for 15 min. The resulting solid was kept in a vacuum oven at 30°C for a weekend. The glass transition temperature Tg of the samples was analyzed using XRPD, TGA and DSC. All results are summarized in Table 2A-6.

[0722] Table 2A-6. ASD screening at 25% drug loading using rotary evaporator

[0723]

[0724] Screening at 50% drug loading was performed using rotary evaporation. For this screen, a higher amount (e.g., more diluted) of solvent, ≥ 6 mL (compared to 4 mL used previously) was used to dissolve 150 mg elraglusib and 150 mg polymer to prevent any risk of precipitation of material in solution prior to rotary evaporation or spray drying experiments. Table 2A-7 summarizes the results of these screens and formulation characterizations.

[0725] Table 2A-7. Summary of ASD screening and characterization by rotary evaporation at 50% elraglusib drug loading

[0726]

[0727] *No obvious Tg pattern was observed, tentative Tg

[0728] These experiments showed that, except for hydroxypropylmethylcellulose (HPMC) in THF: water (7: 3), HPMCP 55 in DCM: EtOH (1: 1), HPMCAS in DCM: MeOH (7: 3), and povidone K30 in THF: water (4: 3), which showed crystalline materials, most experiments obtained amorphous materials. Therefore, a total of 11 amorphous formulations were obtained at a drug loading of 50%. In order to determine the Tg and total residual solvent / water content of these ASDs, the ASDs were characterized by mDSC and TGA, respectively. mDSC was performed in a sealed pan without a pinhole and with a pinhole, and the Tg in the presence of residual solvent (i.e., wet Tg) and the Tg of the solid after the solvent was removed (i.e., dry Tg) were determined, respectively. The results related to mDSC and TGA analysis are summarized in Table 2A-7.

[0729] Kinetic solubility in biorelevant media

[0730] The kinetic solubility of six elraglusib ASD compositions was measured in biorelevant media at 37°C. The three biorelevant media were: SGF, FaSSIF, and FeSSIF. They 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 and stirred at 400 rpm, respectively. Aliquots of the supernatant were taken at 1 hour and 2 hours, syringe filtered using a cellulose acetate filter (0.22 μM pore size), and analyzed by HPLC. The solubility of each ASD in SGF, FaSSIF, and FeSSIF is shown in Table 2A-8, Table 2A-9, and Table 2A-10, respectively. The solubility evaluation showed that all ASDs were more soluble in FaSSIF and FeSSIF compared to SGF. In addition, at 2 hours, the remaining solid was analyzed by XRPD. The data show that all ASDs remain amorphous after solubility analysis. The XRPD of some samples recovered from SGF and FaSSIF shows the presence of a ~32°2θ peak, which corresponds to residual NaCl (from buffer) crystallized on the ASD solid. In addition, the data also show that most ASDs have peaks of ~9°2θ, 17.5°2θ, 26°2θ, and ~36°2θ after 2 hours of solubility in FeSSIF. These peaks correspond to residual FeSSIF buffer crystallized on the ASD solid after drying. (See Tables 2A-8, -9, and -10).

[0731] Table 2A-8. Summary of ASD solubility results in SGF

[0732]

[0733] *NaCl peak = corresponds to residual NaCl crystallized on ASD solids recovered after solubility studies.

[0734] Table 2A-9. Summary of ASD solubility results in FaSSIF

[0735]

[0736]

[0737] *NaCl peak = corresponds to residual NaCl crystallized on ASD solids recovered after solubility studies.

[0738] Table 2A-10. Summary of ASD solubility results in FeSSIF

[0739]

[0740] ASD stability analysis

[0741] The selected six ASDs were stored and studied under accelerated conditions of 40°C / 33% RH and 40°C / 75% RH, and the stability of the ASDs was monitored at different time intervals by XRPD, mDSC, and TGA. According to the XRPD data, all six ASDs remained amorphous after storage at 40°C / 33% RH for two weeks. Figure 4 . Likewise, by XRPD, all six ASDs also remained amorphous after storage at 40°C / 75% RH for three weeks. Figure 5 All six ASDs (stored at 40°C / 33% RH and 40°C / 75% RH) were analyzed again by XRPD at the nine-week time point and were found to be amorphous. Figure 6 , Figure 7 In addition to determining the Tg values ​​and total residual solvent / moisture content of the ASD formulations, six ASDs were characterized by mDSC and TGA after exposure to accelerated conditions. The mDSC of the stability samples was performed in a sealed pan without any pinholes to determine the Tg in the presence of residual solvent or moisture (i.e., wet Tg). Table 2A-11 summarizes the results related to the mDSC and TGA analyses.

[0742] Table 2A-11. Summary of ASD Characterization after Exposure to Accelerated Stability Conditions

[0743]

[0744] *No obvious Tg-like pattern observed, tentative Tg; NA = data not available, mDSC / TGA was performed on six ASDs after screening, while the other ASDs were analyzed only by XRPD.

[0745] Scale-up preparation by spray drying of Elra:PVAP (50% amorphous elraglusib in PVAP) from THF

[0746] Elra: PVAP ASD (comprising 50% w / w amorphous elraglusib in PVAP polymer) was prepared by dissolving 24 g melraglusib and 24 gm PVAP in 600 mL THF and then using a Buchi equipped with a B-295 inert loop. TM The preparation was spray dried using a B-290 spray dryer. The parameters used for spray drying are listed in Table 2A-12. Approximately 26 gm of Elra:PVAP was obtained and dried in a vacuum oven at room temperature for two days. The XRPD of Elra:PVAP (see Table 2A-12) Figure 8 The PLM image (as shown) shows that the material is amorphous. Fig. 9) showed that the material consisted of aggregates of spherical non-birefringent particles. mDSC showed that the material had a Tg of 60.3°C and TGA showed a weight loss of 7.33% up to 150°C (see Fig.10 ). The material was further dried and residual solvent was intermittently monitored by TGA; the results are shown in Table 2A-13. TGA showed that the material dried for an additional 9 days in a vacuum oven at temperatures between 30°C and 40°C had a weight loss of 5.09% up to 150°C. mDSC was performed on this additional dried material to determine the Tg of the material in a DSC pan without a pinhole and in a DSC pan with a pinhole, and was found to be 71.8°C and 77.8°C, respectively (Figure 11). KF (Karl Fischer water analysis) showed the presence of 3.0% water (KF oven temperature was 200°C).

[0747] Approximately 25 mg of Elra:PVAP was dissolved in 100 mL of THF:H2O:ACN (20:40:40) and the drug loading was evaluated by HPLC, which was repeated three times. The obtained drug loading was further corrected to take into account the TGA weight loss of the material used for HPLC determination. The corrected drug loading was 46.42% w / w (Table 2A-14), and the HPLC chromatogram (monitored at 438 nm) showed only the presence of the API peak and the known (elraglusib anhydride) related substance peak, with an RRT of 1.23 ( Fig.12 ). The samples were subjected to PSD (particle size distribution) measurement using a Malvern laser particle size analyzer. About 50 mg of the sample was dispersed in 10 mL of 0.25% lecithin in Isopar-G solution and then subjected to PSD analysis, which was repeated three times without any ultrasound. The data showed that the particle size distributions of D10, D50 and D90 were 0.22, 7.94 and 24.97 μm, respectively (Table 2A-15). As shown in Figure 13, the PSD curve of this material is clearly bimodal.

[0748] Table 2A-12. Spray drying operating parameters for Elra:PVAP preparation

[0749] project parameter Entrance 100℃ exit 55-60℃ Air Extractor 97％ Pump 30％ Drying gas flow rate 50cfm Nozzle cleaning 1

[0750] Table 2A-13. Summary of drying and characterization of Elra:PVAP

[0751]

[0752] Table 2A-14. Summary of drug loading determination of Elra:PVAP

[0753]

[0754] * Corrected for drug loading to account for 4.86% weight loss.

[0755] Table 2A-15. Summary of PSD analysis of Elra:PVAP

[0756] Run #1 Run #2 Run #3 average D10(μm) 0.215 0.220 0.223 0.22 D50(μm) 7.64 8.06 8.12 7.94 D90(μm) 23.6 25.6 25.7 24.97

[0757] Scale-up preparation by spray drying of Elra:CAP (50% amorphous elraglusib in CAP) from THF

[0758] Elra:CAP ASD (comprising 50% w / w amorphous elraglusib in CAP polymer) was prepared by dissolving 24 g melraglusib and 24 gm CAP in 600 mL THF and then using a Buchi equipped with a B-295 inert loop. TM The preparation was spray dried using a B-290 spray dryer. The parameters used for spray drying are listed in Table 2A-16. Approximately 29 gm of ASD was obtained and dried in a vacuum oven at room temperature for two days. XRPD of Elra:CAP ASD (see Table 2A-16) Fig.14 The PLM image is shown as Fig.15 As shown, the material has aggregates of irregularly shaped non-birefringent particles. mDSC shows that the material has a Tg of 84.2°C, while TGA shows that its weight loss at 150°C is 4.62% ( Fig.16 ). Further drying was performed and residual solvent was intermittently monitored by TGA as shown in Table 2A-17. TGA of the additional dried material showed a weight loss of 2.90% at 150°C, and mDSC of the additional dried material was performed to determine the Tg of the material in the DSC pans without and with pinholes and found to be 87.0°C and 87.0°C, respectively (Figure 17). KF showed the presence of 2.9% water (KF oven temperature was 200°C).

[0759] Approximately 25 mg of Elra:CAP ASD was dissolved in 100 mL of THF:H2O:ACN (20:40:40) and the drug loading was evaluated by HPLC, repeated three times. The obtained drug loading was further corrected to take into account the TGA weight loss of the material used for HPLC determination. Elra:CAP ASD has a corrected drug loading of 46.98% w / w (Table 2A-18), and the HPLC chromatogram shows only API peaks and known related substance peaks (elraglusib anhydride), with an RRT of 1.23 ( Fig.18 ).

[0760] The particle size distribution (PSD) of the samples was measured using a Malvern laser particle size analyzer. Approximately 50 mg of the sample was dispersed in 10 mL of 0.25% lecithin in Isopar-G solution and then PSD analysis was performed three times without any application of ultrasound. The average D10, D50 and D90 particle size distributions were 2.38, 7.34 and 16.73 μm, respectively (Table 2A-19). As shown in Figure 19, the PSD curve of this material shows a unimodal or bimodal distribution of particles.

[0761] Table 2A-16. Spray drying operation parameters for preparing Elra:CAP from THF

[0762]

[0763]

[0764] Table 2A-17. Summary of drying and characterization of Elra:CAP

[0765]

[0766] Table 2A-18. Summary of drug loading determination of Elra:CAP

[0767]

[0768] Table 2A-19. Summary of PSD analysis of Elra:CAP

[0769] Run #1 Run #2 Run #3 average D10(μm) 3.4 3.48 0.258 2.38 D50(μm) 7.45 7.72 6.86 7.34 D90(μm) 15.8 17.3 17.1 16.73

[0770] Kinetic solubility study of Elra:PVAP and Elra:CAP (scaled up)

[0771] The kinetic solubility curves of Elra:PVAP ASD and Elra:CAP ASD were determined in biorelevant media at 37°C. Suspensions of each ASD were prepared in three biorelevant media, namely: SGF, FaSSIF, and FeSSIF. These suspensions were stirred at 400 rpm. Equal amounts of the supernatant were sampled at 5 min, 10 min, 30 min, and 4 h, syringe filtered using a cellulose acetate filter (0.22 μM pore size), and analyzed by HPLC. The solubility curves of these ASDs in SGF, FaSSIF, and FeSSIF are shown in Table 2A-20. The solubility assessment showed that the two ASDs had higher solubility in FaSSIF and FeSSIF compared to SGF; and Elra:PVAP had higher solubility under similar conditions compared to Elra:CAP. In addition, the XRPD of the solids recovered after the 4-hour solubility analysis showed that both ASDs remained amorphous after dissolution ( Fig. 20). XRPD of samples recovered from SGF and FaSSIF showed the presence of a peak at -32° 2θ corresponding to crystallized residual NaCl (from the buffer).

[0772] Table 2A-20. Summary of Kinetic Solubility Analysis of Elra:CAP and Elra:PVAP ASDs

[0773]

[0774]

[0775] *NaCl peak = corresponds to residual NaCl crystallized on ASD solids recovered after solubility studies.

[0776] LOD=0.006mg / mL

[0777] Elra:PVAP and Elra:CAP ASD Stability Study

[0778] To examine the sensitivity of the 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 week time points. Under the above conditions, both ASDs remained amorphous after 12 weeks of storage (Figure 21). The mDSC of the stability samples was performed in a sealed pan without any pinholes to determine the Tg in the presence of residual solvent or moisture (i.e., wet Tg). The results related to the mDSC and TGA analyses are summarized in Tables 2A-21 and are shown in Tables 2A-22. Fig. 22 and Fig.23 Both ASDs stored at 40°C / 33% RH for six weeks showed 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 25°C and 60-70% RH for the starting materials). Under most of these conditions, the Tg of both ASDs was within 10% of the initial Tg value, with the exception of Elra:CAP, which had a Tg value that dropped by ~11.5% from the initial Tg value.

[0779] When detected at 438nm, HPLC analysis of both ASDs stored under all three conditions did not show any degradation, showing only peaks of known impurities at RRT ~1.26. The HPLC samples monitored at 438nm and their respective % area purity characteristics are shown in Tables 2A-22 and 2A-23. The data show that the % area purity remained at about 99% in all initial (t=0) and stable samples. Samples stored for 12 weeks under different conditions were monitored using HPLC at 210nm to obtain HPLC chromatograms. The results show that the % area purity in all stability samples remained at about 99% (Tables 2A-24 and 2A-25). These results collectively show that the physical and chemical stability of the ASD samples is up to 12 weeks at 40°C / 33% RH and 40°C / 75% RH.

[0780] Overlay of the elraglusib, Elra:CAP, and Elra:PVAP ASDs by ssNMR showed a baseline-separated peak for the API at 87 ppm, indicating a suitable location for monitoring the crystallization stability of the ASD batches under accelerated stability conditions ( Fig.24 ). The first-order derivative is applied to the stability sample spectrum ( Figure 25-29 ). For pure amorphous samples, ssNMR produces a Gaussian curve, which becomes a flat baseline when the first derivative is applied. Crystalline materials produce a Laplace curve by ssNMR, which can be clearly observed after applying the first derivative.

[0781] The API reference had a signal-to-noise ratio of 8.18. The signal-to-noise ratio of the first derivative peak at 87 ppm remained < 2 in all four stability samples. The results are summarized in Table 2A-26.

[0782] The results of CPMAS ssNMR showed that no crystallinity was detected in any of the ASDs tested after they were exposed to both stability conditions.

[0783] Table 2A-21. Summary of Characterization of Elra:CAP and Elra:PVAP Stability Samples

[0784]

[0785] Pure Phthalavin (PVAP) has a Tg of 120°C and shows a weight loss of 1.73% to 150°C

[0786] Pure CAP has a Tg of 180°C and shows a weight loss of 2.77% to 150°C

[0787] Table 2A-22. Summary of HPLC Peak % Area Purity Characteristics of Elra:PVAP ASD Samples Monitored at 438 nm

[0788]

[0789] Table 2A-23. Summary of HPLC Peak % Area Purity Characteristics of Elra:CAP ASD Samples Monitored at 438 nm

[0790]

[0791] Table 2A-24. Summary of HPLC Peak % Area Purity Characteristics of Elra:PVAP ASD Samples Monitored at 210 nm

[0792] RRT 5℃ 40℃ / 33%RH 40℃ / 75%RH 1.00 99.19 98.83 98.99 1.13 0.44 - - 1.26 0.37 1.17 1.01

[0793] Table 2A-25. Summary of HPLC Peak % Area Purity Characteristics of Elra:CAP ASD Samples Monitored at 210 nm

[0794] RRT 5 ℃ 40℃ 33% RH 40℃ 75%RH 1.00 99.44 99.37 99.29 1.13 0.12 0.27 - 1.26 0.44 0.36 0.71

[0795] Table 2A-26. Summary of ssNMR signal-to-noise results for first derivative spectra

[0796]

[0797] Analytical Methods: Characterization of ASD Powders

[0798] HPLC test of Elra:CAP. Transfer 10.254 mg of Elra:CAP ASD from bottle 1 and 10.465 mg of Elra:CAP ASD from bottle 2 to each 50 mL volumetric flask. Dilute to volume with acetonitrile and mix to dissolve. Filter the solution with a 0.45 μm PVDF filter to remove fine transparent crystals in the solution. Transfer the solution to an HPLC vial and store at 5°C. The shelf life is 5 days.

[0799] Elra: HPLC test of PVAP. Transfer 10.177 mg of 9-ING-41-Phth ASD from bottle 1 and 10.105 mg from bottle 2 to each 50 mL volumetric flask. Dilute to volume with acetonitrile and mix to dissolve. Ultrasonicate the solution to break up the white clumps that form. Filter with a 0.45 μm PVDF filter to remove insoluble particles from the solution. Transfer the solution to an HPLC vial and store at 5°C. The shelf life is 5 days.

[0800] ATR FT-IR Analysis of ASD Powders: FT-IR analysis of CAP polymer, PVAP polymer, Elra:CAP ASD, Elra:PVAP ASD, and elraglusib API was performed using an attenuated total reflectance (ATR) accessory. A background scan (16 scans) was performed before each sampling. A small sample was placed on the ATR crystal and the pressure plate was tightened. 16 scans were performed for each sample. The crystal was cleaned with isopropanol after each analysis.

[0801] XRPD analysis: XRPD was performed using a PANalytical X'Pert3 powder XRPD on a silicon zero background stand. The 2θ position was calibrated against a Panalytical Si reference standard disk. The XRPD parameters are listed in Table 2A-27.

[0802] Table 2A-27. XRPD operating parameters

[0803]

[0804] TGA / DSC Analysis: TGA data were collected using a TA Discovery 550 TGA from TA Instrument. DSC was performed using a TA Q2000 DSC from TA Instrument. The DSC was calibrated with an indium reference standard and the TGA was calibrated with a nickel reference standard. The specific parameters used are listed in Table 2A-28.

[0805] Table 2A-28. TGA and DSC operating parameters

[0806]

[0807] mDSC analysis: mDSC was performed using a TA Q2000 DSC from TA Instrument. The DSC was calibrated with an indium reference standard. The specific parameters used are listed in Table 2A-29.

[0808] Table 2A-29. mDSC operating parameters

[0809]

[0810] PSD analysis: A Malvern Mastersizer 3000E particle size analyzer with a Hydro EV accessory was used. The parameters used are listed in Table 2A-30:

[0811] Table 2A-30. PSD test operating parameters

[0812] parameter set up instrument Malvern 3000E distributed volume Shading 2-15％ Particle shape Non-spherical Particle RI 1.60 Dispersants Isopar G* Dispersant RI 1.42 Run time 10 seconds / run Measurement N＝3 Flow rate 2500rpm Ultrasonic power 30W Ultrasound time 30s

[0813] ssNMR:

[0814] Solid-state NMR experiments were performed on a 2-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 modified with a 7 mm magic angle spinning module (Revolution NMR, Fort Collins, CO). Each sample was loaded into a 7 mm zirconia rotor with a Kel-F shim. The magic angle spinning (MAS) frequency used to acquire all data was 5 kHz. 13C chemical shifts are reported relative to the methyl peak of 3-methylglutaric acid at 18.84 ppm with an accuracy of ±0.4 ppm.

[0815] Saturation recovery was used to measure 1H T1 relaxation times. 13C spectra were collected using a presaturation cycle (1Hπ / 2, 15μs delay, cycle 20x), variable delay, 1Hπ / 2 pulses, followed by a cross-polarization total suppression of rotating sidebands (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 ​​were determined by a 1Hπ / 2 pulse, variable pulses (0.5-64ms), followed by a cross-polarization total suppression of rotating sidebands (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 images were acquired at 5kHz MAS using the CPTOSS sequence, 1.5ms contact time, 3960 acquisition points (~50ms acquisition time). 13 C CPTOSS spectra. Data collection was performed at a nominal temperature of 18.5°C. 13C (KAS-RS-011, MGA) Information: 13 C chemical shifts are reported relative to the methyl peak of 3-methylglutaric acid (MGA, KAS-RS-011) at 18.84 ppm with an accuracy of ±0.4 ppm. KAS-RS-011 (3-methylglutaric acid, batch #0000062292) was purchased from Sigma-Aldrich and used without further purification.

[0816] Using Bruker Biospin's Topspin The software package processes the data. The data are Fourier transformed, phased (apk), and baseline corrected (abs) using a full FID (1536 points) and 0 Hz line broadening. Manual phase separation is performed as needed.

[0817] Using the unsubtracted 13C spectra were then processed fully automatically using the "Build First Derivative" function of the Topspin software package. The first derivative spectra were then processed using the automatic phase (apk) in the Topspin software. The S / N calculations were then performed using the "sinocal" AU program on Topsin with the following parameters: left limit = 93 ppm, right limit = 91.5 ppm, noise range left limit = 300 ppm, noise range right limit = 250 ppm, noise width = 8 ppm.

[0818] HPLC method 1 was used for solubility, stability monitoring at 438 nm, and drug loading determination of ASD, which are summarized in Table 2A-31; HPLC method 2 was used for stability monitoring at 210 nm, which are summarized in Table 2A-32.

[0819] Table 2A-31. HPLC Method 1 for Solubility, Stability Monitoring at 438 nm and Drug Loading Determination

[0820]

[0821] Table 2A-32. HPLC Method 2 for Stability Monitoring at 210 nm

[0822]

[0823]

[0824] Formulation of Bulk ASD Powder for Encapsulation

[0825] Elra:CAP formulation blended with croscarmellose sodium:silicon dioxide (90:10)

[0826] A croscarmellose sodium:silicon dioxide (90:10) blend was prepared by combining 45.02 g croscarmellose sodium and 5.00 g colloidal silica in a large mortar and stirring well with a pestle. In a humidity controlled room, 1.00 g of croscarmellose sodium:silicon dioxide (90:10) blend was added to every 19.04 g of Elra:CAP ASD and mixed in a mortar / pestle to give 20 g of the formulation (ASD:croscarmellose sodium:silicon dioxide 95:4.5:0.5) which was filled into capsules.

[0827] Elra:PVAP formulation blended with croscarmellose sodium:silicon dioxide (90:10)

[0828] In a humidity controlled room, 1.00 g of croscarmellose sodium:silicon dioxide (90:10) blend was added to every 19.00 g of Elra:PVAP ASD and mixed in a mortar / pestle to give 20 g of the formula (ASD:croscarmellose sodium:silicon dioxide 95:4.5:0.5) which was filled into capsules.

[0829] Filling of hard capsules

[0830] Both ASD powders were formulated with a 90:10 blend of croscarmellose sodium:silicon dioxide as a filler (19:1 ratio) to improve powder flow and capsule dissolution. Fill size was #00 hard gelatin capsules, sized for 200 mg ASD powder; target dose elraglusib 90 mg (= 200 mg of 45% w / w ASD). Two ASD formulations: Elra:CAP, Elra:PVAP.

[0831] Elra:CAP ASD capsule preparation

[0832] 60 #00 opaque hard gelatin capsules were filled with approximately 235 mg of Elra:CAP and a blend of croscarmellose sodium:silicon dioxide at low humidity (≤20% RH). The capsules were packed into HDPE screw-top bottles at low humidity (≤10% RH), 12 capsules per bottle. The bottles were stored at room temperature and protected from light. The appearance of the contents of the Elra:CAP capsules was an orange, free-flowing, mobile powder.

[0833] Elra:PVAP ASD capsule preparation

[0834] At low humidity (≤20% RH), 60 #00 opaque hard gelatin capsules were filled with approximately 235 mg of Elra:PVAP and a blend of croscarmellose sodium:silicon dioxide. The capsules were packed into HDPE screw-top bottles at low humidity (≤10% RH), 12 capsules per bottle. The bottles were stored at room temperature and protected from light. The appearance of the contents of the Elra:PVAP capsules was an orange, free-flowing, mobile powder.

[0835] Characterization of hard capsules

[0836] 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 prepared for HPLC determination. The HPLC results are summarized in Tables 2A-33 to 2A-35.

[0837] Table 2A-33. HPLC Characterization of Elra:CAP and Elra:PVAP Powders

[0838] Sample name 9ING41%w / w Total impurities% %purity 9ING41-CAP ASD bottle 1 48.0 0.86 99.14 9ING41-CAP ASD bottle 2 48.2 0.86 99.14 Average = 48.1 9ING41-Phth ASD bottle 1 46.9 0.87 99.13 9ING41-Phth ASD bottle 2 46.6 0.85 99.15 Average = 46.75

[0839] Table 2A-34. HPLC Characterization of Elra:CAP Capsule Contents

[0840]

[0841] *9ING41 mg per capsule = (total ASD powder, mg) * (9ING41% w / w)

[0842] 9ING41mg per 900mL dissolution medium = (2 capsules) * (9ING41mg / capsule)

[0843] Table 2A-35. HPLC Characterization of Elra:PVAP Capsule Contents

[0844]

[0845] *9ING41 mg per capsule = (total ASD powder, mg) * 9ING41% w / w)

[0846] 9ING41mg per 900mL dissolution medium = (2 capsules) * (9ING41mg / capsule)

[0847] Dissolution tank settings

[0848] Prepare a 3% w / v sodium dodecyl sulfate (SDS) solution. Transfer 180.0239 g of SDS to a 6L volumetric flask. Dilute to volume with milliQ water and mix thoroughly. Store at room temperature and have a shelf life of 1 month. Use a measuring cylinder to add 900 mL of 3% SDS to each dissolution container (6 in total). The water bath temperature is set to 37.5°C and the containers are gently stirred at 50 rpm for about 15 minutes to reach equilibrium. The average temperature of the containers before adding the capsules is 37.4°C. Two capsules are added to each container. Containers 1-3 contain Elra:CAP capsules and containers 4-6 contain Elra:PVAP capsules. Take 5 mL samples at time points of 0.5, 1, 2, and 4 hours. Each Elra:CAP dissolution sample extracted at the specified time point is a turbid orange solution without precipitation. Both Elra:CAP and Elra:PVAP capsules are completely dissolved in 3% aqueous SDS dissolution medium within 0.5 hours. Based on visual inspection, the Elra:CAP dissolution sample was slightly turbid, while the Elra:PVAP dissolution sample was clear. Each Elra:PVAP dissolution sample extracted at the designated time point was a clear orange solution without precipitation. The samples were diluted 1:1 with acetonitrile and filtered through a 0.45 μm PVDF filter before being transferred to an amber HPLC vial.

[0849] HPLC samples were stored at 5°C prior to analysis. Tables 2A-36 and 2A-37 summarize the dissolution profiles.

[0850] Table 2A-36. Elra: CAP capsule dissolution rate characteristics results

[0851]

[0852] Total mean value = 184 μg / mL ± 11% RSD

[0853] *Maximum 9-ING-41%=100*([9-ING-41]obs÷(187,400μg / 900mL)

[0854] Table 2A-37. Elra: PVAP capsule dissolution rate characteristics results

[0855]

[0856] Total mean value = 155 μg / mL ± 17% RSD

[0857] *Maximum 9-ING-41%=100*([9-ING-41]obs÷(170,300μg / 900mL)

[0858] Example 2B. Elra: CAP ASD, Elraglusib and Micronized Elraglusib

[0859] Tablets comprising the Elra:CAP ASD, elraglusib API or micronized elraglusib API of the present application are prepared as described below.

[0860] Materials used in the Elra:CAP ASD tablet studies are summarized in Table 2B-1 (raw materials) and Table 2B-2 (analytical reagents). Equipment used in the Elra:CAP ASD tablet development studies is shown in Table 2B-3.

[0861] Table 2B-1. Materials used in the development study of Elra:CAP ASD tablets

[0862]

[0863] Table 2B-2. Materials used in Elra:CAP tablet analysis method

[0864]

[0865] Table 2B-3. Equipment used in the development study of Elra:CAP ASD tablets

[0866] equipment describe Spray Dryer Buchi B-290 Gerteis MiniPactor Roller Press High Shear Wet Granulator GlobePharma High Shear 1-6 Tablet press (manual), for compression molding Globe Pharma MTCM-1 Fluidized bed dryer SolidLab1 Tablet Hardness Tester Varian VK200 Friability Tester Sotax FT2 Automatic disintegration tester Sotax DT50 Online UV Dissolution Tester Sotax MD / Mettler Toledo UV Karl Fischer Titrator Mettler Toledo V20S Automated sample preparation workstation Sotax TPW HPLC Agilent 1100 with Chemstation software HPLC Agilent 1260 with OpenLab CDS software Scanning electron microscopy Phenom Pro, 10kV X-ray powder diffraction Rigaku–MiniFlex 6G

[0867] Test Method of Example 2B

[0868] HPLC testing was performed using an Agilent 1100 series HPLC equipped with CHEMSTATION data collection software.

[0869] Chromatographic separations were performed using a Waters Atlantis T3 4.6 x 150 mm, 3 μm column and the parameters provided in Table 2B-4. External standards were prepared at 0.2 mg / mL elraglusib in diluent for detection. Test samples of the tablet prototype were prepared by serial dilution to a target concentration of 0.2 mg / mL elraglusib. All samples were diluted as necessary on a Sotax TPW automated sample preparation workstation. Validation formulations were prepared using volumetric flasks as appropriate.

[0870] Table 2B-4. Analytical Conditions for Elraglusib ID, Detection, and Related Substances Methods

[0871]

[0872] Dissolution Testing

[0873] The dissolution test was performed on a Sotax MD automated dissolution apparatus with online UV detection. The elraglusib standard was used for quantification of the percentage of dissolution using UV absorbance at 282 nm. The dissolution test was performed using the parameters shown in Table 2B-5.

[0874] Table 2B-5. Dissolution method operating parameters

[0875]

[0876] a 2% w / w CTAB in water used in 35044-018, 1% w / w CTAB in 0.7 M sodium chloride used in 35044-026, and 6% w / w CTAB in 0.7 M sodium chloride used in 35044-021, 35044-023, 35044-025, and 35044-031

[0877] b 35044-018 and 35044-021 use 75 rpm, and 35044-023, 35044-025, 35044-026 and 35044-031 use 100 rpm

[0878] Determination of water content by Karl Fischer

[0879] The water content was determined by volumetric Karl Fischer (KF) titration using a Mettler-Toledo V20S Karl Fischer titrator. The titration was standardized with standard water sample 10.0 and Check P solution. A sample amount of 300 mg was used for KF water titration.

[0880] Bulk density and tap density

[0881] Bulk density and tapped density determination according to USP <616> Method I was performed. To determine the 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 powder in the measuring container was determined and divided by the test article volume.

[0882] To determine the tap density, shake the cylinder until the volume remains constant. Record the final powder volume after shaking. Calculate the tap density by dividing the initial mass by the final volume.

[0883] The Hausner ratio and compressibility index were calculated using the experimental bulk density and tap density using Equation 1 and Equation 2, respectively.

[0884]

[0885] hardness

[0886] According to USP <1217> The tablet hardness was measured using a Varian VK200 tablet hardness tester.

[0887] Disintegration

[0888] According to USP <701> , disintegration test was performed using Sotax DT50 and distilled water.

[0889] friability

[0890] A Sotax FT2 friability tester was used for friability testing, where tablets weighing not less than 6.5 g were tumbled at 25 rpm for 4 minutes, for a total of 100 revolutions.

[0891] Focused beam reflectivity measurement

[0892] Using a Focused Beam Reflectometry (FBRM) probe ( The particle size distribution was measured by using an overhead mixer (model S400, Mettler Toledo, Columbia, MD). S400 mixer controller) was used to keep the particles suspended during the test. The acquisition and analysis software was iC-FBRM TM Version 4.3 (Mettler Toledo, Columbia, MD).

[0893] Compression curve

[0894] Compression curves were generated for tablets prepared using a Globe Pharma Model MTCM-1 manual tablet press with 5 / 16 inch flat upper and lower dies.

[0895] X-ray powder diffraction

[0896] X-ray powder diffraction (XRPD) was performed on the micronized and blended materials using a Rigaku-Miniflex 6G desktop X-ray diffractometer. About 100 mg of sample was pressed onto a non-diffraction silicon substrate using a round siliconized glass slide. The X-ray source was operated at 40 kV and 15 mA. When collecting sample data, a running speed of 0.4 degrees / minute and a step length of 0.02 ° were used, from 3-40 °. Sample rotation was turned on for all measurements.

[0897] Scanning electron microscopy

[0898] Scanning electron microscope (SEM) images were captured using a Phenom Pro in 10 kV high resolution mode. Carbon paper was used as the conductive substrate. The sample was prepared by rolling on a sample <100 mg with a plastic scraper and then carefully rolling on the double-sided adhesive carbon paper on top of the platform. Three left turns of the sample holder were used to position the sample approximately 2 mm below the top of the platform for imaging.

[0899] Preparation of Elra:CAP ASD and Elra:CAP Tablets for Example 2B

[0900] Preparation of Elra:CAP ASD:

[0901] Elraglusib and CAP were weighed and dispensed into 1.0L or 2.0L graduated media storage bottles. These materials were dissolved in THF to make a total solid spray solution of about 8% weight / weight (w / w). The solution was stirred for 30 minutes before spraying to ensure that the solids were completely dissolved. The B-290 micro spray dryer was set according to the parameters summarized in Table 2B-6 and Table 2B-7. After reaching a target oxygen percentage of no more than (NMT) 6% (actual value: batch number 35044-004-4.6%, batch number 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 kept stable. Pure solvent was run until a steady state was reached. After reaching a steady state, elraglusib / CAP mixture in THF was started using a 30% pump flow and a pipe with a specification of 14L / S. After spraying as much product as possible and allowing the instrument to cool, the product was collected and oven dried overnight at 60°C.

[0902] Table 2B-6. Process parameters using B-290 Micro Spray Dryer

[0903] Batch No. 35044-004 Batch No. 35044-030 Loop Configuration closed loop closed loop Cyclone volume 1.1L 1.1L B-295 Loop System Lazy loop Lazy loop Pump speed 100％ 100％ Nitrogen flow rate 30mm 30mm Cooling temperature -10℃ -10℃

[0904] Table 2B-7. Elra:CAP ASD process target parameters

[0905] Process parameters Target scope Inlet temperature(℃) 100 95–100 Air extractor (%) 97 97–100 Pump rate (%) 30 30–40 Spray gas flow meter (mm) 30 30 US nozzle temperature (℃) NA NA US nozzle power (W) NA NA Nozzle cleaning 1 1

[0906] Spray drying of Elra:CAP in tetrahydrofuran was successfully completed and the summary of the spray drying is shown in Table 2B-8 and Table 2B-9.

[0907] Table 2B-8. Summary of spray drying parameters for Elra:CAP batch 35044-004

[0908]

[0909] Table 2B-9. Summary of spray drying parameters for Elra:CAP batch 35044-030

[0910]

[0911] a Bottle tilted at end of run. Weight and spray rate unknown.

[0912] Elra: ASD symptoms:

[0913] Elra: CAP batch 35044-004 was characterized by XRPD ( Fig.31 ), showing the single-mode distribution characteristics of amorphous materials. Fig.32 The morphology of ASD was examined using SEM imaging as shown in Figure 1. The image shows a mixture of hollow spheres, collapsed spheres, and broken spheres typical of spray-dried materials.

[0914] 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 the typical mixed morphology of the ASD process.

[0915] Elra: CAP ASD Granulation Batch 35044-014:

[0916] Prior to granulation, Elra:CAP ASD was passed through a #20 screen. All granular ingredients except magnesium stearate were then added to a 250 mL high density polyethylene (HDPE) bottle and mixed for 50 turns. Magnesium stearate was added to the mixture and mixed for an additional 50 turns.

[0917] The premix was roller compacted using a Gerteis compactor with the parameters summarized in Table 2B-10. The blend was collected in a 500 mL HDPE bottle and weighed to calculate the adjustment factor for the extragranular excipients. The extragranular excipients were added and the mixture was blended to make the final blend.

[0918] Table 2B-10. Gerteis granulation parameters for Elra:CAP ASD batch 35044-014

[0919]

[0920] Elra: CAP ASD Granulation Batch 35044-019:

[0921] About 1 g of premix was used to prepare compacts using a manual tablet press (MTCM-1, Globe Pharma) with a Gerteis compaction simulation (12.5 kN target pressure, equivalent to about 3200 psi on MTCM 1). The compacts were milled through a 1.25 mm screen to produce a free-flowing granular blend. Extragranular excipients were added and the blend was blended for 50 turns to produce the final blend.

[0922] Elra:CAP ASD tableting:

[0923] Use MTCM-1 or Korsch XP-1 tablet press.

[0924] Dry Granulation of Non-Micronized API - Feasibility:

[0925] Prior to granulation, the elraglusib non-micronized API was passed through a #20 screen. All intragranular ingredients except magnesium stearate were then added to a 250 mL HDPE bottle and mixed for 50 turns. Magnesium stearate was added to the mixture and mixed for another 50 turns. About 1 g of premix was used to prepare the compact using MTCM-1 with Gerteis compaction simulation (12.5 kN target pressure, equivalent to about 3200 psi on MTCM 1). The compact was milled through a 1.25 mm screen to make a free-flowing granular mixture. Extragranular excipients were added and the mixture was blended to make the final blend.

[0926] Non-micronized API Dry Granulation - Prototype:

[0927] Prior to granulation, the elraglusib non-micronized API was passed through a #20 sieve. All granular ingredients except magnesium stearate were then added to a 500 mL HDPE bottle and mixed at 25 revolutions per minute (rpm) for 10 minutes. Magnesium stearate was added to the mixture and each ingredient was mixed for another 5 minutes at 25 rpm. The premix was roller compacted using a Gerteis compactor, and the parameters are summarized in Table 2B-11. The blend was collected in a 500 mL HDPE bottle and weighed to calculate the adjustment factor for the extragranular excipients. Extragranular microcrystalline cellulose (MCC) and cross-linked sodium carboxymethyl cellulose (CSS) were added and the mixture was blended at 25 rpm for 5 minutes. Magnesium stearate was sieved through a #20 sieve, added to the mixture, and blended at 25 rpm for 5 minutes to make the final blend.

[0928] Table 2B-11. Gerteis parameters for dry granulation of non-micronized API

[0929]

[0930] Wet Granulation of Non-Micronized API - Feasibility:

[0931] Prior to granulation, the elraglusib non-micronized API was passed through a #20 screen. The intragranular ingredients were added and mixed in a mortar for 1 minute. 30% w / w water for injection was added at approximately 2.5 g / min. The wet massing time of the blend was 1 minute before the blend was transferred to an oven at 60°C for 6 hours. After the time was over, the drying loss was determined and a 1.00 mm screen was used for granulation of the dry blend. The blend was weighed to calculate the adjustment factor for the extragranular excipients. The extragranular MCC and CSS were added to the HPDE container and the mixture was mixed for 50 turns. Magnesium stearate was added to the mixture and mixed for another 50 turns to make the final blend.

[0932] Non-micronized API Wet Granulation - Prototype:

[0933] The intragranular ingredients were added in a high shear wet granulator, half of the MCC was added before the non-micronized API and excipients, and the other half of the MCC was added on top of the 1.0L bowl. The ingredients were dry mixed to homogenize in a GlobePharma high shear granulator 1-6 at an impeller speed of 300 rpm and a mill speed of 1000 rpm. Wet granulation started with a spray rate of approximately 10 mL / min using an impeller speed of 300 rpm and a mill speed of 1000 rpm. After water was added to the target of 30% w / w, the sprayer was turned off and wet massing was performed for 90 seconds to promote the distribution of water in the solid. The wet granules were then manually ground through a #6 screen (3.35 mm). SolidLab1 equipped with a 0.5L bowl was used for fluidized bed drying of the granules. The air intake was set to 15 cubic feet per minute (CFM) and the temperature was 60.0°C. Once the product temperature reaches 45°C, the fluid bed dryer is loaded with wet ground granules. After 20 minutes of drying time, the drying loss observed at 105°C is less than 2.0% (Batch No. 35044-027-0.49%). The dried granules are discharged and manually ground through a 1.00 mm screen. The granulated mixture is transferred to a 500 mL polypropylene bottle and weighed to calculate the adjustment factor for extragranular excipients. Extragranular MCC and CSS are added and the mixture is blended at 25 rpm for 5 minutes. Magnesium stearate is sieved through a #30 screen (0.595 mm), added to the mixture, and blended at 25 rpm for 3 minutes to make the final blend.

[0934] Elra:CAP ASD tableting:

[0935] Use MTCM-1 or Korsch XP-1 tablet press.

[0936] Spray drying of Elra:CAP in tetrahydrofuran was successfully completed and the summary of the spray drying is shown in Table 2B-12 and Table 2B-13.

[0937] Table 2B-12. Summary of Elra:CAP spray drying parameters, batch 35044-004

[0938]

[0939] Table 2B-13. Summary of Elra:CAP spray drying parameters, batch 35044-030

[0940]

[0941] a Bottle tilted at end of run. Weight and spray rate unknown.

[0942] Elra: ASD symptoms:

[0943] Elra:CAP from batch 35044-004 was characterized by XRPD ( Fig.31 ), showing the single-mode distribution characteristics of amorphous materials. Fig.32 The morphology of ASD was examined using SEM imaging as shown in Figure 1. The image shows a mixture of hollow spheres, collapsed spheres, and broken spheres typical of spray-dried materials.

[0944] ASD production 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 the typical mixed morphology of the ASD process.

[0945] Micronized Elraglusib API:

[0946] Elraglusib API was micronized using a jet mill and evaluated for compressibility.

[0947] Characterization of Micronized Elraglusib API:

[0948] SEM images of elraglusib material before and after jet milling ( Fig.33 ), particle size distribution (PSD, Fig.34 ) and XRPD( Fig.35 ) for evaluation of the micronization process. The SEM, PSD, and XRPD data before and after milling were in line with expectations. A bimodal particle size distribution was observed after milling, which could be due to a single pass through the mill.

[0949] API micronization was successfully performed to produce a material with improved compressibility compared to the non-ground material. Particle size analysis showed that the micronized material had a bimodal distribution, which could be evaluated and further optimized to produce a unimodal distribution.

[0950] Development of dry granulation formulations for micronized API

[0951] The formulation development for the dry granulation process of micronized API was aimed at producing tablets with the formulation components shown in Table 2B-14. Formulation 35044-008 was eventually modified to use more extragranular microcrystalline cellulose (formulation 35044-015).

[0952] Table 2B-14. Micronized API dry granulation formulation components

[0953]

[0954] Development of formulations for wet granulation of micronized API

[0955] The micronized API wet granulation formulation was developed to produce tablets with the formulation components shown in Table 2B-15.

[0956] Table 2B-15. Micronized API wet granulation formulation components

[0957]

[0958] The modified micronized API wet granulation formulation (35044-027) was processed using a GlobePharma high shear wet granulator and the granulation data are shown in Table 2B-16. The wet granules were manually ground through a #6 (3.35 mm) screen before loading the material into a 0.5 L fluid handling bowl. The fluid bed drying data are shown in Table 2B-17.

[0959] Table 2B-16. Micronized API wet granulation process data, batch 35044-027

[0960]

[0961] Table 2B-17. Fluid Bed Drying Data for Micronized API, Batch 35044-027

[0962]

[0963] Wet granulation of micronized elraglusib API was successfully accomplished using high shear wet granulation. A small increase in power was used during the granulation process, indicating that additional water could be used for granulation.

[0964] Dissolution

[0965] Wet and dry granulation and dissolution of the ASD materials in 6% w / w CTAB in 0.7 M sodium chloride solution were evaluated at paddle speeds of 75 rpm and 100 rpm. Fig.36 .

[0966] The effect of compaction pressure on the observed dissolution profiles of dry and wet granulated materials was evaluated using the same conditions of 6% w / w CTAB in 0.7 M sodium chloride solution and 100 rpm paddle speed.

[0967] The dissolution medium for ASD material testing was changed to 1% w / w CTAB in 0.7 M sodium chloride. The dissolution profile of ASD tablets in 1% w / w CTAB in 0.7 M sodium chloride was improved compared to 6% w / w CTAB in 0.7 M sodium chloride, as no drop in dissolution was observed between 45 and 60 min. It was speculated that the increase in CTAB concentration may have disrupted the ASD polymer and released the API from the complex.

[0968] Example 3. Bioavailability study

[0969] PK Study 1 - Comparison of the Bioavailability of IV Formulations with Oral Administration in Dogs

[0970] This study aimed to evaluate the pharmacokinetic profile of elraglusib following single oral and intravenous doses in beagle dogs.

[0971] Dogs were dosed with the test article (elraglusib in a vehicle of 85% PEG400, 10% ethanol, 5% water (all components weight / weight / weight)) orally and by intravenous infusion according to the table below.

[0972] Male beagle dogs were selected for this study. Animals were at least 6 months old and males weighed approximately 9.3-10.8 kg at the start of dosing.

[0973] The study animals received a single oral dose of elraglusib, followed by a washout period of approximately 7 days, after which they received a single intravenous infusion of elraglusib. The animals underwent standard assessments, such as body weight and clinical observations, and blood was drawn after each dose for pharmacokinetics. A summary of the study design is shown in Table 3-1 below:

[0974] Table 3-1: Experimental design of bioavailability study 1 in dogs

[0975]

[0976] NOTE: Following oral administration of elraglusib, after a washout period of approximately 7 days, dogs were again used for an intravenous infusion of elraglusib (approximately 15 minutes).

[0977] Plasma concentrations of elraglusib were measured in dogs treated with 20 mg / kg elraglusib orally on Day 1 and again by intravenous infusion on Day 8. All animals achieved systemic exposure to elraglusib following both oral and intravenous administration. Intravenous administration produced higher plasma concentrations of elraglusib compared to oral administration. Individual plasma concentrations peaked approximately 2-8 hours after oral administration (1410-1880 ng / mL) and approximately 5 minutes after intravenous administration (11800-13600 ng / mL).

[0978] Overall, the half-life was similar for both oral and intravenous routes of administration. The mean C max The AUC was approximately 7.5-fold higher when administered by intravenous (IV) route compared to oral (PO) route. lastAbout 3 times higher. Comparing the plasma AUC values ​​of oral gavage (21300hr*ng / mL) and IV injection (68900hr*ng / mL), the oral bioavailability percentage (%BA) can be estimated to be 100*(21300 / 68900)=31%BA. The PK parameters of each route are summarized as follows:

[0979] Table 3-2. Summary of individual and group mean PK parameters of test article elraglusib on day 1 (oral route)

[0980]

[0981]

[0982] a Data from the terminal elimination phase of elraglusib were insufficient to calculate parameters.

[0983] b Values ​​are reported to 3 significant figures.

[0984] Table 3-3. Summary of individual and group mean PK parameters of test article elraglusib on day 8 (IV route)

[0985]

[0986] a Values ​​are reported to 3 significant figures.

[0987] PK Study 2 - Bioavailability of Oral Solution, Oral Suspension, Elra:CAP, and Elra:PVAP Capsule Dosage Forms in Dogs

[0988] A five-way crossover study was conducted in which three animals were first dosed with 10 mg / mL elraglusib in PEG400:EtOH:water (85:10:5% w / w) via IV injection at 10 mg / kg.

[0989] Three male, drug-treated and / or drug-naive beagles were selected for use in this study. The animals were 7-12 months old and weighed 8-12 kg at the start of the quarantine period for this study. Actual weight and age may vary but will be recorded and stored with the original data.

[0990] Each animal was provided approximately 250-350 grams of Harlan Teklad Certified Dog Food #2025 (or other appropriate food documented in the study records) per day. Each batch of food was analyzed for contaminants to ensure that they were not present at concentrations that would be expected to interfere with the conduct or purpose of this study. In addition, each dog was fed a commercial canned dog food to ensure that the animal was fed prior to dosing. 1 / 2-1 can of canned dog food was provided at least 1 hour prior to each dosing. The batch number and brand of dog food was recorded in the study records.

[0991] The study consisted of a single group of 3 dogs, each receiving 5 doses of elraglusib formulations, each separated by a minimum 3-day treatment-free period (washout period). The first dose was a single intravenous (IV) infusion of elraglusib TA#1 (10 mg / mL solution in PEG400:EtOH:water, 85:10:5% w / w), followed by oral administration of TA#2 (Elra:CAP capsules, 100 mg elraglusib), followed by oral administration of TA#3 (Elra:PVAP capsules, 100 mg elraglusib), followed by oral gavage of TA#4 (2 mg / mL oral suspension formulation), followed by oral gavage of TA#5 (50 mg / mL oral solution). Animals underwent standard assessments, such as body weight and clinical observations, and blood was drawn before and after each dose for pharmacokinetic testing. The experimental design of Study 2 is summarized in Tables 3-4.

[0992] Table 3-4

[0993]

[0994] a 9-ING-41 API was diluted into vehicle (PEG400:EtOH:water 85:10:5% w / w) and administered.

[0995] b TA#5 was diluted 25 times in D5W and administered intragastrically.

[0996] NOTE: Following a single IV dose of elraglusib, dogs were re-administered oral gavage and capsule administration of elraglusib after a minimum 3-day washout period between doses.

[0997] 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 injected into the cephalic vein (or other appropriate blood vessel). Following the intravenous administration, dogs received 4 additional oral (gavage or capsule) administrations of the test article (TA#2, 3, 4, and 5) in order of the test article #. Doses for intravenous and oral gavage administrations were based on the most recent body weight. For capsule administration, the pre-filled capsules were weighed prior to dosing and then calculated based on the dog's body weight.

[0998] Blood samples were collected from the jugular vein (or other suitable blood vessels) of each dog at the following time points and placed in 2 mL vacuum blood collection tubes containing K2EDTA as an anticoagulant:

[0999] a) Intravenous administration: before (0), 5, 15, 30, 60 minutes, and 2, 4, 8, and 24 hours after the end of the injection. Time zero (trough) was collected within approximately 24 hours before administration.

[1000] b) Oral administration: before (0), 15, 30, 60 minutes, and 2, 4, 8, and 24 hours after dosing. Time zero (trough) values ​​were collected within approximately 24 hours before dosing.

[1001] The animals were maintained on a prescribed feeding regimen and were fed shortly before dosing to ensure that the animals remained fed during the dosing period. After a washout period, the same three animals were dosed with 20 mg / kg or 10 mg / kg of each of the four oral formulations of the present application:

[1002] 1) 20 mg / kg dose, using size 00 hard gelatin capsules containing 100 mg Elra:CAP ASD;

[1003] 2) 20 mg / kg dose, using size 00 hard gelatin capsules containing 100 mg of Elra:PVAP ASD;

[1004] 3) 20 mg / kg dose, using elraglusib 50 mg / mL in carrier variant 7 (PEG400:EtOH:Tween 8094:5:1% w / w) oral solution;

[1005] 4) 10 mg / kg, using elraglusib 50 mg / mL vector variant 7 solution after dilution in 5% glucose injection (D5W) to a 2 mg / mL suspension.

[1006] Blood samples were drawn at timed intervals and plasma [elraglusib] was measured using a validated LC-MS / MS method.

[1007] Table 3-5. Mean plasma concentration results of dog PK study 2

[1008]

[1009] *%BA=100*(AUC 口服 ÷AUC IV )

[1010] %BA=100*(0.5*AUC 口服 ÷AUC IV )

[1011] These results demonstrate high oral percent bioavailability of Elra:CAP solid oral dosage form (%BA=97) and 50 mg / mL oral solution of carrier variant 7 (%BA=80). The 50 mg / mL oral solution of carrier variant 7 exhibited significantly shorter Tmax values ​​compared to both solid oral dosage forms (Tmax=8 hours for the solid dosage form vs. Tmax=2 hours for the oral solution).

[1012] PK Study 3.-Bioavailability of Oral Solution and Tablet Dosage Forms in Dogs

[1013] Three male beagle dogs that had been treated with medication were selected from the colony's internal breeding pool for use in this study. These animals were approximately 11-16 months old and weighed 10-12 kg at the start of the quarantine period of this study.

[1014] Each animal was provided approximately 250-350 grams of Harlan Teklad Certified Dog Food #2025 (or other appropriate food as documented in the study records) per day. Each batch of food was analyzed for contaminants to ensure that no contaminants were present at concentrations that would be expected to interfere with the conduct or purpose of this study. In addition, each dog was fed a commercial canned dog food to ensure that the animal was fed prior to dosing. 1 / 2-1 can of canned dog food was provided at least 1 hour prior to each dosing.

[1015] All animals were provided with city water ad libitum via an automatic drinking system. The water supply was analyzed for contaminants in accordance with the U.S. Environmental Protection Agency's 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 study results.

[1016] Each dog is identified with an ear tattoo; provided the animal is assigned. The assigned identification number is unique within the animal room being used.

[1017] Controls were set to maintain a temperature range of approximately 22 ± 3°C (approximately 66 to 77°F) and a relative humidity range of 30 to 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 checked at least once a day to ensure that the environmental systems were operating properly.

[1018] During completion and the study, dogs were housed in groups by sex (when possible) in kennels or individually in tandem cages with matching doors to allow socialization / exercise. Co-housing was limited to animals of the same sex and dose group. During dosing and observation phases, animals were housed individually. Each kennel or cage was equipped with an automatic drinking water system.

[1019] Animal cages / kennels and rooms were cleaned and disinfected prior to animals being placed in them and regularly thereafter in accordance with accepted animal care practices and relevant standard operating procedures.

[1020] The test products are as follows:

[1021] TA#1 is a 10 mg / mL weight to volume solution of elraglusib in vehicle, microfiltered using a syringe filter (or other suitable filtration system) and dispensed into sterile vials for use. The IV solution is formulated based on the assay value for elraglusib. The IV solution is administered by infusion at 10 mg / mL, followed by an ample washout period. The vehicle is 85% PEG-400, 10% ethanol, 5% water (all components weight / weight / weight).

[1022] Tablets (TA#2): Each dog was given one tablet of TA#2 orally, followed by an adequate washout period.

[1023] Tablets (TA#3): Each dog was given one tablet of TA#3 orally, followed by an adequate washout period.

[1024] Tablets (TA#4): Each dog was given one tablet of TA#4 orally, followed by an adequate washout period.

[1025] The 50 mg / mL solution was used for oral suspension (TA#5) and was administered orally to dogs at 0.4 mL / kg.

[1026] The experimental design for Dog PK Study 3 is summarized in Tables 3-6 below.

[1027] Table 3-6

[1028]

[1029]

[1030] The study consisted of a single group of 3 dogs. Each received 5 doses of elraglusib formulations, with each dose separated by a minimum 3-day treatment-free period (washout period). The first dose was a single intravenous (IV) infusion dose of elraglusib (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 50 mg / mL oral solution (TA#5). Animals underwent standard assessments, such as body weight and clinical observations, and blood was drawn before and after each dose for pharmacokinetic testing. The experimental design of Dog PK Study 3 is summarized in Tables 3-7.

[1031] Table 3-7

[1032]

[1033] a Elraglusib API was diluted into vehicle and administered. Following intravenous administration of elraglusib, dogs were re-administered with elraglusib tablets and oral gavage after a minimum 3-day washout period between doses.

[1034] Pharmacokinetics (PK): Blood samples were collected from the jugular vein (or other suitable blood vessels) of each dog at the following time points and placed in 2 mL vacuum blood collection tubes containing K2EDTA as an anticoagulant:

[1035] Intravenous administration: Before (0), 5, 15, 30, 60 minutes, and 2, 4, 8, and 24 hours after the end of the injection. Time zero (trough) was collected approximately 24 hours before dosing.

[1036] Oral administration: Before (0), 15, 30, 60 minutes and 2, 4, 8 and 24 hours after dosing. Time zero (trough) values ​​were collected approximately 24 hours before dosing.

[1037] Approximately 2.0 mL of whole blood was collected at each time point. The blood samples were placed in tubes containing K2EDTA as an anticoagulant. The tubes were inverted several times to disperse the anticoagulant and then placed in wet ice or a freezing rack to cool until centrifugation. The date and time of each blood collection were recorded. The blood samples were centrifuged using a refrigerated centrifuge (at approximately 3000 rpm, 4±3°C for 10 minutes). Plasma was collected and transferred to pre-labeled plastic cryovials. Each sample tube was labeled with at least the following information: study number, animal number, sex, treatment (defined as TA#1, 2, 3, 4, or 5), collection time (hours), date, and study day (dose). Complete blood sample processing and plasma collection, and place plasma samples in dry ice or a freezer within approximately 1 hour of blood collection. Subsequently, all samples were stored in a freezer at approximately -70±15°C.

[1038] Fig.38The mean plasma profiles of elraglusib observed in Study 3 and the mean plasma profiles of elraglusib in Studies 2 and 3 for IV and oral solutions are shown.

[1039] Tables 3-8 below summarize the bioavailability data for each of the dog PK studies 1, 2, and 3:

[1040] Table 3-8

[1041]

[1042] *Data from N=6 animals in Study 2 and Study 3 combined are the average of these two groups.

[1043] Bioavailability = 100*(AUC of study group) / (AUC of IV group)

[1044] PK Study 4 - Comparison of IV and oral solutions in normal human volunteers

[1045] An oral clinical proof-of-concept study of elraglusib was conducted as a companion study to the ongoing Phase 2 study of IV elraglusib. Patients in a subgroup of recurrent or metastatic PDAC (pancreatic ductal adenocarcinoma) who had not previously received systemic therapy in the recurrent / metastatic setting received a single oral dose of elraglusib 50 mg / mL oral solution drug product in combination with gemcitabine and nab-paclitaxel. Patients received a single oral dose of elraglusib 50 mg / mL oral solution on Day 1 of Cycle 1 in place of the intravenous (IV) dose and received IV dosing per the primary schedule for all subsequent doses. The first three patients received an oral dose of 9.3 mg / kg. In the absence of any overt toxicity, subsequent cohorts of 3 patients received oral doses of 12.4 mg / kg, 15 mg / kg, and 17.8 mg / kg to match dose levels previously evaluated in Phase 1 patients and including an additional level commensurate with exposure at 15 mg / kg based on the bioavailability of elraglusib 50 mg / mL oral solution in fed dogs (80% compared to IV dosing).

[1046]

[1047]

[1048]

[1049]

[1050] This clinical study showed that oral administration of elraglusib 50 mg / mL oral solution produced AUC, C max , T max and t 1 / 2 This study also demonstrated that administration of elraglusib 50 mg / mL oral solution did not induce any significant adverse events.

[1051] The bioavailability studies described in Example 3 demonstrate the following:

[1052] 1) Oral administration of the IV solution formulation resulted in a bioavailability of approximately 31% of the bioavailability of the IV solution formulation administered intravenously. (PK Study 1)

[1053] 2) The oral dosage form of the present application produces an elraglusib bioavailability comparable to that obtained by intravenous administration. (PK Study 2, PK Study 3)

[1054] 3) Oral administration of elraglusib with food resulted in improved bioavailability compared to administration without food (PK Study 2, PK Study 3 vs. PK Study 1).

[1055] 4) The oral dosage form of the present application produces clinically significant bioavailability of elraglusib (PK study 4).

[1056] Example 4 - Photostability Study

[1057] background

[1058] Drug product development studies have shown occasional abnormal results with respect to [elraglusib], label claim percentage (%LC), elraglusib main peak area % and peak area % values ​​of the related substances elraglusib RelS1 (HPLC RRT 0.96) and elraglusib RelS2 (HPLC RRT 0.97).

[1059] These apparently unusual results suggest that the elraglusib injection, solution drug product is more susceptible to the effects of light exposure than solid elraglusib or elraglusib acetonitrile solution.

[1060] Therefore, elraglusib photosensitivity studies were conducted with exposure to the following conditions:

[1061] · UV or visible light in a calibrated light chamber, and

[1062] Ambient light.

[1063] Light chamber and ambient light studies use RP-HPLC methods to monitor the following:

[1064] Elraglusib concentration and %LC

[1065] ·Elraglusib main peak area%

[1066] • Elraglusib RelS1, elraglusib RelS2 and elraglusib anhydride peak area % values.

[1067] Light chamber studies included the following experimental variables:

[1068] ·Pharmaceutical carrier / solvent

[1069] Formulation vehicle PEG400:EtOH:Polysorbate 80 75:17:8% w / w ("FV")

[1070] Carrier variant 7 PEG400:EtOH:Polysorbate 80 94:5:1% w / w ("V7")

[1071] PEG400 (“PEG only”)

[1072] ·PEG400:EtOH 95:5% w / w (“PEG-E”)

[1073] PEG400:polysorbate 80 95:5% w / w ("PEG-T")

[1074] Acetonitrile ("AN")

[1075] Elraglusib concentrations (2, 10, 15, and 50 mg / mL)

[1076] Light source (ultraviolet and visible light)

[1077] Irradiation time (0, 25, 50, 75 and 100% ICH Q1B conditions)

[1078] Containers (transparent glass bottles and cuvettes with or without foil outer wrapping)

[1079] Dissolved gas (oxygen injection, nitrogen injection, or no injection)

[1080] Ambient light studies include the following experimental variables:

[1081] Primary container (transparent glass bottle and amber glass bottle)

[1082] · Secondary container (translucent plastic divider box), and

[1083] Tertiary container (opaque cardboard box)

[1084] Results from three light chamber studies support the following conclusions:

[1085] For elraglusib in different solvents and within the concentration range of 10 to 50 mg / mL, the elraglusib %LC and main peak area % values ​​decreased approximately linearly with increasing illumination.

[1086] The % LC loss of elraglusib upon illumination exceeded the % area loss of the main peak by approximately 6-fold (due to the shift of the elraglusib absorbance maximum from ~440 nm for elraglusib to ~330 nm for elraglusib ReI S2).

[1087] Among the solvents studied, the rate of elraglusib loss under visible light increased in the following order: AN << PEG only ~ PEG-E <FV<V7<PEG-T

[1088] The rate of elraglusib light loss relative to visible light was essentially independent of elraglusib concentration over the range of 10 to 50 mg / mL

[1089] The rate of photoloss of elraglusib was approximately five times faster with exposure to visible light compared to UV light

[1090] The rate of elraglusib photoloss from samples exposed to visible light was essentially independent of the presence of dissolved gases (oxygen and nitrogen).

[1091] After exposure of elraglusib injection and solution to 100% visible light at 1200 klux-hr, elraglusib %LC loss was significant (approximately 20% loss)

[1092] After exposure of elraglusib injection and solution to 100% visible light at 1200 klux-hr, the change in elraglusib RelS1 peak area % could not be quantified due to incomplete resolution between elraglusib RelS1 and elraglusib RelS2 using the RP-HPLC method.

[1093] After exposure of elraglusib injection and solution to 100% 1200 k-hr visible light, the elraglusib RelS2 peak area % increased significantly (to approximately 3% to 5% peak area %)

[1094] After exposure of elraglusib injection and solution to 100% 1200 klux-hr visible light, the elraglusib anhydride peak area % value remained unchanged or slightly decreased

[1095] Results from three ambient light studies support the following conclusions:

[1096] Elraglusib injection and solution drug products convert to elraglusib RelS2 after exposure to ambient light in clear glass serum bottles for 28 days

[1097] Exposure to ambient light for 3 to 7 days had little effect, but elraglusib %LC and main peak area % values ​​decreased significantly after 14 to 28 days of exposure, while elraglusib RelS2 peak area % values ​​increased in the 7 to 28 day interval

[1098] Amber glass bottles and plastic dividers are used as secondary packaging for clear glass bottles to reduce but not completely prevent phototransformation of elraglusib under ambient light.

[1099] Placing the clear glass bottles in the plastic dividers inside the opaque cardboard boxes can minimize photoconversion of elraglusib under ambient light.

[1100] Light chamber research

[1101] Light Chamber Study 1

[1102] The effect of light irradiation on elraglusib in three solutions was studied, namely:

[1103] 10FV (10 mg / mL elraglusib in a formulation vehicle (PEG400:EtOH:Tween 80 75:17:8% w / w) solution),

[1104] 50FV (50 mg / mL elraglusib formulation vehicle solution)

[1105] 50V7 (50 mg / mL elraglusib in carrier variant 7 (PEG400:EtOH:Tween 80 94:5:1% w / w) solution).

[1106] 10FV solution is the same as elraglusib injection solution.

[1107] The three solutions were stored in 5 mL glass serum bottles and UV clear plastic cuvettes (each with and without foil outer packaging) and exposed to ICH Q1B photostability conditions (1200 klux-hr in the visible region, 200 watt-h / m 2 ) fractions (approximately 0, 25, 50, 75 and 100%).

[1108] Photoirradiation converts elraglusib to elraglusib Rel S2. Solutions exposed to ≤25% visible light at 1200 klux-hr are characterized by two partially resolved peaks for elraglusib Rel S1 and elraglusib Rel S2, but the peak for elraglusib Rel S2 increases with increasing irradiation interval and the resolution between the two peaks decreases.

[1109] Elraglusib %LC and main peak area % values ​​decreased linearly with increasing intervals of visible and UV light exposure. The %LC loss rate was approximately 6 times faster than the main peak area % loss rate.

[1110] The % LC photoconversion in the vial (no foil) exposed to visible light was about 60% of the conversion in the cuvette (no foil). The foil overwrap severely reduced the photoconversion in both the cuvette and the vial.

[1111] The photoconversion of %LC and % major peak area in vials and cuvettes was significantly faster under visible light irradiation compared to UV light irradiation. The photoconversion was approximately 5 times faster under exposure to visible light compared to UV light.

[1112] For samples stored in vials (no foil) and exposed to visible light, the %LC and main peak area % photoconversion for 10FV was approximately 1.6 times higher than that for 50FV or 50V7, which were approximately equal. Table 4-1 summarizes the photoconversion comparisons.

[1113] Table 4-1. Vial Photoconversion (Slope) Values, Comparison of Formulations and %LC vs. Main Peak Area %

[1114]

[1115] * Slope = (% of main peak area) / (% of 1200 klux / hr)

[1116] Slope = (%LC) / (% of 1200 klux / hr)

[1117] For the 10FV sample in the vial exposed to 1200 klux-hr, the elraglusib % LC loss was significant (approximately 20% loss). Under the same conditions, the elraglusib RelS2 peak area % values ​​increased to approximately 3% to 5%. Due to incomplete resolution between the elraglusib RelS1 peak and the elraglusib RelS2 peak, the elraglusib RelS1 peak area % values ​​could not be reliably quantified.

[1118] Light Chamber Study 2

[1119] Effects of visible light irradiation in a light chamber on 10 mg / mL elraglusib in four carriers, namely:

[1120] FV (PEG400:EtOH:polysorbate 75:17:8% w / w, which is the elraglusib injection vehicle)

[1121] PEG only (100% PEG 400);

[1122] ·PEG-E (PEG400:EtOH 95:5%w / w) and

[1123] · PEG-T (PEG400: polysorbate 95: 5% w / w).

[1124] Visible light irradiation converted elraglusib to elraglusibRelS2 in each of the four tested articles. In all tested articles, the peak area % values ​​of elraglusib anhydride-related substances decreased slightly with increasing light irradiation.

[1125] For all four tested articles, elraglusib %LC and main peak area % values ​​decreased linearly with increasing illumination interval.

[1126] Table 4-2 below shows that the order of increasing %LC and main peak area % photoconversion rate (slope) values ​​is: only PEG to PEG-E <FV<PEG-T。

[1127] Table 4-2. Slope ratios of 10 mg / mL FV, PEG only, PEG-E, and PEG-T test products exposed to visible light

[1128]

[1129] * Slope = (% of main peak area) / (% of 1200 klux / hr)

[1130] Slope = (%LC) / (% of 1200 klux / hr)

[1131] Light Chamber Study 3

[1132] Effects of visible light exposure on the elraglusib test article, including:

[1133] 10FV (10 mg / mL elraglusib formulation vehicle PEG400:EtOH:polysorbate 75:17:8% w / w solution)

[1134] 2AN (2 mg / mL elraglusib in acetonitrile).

[1135] The 10FV test article is the same as the elraglusib injection and solution drug products. This study used the 2AN test article to explore the effects of protic and aprotic solvents on the photosensitivity of elraglusib and to complement the previous results of the photoirradiation study of elraglusib in acetonitrile.

[1136] The 10FV test articles were initially sparged with either oxygen or nitrogen, while the 2AN test articles were not sparged.

[1137] Test articles were stored in glass serum bottles (25 mL filled in 50 mL vials) and exposed to fractions (0, 25, 50, 75 and 100%) of 1200 klux-hr using a calibrated light chamber.

[1138] For all four test articles, the elraglusib %LC and main peak area % values ​​decreased linearly with increasing visible light irradiation interval.

[1139] The %LC and % photoconversion of the main elraglusib peak area were essentially the same for the oxygen sparged and nitrogen sparged samples.

[1140] The photoconversion rate of elraglusib was significantly slower in the 2AN test article compared to the 10FV test article.

[1141] For the 10FV test article, the elraglusib RelS2 peak area % values ​​increased approximately linearly with increasing irradiation interval to 4% peak area %, regardless of the spray conditions. The elraglusib RelS2 peak area % values ​​were below the method quantification limit (0.08 peak area %) at all visible light irradiation intervals for the 2AN test article. The peak area % values ​​of elraglusib anhydride-related substances decreased slightly or did not change significantly with increasing visible light irradiation intervals.

[1142] Ambient light study

[1143] This ambient light study used the same test articles, analytical methods, and procedures as Light Chamber Study 1, except for the time intervals (t=0, 1, 3, 7, 14, 21, and 28 days) during which the test articles were exposed to ambient light.

[1144] For all three test articles exposed to ambient light, elraglusib %LC and main peak area % values ​​remained essentially constant at t = 0, 1, and 3 days, but then decreased approximately linearly with increasing illumination intervals. Foil overwrap severely reduced light conversion in cuvettes and vials.

[1145] Ambient light exposure converts elraglusib to elraglusib RelS2. Elraglusib RelS2 area % values ​​were not detected at time points t=0, 1, and 3 days, but increased approximately linearly thereafter with increasing ambient light exposure time. The elraglusib RelS2 area % values ​​of the 10FV test article increased significantly faster than those of the 50FV and 50V7 test articles, but the rates of increase for the 50FV and 50V7 test articles were approximately equal.

[1146] Example 5 - Bioavailability of oral solution and intravenous injection in human volunteers

[1147] Example 5 describes the results of PK Study 4 in Example 3.

[1148] This pharmacokinetic (PK) study was conducted in healthy subjects to characterize and compare the PK parameters in plasma after a single intravenous (IV) dose of Elraglusib injection, Elraglusib oral solution after fasting, and Elraglusib oral solution after a high-fat meal (eating). The study was designed to evaluate the potential feasibility of an oral formulation of elraglusib based on systemic exposure within the biological activity range. In clinical studies conducted to date, elraglusib injection (10 mg / mL) was administered intravenously once or twice a week for several hours, which required a significant amount of time and resources for patients and field staff. An oral solution has been developed, and PK studies 2 and PK studies 3 showed approximately ~70% to 80% of the drug dose-normalized bioavailability in dogs in the fed state, which supports further research. See Example 3 above.

[1149] This open-label, single-center, phase 1, randomized, single-dose, crossover, PK study of elraglusib administered as an oral solution in the fed and fasting states and as an intravenous infusion in healthy subjects was conducted in 18 subjects to compare the PK properties of elraglusib oral solution with those of elraglusib injection.

[1150] The primary objectives of the study were: (1) Pharmacokinetics: to evaluate the plasma pharmacokinetics (PK) of a single dose of elraglusib administered as an intravenous (IV) infusion and as an oral solution under fasting and fed conditions in healthy subjects; and (2) Safety: to determine the tolerability of elraglusib administered as an IV infusion and as an oral solution.

[1151] Patient Populations: 18 subjects received at least 1 dose of elraglusib and were included in the safety population. 18 subjects had at least 1 blood sample that provided evaluable PK data for elraglusib and were included in the PK evaluable population. 16 subjects had sufficient data to calculate at least one PK parameter of Cmax, AUC, or λz and were included in the PK analysis population for each treatment.

[1152] Inclusion criteria:

[1153] Subjects must meet all of the following criteria to be eligible for the study:

[1154] 1. Ability to sign informed consent for the protocol, which includes compliance with the requirements and restrictions outlined in the ICF.

[1155] 2. Be between 18 and 55 years of age (inclusive) at the time of signing the ICF.

[1156] 3. Apparently healthy as determined by medical evaluation, including medical history, physical examination, ophthalmological examination (ophthalmoscopy and visual acuity), laboratory tests, and electrocardiogram (ECG).

[1157] 4. Systolic blood pressure (BP) 95-140 mmHg, diastolic blood pressure 45-90 mmHg, heart rate 45-100 beats / minute (bpm).

[1158] 5. Standard 12-lead ECG parameters are normal unless the investigator believes that the ECG tracing abnormality is not clinically relevant. QTc must be ≤450 milliseconds (ms) for both males and females.

[1159] 6. Laboratory parameters are within normal ranges unless the investigator believes the abnormality is not clinically relevant to healthy participants; however, serum creatinine, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are not more than 1.25 times the upper limit of normal (ULN). Total bilirubin values ​​up to 1.5 times the ULN are acceptable if combined with normal conjugated bilirubin values ​​(unless the participant has documented Gilbert's syndrome, in which case bilirubin may be as high as 3.0 times the ULN).

[1160] 7. If male, body weight is between 50.0 kilograms and 100.0 kilograms (kg) (inclusive); if female, body weight is between 40.0 kg and 90.0 kg (inclusive); body mass index (BMI) is between 18.0 and 32.0 (inclusive).

[1161] 8. If female, not pregnant, breastfeeding, lactating, or planning to become pregnant during the study, and a negative urine pregnancy test within 24 hours before the start of the study. If postmenopausal, a recorded serum follicle-stimulating hormone (FSH) level >40mIU / mL must be confirmed.

[1162] a. Women of childbearing potential (WOCBP) and men with reproductive partners must agree to use adequate contraception from the first dose of elraglusib until 4 months after the last dose of elraglusib (unless in an exclusively same-sex relationship).

[1163] b. Start using hormonal contraceptives at least 1 month before screening to ensure complete contraception effectiveness.

[1164] c. The male partner of the WOCBP who is not currently pregnant must agree to use condoms and be informed of the risks of condom breakage or leakage during intercourse and the benefits of the WCOBP partner using a highly effective contraceptive method as prescribed.

[1165] 9. If male, must agree not to donate sperm within 4 months after the last dose of elraglusib.

[1166] Exclusion criteria:

[1167] Subjects who meet any of the following conditions are not eligible for this study:

[1168] 1. At screening, patients are symptomatic and have a history of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematologic, neurological, musculoskeletal, joint, psychiatric, systemic, ocular, or gynecologic (if female) disease; infectious disease; or signs of acute illness.

[1169] 2. Donated any volume of blood (including plasma) within 2 months before inclusion.

[1170] 3. Symptomatic hypotension

[1171] 4. Have a clinically significant drug allergy or allergic disease or history, diagnosed and treated by a healthcare provider. Participants with known hypersensitivity to any component of the investigational product (IP) formulation are excluded.

[1172] 5. Drug abuse or history of drug abuse in the past year.

[1173] 6. A history of heavy drinking in the past year (i.e., 21 drinks per week for men and 14 drinks per week for women) and the risk of withdrawal symptoms during the study may affect the safety assessment.

[1174] a. A drink is defined as a 4- to 5-ounce glass of wine, a 12-ounce glass of beer, or a standard cocktail containing 1.5 ounces of alcohol.

[1175] 7. Regularly smoke more than 2 cigarettes (or equivalent e-cigarettes) per day and are unable to quit during the study restriction period.

[1176] 8. Used cannabinoids within 1 week before inclusion or disagreed to stop using cannabinoids during the study.

[1177] 9. Excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day)

[1178] 10. Taking any prescription or concomitant medication within 3 days before the first dose of elraglusib [except birth control pills, inactive coronavirus disease (COVID) vaccines, supplements (e.g., vitamins)]. Occasional use of acetaminophen and ibuprofen is permitted.

[1179] 11. Any positive test result for the following: hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus antibody (anti-HCV Ab), or anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab).

[1180] 12. Positive urine drug screen (amphetamine / methamphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, or opioids)

[1181] a. Subjects may be included in the study if the urine drug screen is positive for cannabinoids but the subject indicates that they have not used cannabinoids in the week prior to inclusion and agrees to stop using cannabinoids during the study.

[1182] 13. Positive urine alcohol test

[1183] 14. Tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

[1184] Randomization

[1185] Subjects were randomized to receive 1 of 6 dosing sequences:

[1186] 1. Oral feeding - oral fasting - IV

[1187] 2. Oral feeding - IV - oral fasting

[1188] 3. Oral fasting-Oral feeding-IV

[1189] 4. Oral fasting-IV-oral feeding

[1190] 5.IV-Oral feeding-Oral fasting

[1191] 6.IV-Oral Fasting-Oral Feeding

[1192] Randomization followed a block size of 6. No stratification factors were implemented in the randomization scheme of this study. Subjects were randomized using a paper-based randomization scheme.

[1193] Dosage form

[1194] Elraglusib injection is a light red to red clear solution of 10 mg / mL elraglusib in an inactive 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 intravenous infusion after diluting elraglusib for injection with 0.9% sodium chloride injection.

[1195] Elraglusib oral solution is a solution of 50 mg / mL elraglusib in carrier variant 7 (a co-solvent mixture of PEG400:EtOH:Tween 80 (94:5:1% / w / w)). It is a clear red solution without visible particulate matter and is a low bioburden liquid dosage form that is self-preserving and prevents microbial growth.

[1196] Dosage:

[1197] Elraglusib was administered on Day 1 of each of three 2-week study cycles.

[1198] Subjects received a single 3.3 mg / kg dose of each of the following in the order randomly assigned, with 2 weeks between each drug.

[1199] Fed Elraglusib Oral Solution (50 mg / mL): Within 30 minutes, fed subjects consumed a high-fat meal (breakfast). Elraglusib oral solution was also ingested within these 30 minutes. During the study, high-fat meals were administered over a period of less than 30 minutes (28 minutes in almost all cases). The elraglusib dose was administered within 1 minute of the end of the meal, which effectively resulted in the elraglusib oral dose being administered within 20 minutes of the start of the high-fat meal.

[1200] Elraglusib Oral Solution (50 mg / mL) in the Fasting State: Subjects should fast overnight (except water) for at least 8 hours prior to administration of the oral solution.

[1201] Precautions for oral administration:

[1202] Subjects should not consume food for at least 4 hours after taking elraglusib oral solution.

[1203] Subjects should not eat or drink any liquids within 1 hour after taking the elraglusib oral solution. However, if subjects have problems with the taste of the oral solution, consuming lozenges, hard candies, or chewing gum after dosing is acceptable.

[1204] Elraglusib injection (10 mg / mL) was administered as an intravenous infusion over 60 minutes (concentration in mg / mL, and infusion rate in mL / kg / hour, which can be varied based on the subject's body weight).

[1205] Subjects fasted overnight (except water) for at least 8 hours prior to intravenous infusion.

[1206] Subjects were not allowed to eat for at least 4 hours after the infusion was completed.

[1207] The 3.3 mg / kg dose is based on the subject's body weight on Day 1 of Cycle 1 (rounded to the nearest 0.1 kg), unless the subject's body weight changes by more than 10%. In this case, the dose for Cycle 2 and / or Cycle 3 is recalculated using the Day 1 weight (rounded to the nearest 0.1 kg) as described.

[1208] result:

[1209] The standard non-compartmental analysis (NCA) method was used to analyze the PK parameters of elraglusib after each administration, including AUC, C max , T max and t 1 / 2 Log transformed C in subjects with adequate PK data after at least one oral and intravenous dose max The AUC and AUC parameters were used to assess the relative bioavailability of oral administration (fed and / or fasting) compared with intravenous administration.

[1210] Blood samples were drawn from all study subjects for PK analysis of elraglusib.

[1211] Every effort was made to obtain PK samples at the predetermined nominal time relative to dosing. PK samples were analyzed using validated analytical methods.

[1212] Drug dosage, drug concentration

[1213] Target subjects received 3.3 mg / kg of elraglusib per protocol. One subject (106) received only approximately 3% of the target dose during intravenous infusion therapy after interruption of the infusion in cycle 2 due to an adverse event of flushing (grade 2), which the investigator assessed may be related to the elraglusib injection solution. The oral dose was administered evenly as an oral solution containing 50 mg / mL elraglusib. The oral dose ranged from 3.6 mL to 6.3 mL based on body weight. No other oral fluids were allowed for at least one hour, but if the subject had a problem with the taste, a lozenge, hard candy, or gum could be consumed after dosing.

[1214] Table 5-1: Summary of Dose, Volume, and Concentration for Elraglusib Administration by Treatment (PK Analysis Population)

[1215]

[1216] a For intravenous infusion, the original drug solution volume is 20 mL before adding the volume to an infusion bag containing 500 mL of 0.9% saline.

[1217] b For intravenous infusion, the drug concentration in the drug solution before adding to the infusion bag containing 500 mL of 0.9% saline

[1218] c Infusion time: The time when 500+mL of the original injected dose is emptied from the infusion bag, but before the bag and tubing are flushed with approximately 25mL of 0.9% saline at approximately 580mL / hr to ensure complete dose delivery. Collect EOI PK samples within 5 minutes after EOI.

[1219] CV = coefficient of variation; Min = minimum value; Max = maximum value; n = number of observations; NA = not applicable; SD = standard deviation;

[1220] Elraglusib mean PK profile by treatment

[1221] Plasma concentrations of elraglusib were collected 96 hours after dosing for each of the 3 treatments. Fig.41 The mean concentration-time curves for the three treatments are shown, using linear coordinates in the upper panel and semi-log coordinates in the lower panel.

[1222] Fig.41The plots show that intravenous infusion produced the highest peak mean concentrations, while oral administration under fasting conditions produced the lowest peak mean. The plot also demonstrates that co-administration of the drug with a high-fat meal resulted in a substantial increase in exposure and delayed the time to peak mean concentration by several hours compared to administration under fasting conditions. All 3 mean curves showed similar rates of decline during the terminal elution phase. Twelve of the 15 PK-evaluable subjects across all 3 treatments had elraglusib plasma concentrations above the LLOQ for at least 96 hours. Plasma concentrations decreased to below the detection LLOQ (0.200 ng / mL) at 72 hours in 1 subject treated with intravenous infusion (118), 1 subject treated with oral fasting (112), and 2 subjects treated with oral feeding (112, 118), and decreased to below the LLOQ at 48 hours post-dose in 1 subject treated with oral fasting (118). Only 1 subject (118) had C last Less than 96 hours. Quantifiable concentrations in other subjects at 96 hours post-dose ranged from 0.273 ng / mL (109 in the oral, fasting treatment) to 7.18 ng / mL (111 in the intravenous infusion treatment).

[1223] Elraglusib plasma concentrations are highly variable between subjects. For intravenous infusions, CVs in the first 24 hours after dosing are generally between 35% and 45% but range from 20% to 40% if data from subjects who received only 3% of the planned dose are omitted (106). However, following oral treatment, CVs are generally in the range of 60% to 100% when the drug is administered in the fasted state and 45% to 150% when administered in the fed state.

[1224] Mean PK properties of elraglusib by treatment

[1225] Plasma PK parameters of elraglusib were measured over a 96-hour PK observation window for each of the 3 treatments. Descriptive statistics are summarized in Table 5-2 after intravenous infusion, in Table 5-3 after oral administration in the fasting state, and in Table 5-4 after oral administration in the fed state. Subject 106 was not evaluated for C-reactive protein after intravenous infusion due to missed sample collection during the intravenous infusion. max PK parameters related to AUC were not available, but PK parameters related to the terminal elimination phase were calculable. Subject 114 had evaluable PK parameters following IV treatment, but discontinued the study after treatment, so no comparative information for oral administration in the fasted or fed state is available. Both subjects are included in the descriptive statistics for treatment and PK parameters that could be evaluated.

[1226] Table 5-2: Descriptive Statistics of Elraglusib PK Parameters Following Intravenous Infusion of 3.3 mg / kg Elraglusib (PK Evaluable Population)

[1227]

[1228]

[1229] AUC t = area under the curve from time = 0 to t; CI = confidence interval; CL = clearance; CL / F = apparent clearance; C last = Final quantifiable concentration; C max = maximum observed concentration; CV = coefficient of variation; F = fractional bioavailability; GCV = geometric CV; GMean = geometric mean; LB = lower limit; Max = maximum value; Min = minimum value; n = number of observations; NC = not calculable; SD = standard deviation; R 2 = determination coefficient; t 1 / 2 = terminal elimination half-life; T max = Observed C max time; UB = upper limit; Vz = volume of distribution; Vz / F = apparent volume of distribution; λz = terminal elimination rate constant.

[1230] Table 5-3: Descriptive statistics of elraglusib PK parameters after oral administration of elraglusib in the fasting state

[1231] (PK evaluable population)

[1232]

[1233]

[1234] AUC t = area under the curve from time = 0 to t; CI = confidence interval; CL = clearance; CL / F = apparent clearance; C last = Final quantifiable concentration; C max = maximum observed concentration; CV = coefficient of variation; F = fractional bioavailability; GCV = geometric CV; GMean = geometric mean; LB = lower limit; Max = maximum value; Min = minimum value; n = number of observations; NC = not calculable; SD = standard deviation; R 2 = determination coefficient; t 1 / 2 = terminal elimination half-life; T max = Observed C max time; UB = upper limit; Vz = volume of distribution; Vz / F = apparent volume of distribution; λz = terminal elimination rate constant.

[1235] Table 5-4: Descriptive statistics of elraglusib PK parameters after oral administration of elraglusib in the fed state

[1236] (PK evaluable population)

[1237]

[1238]

[1239] AUC t = area under the curve from time = 0 to t; CI = confidence interval; CL = clearance; CL / F = apparent clearance; C last = Final quantifiable concentration; C max = maximum observed concentration; CV = coefficient of variation; F = fractional bioavailability; GCV = geometric CV; GMean = geometric mean; LB = lower limit; Max = maximum value; Min = minimum value; n = number of observations; NC = not calculable; SD = standard deviation; R 2 = determination coefficient; t 1 / 2 = terminal elimination half-life; T max = Observed C max time; UB = upper limit; Vz = volume of distribution; Vz / F = apparent volume of distribution; λz = terminal elimination rate constant.

[1240] These summary tables show that the mean C max The C value (arithmetic mean) was higher than that of the two oral doses, and the C value of oral administration (591.8 ng / mL) in the fed state was max The values ​​were significantly higher than those observed in the fasting state. max A similar pattern was observed in the partial and total AUC estimates, with the mean AUC ∞ Values ​​ranged from 8072 h·ng / mL after intravenous administration to 1811 h·ng / mL after oral administration in the fasting state, with a median value of 5001 h·ng / mL after oral administration in the fed state. The 96-hour PK observation window was sufficient to capture the estimated AUC after each of the 3 treatments. ∞ 98% to 99% of the value.

[1241] Fig.42 The plasma exposure (measured by C max and AUC ∞ The transition plot showed that only 1 subject (118) had a significant difference in C between fed and fasted subjects.max Exposures were similar, with only one subject (also 118) showing differences in AUC between fed and fasted conditions. ∞ The transition plot also shows that only one subject (105) had an AUC of ∞ The second patient (106) may also belong to this group, but the C of the intravenous infusion could not be evaluated in this patient due to missing data early in the infusion and incomplete delivery of the target dose. max or AUC ∞ Exposure amount.

[1242] The average terminal elimination half-life of all three treatments is between 16 and 21 hours. The longest terminal half-life (50.5h, 113) was observed after oral treatment in the fed state, and the shortest half-life (6.92h, 118) was observed after oral administration in the fasted state. In general, the terminal elimination half-life does not seem to be related to the treatment method, and most subjects have a half-life between 15 and 25 hours in the three treatments. Subjects with a shorter half-life (<11 hours) in 1 treatment show similar situations in all 3 treatments. Except for a single case in which 1 subject has a half-life of 50.5 hours, the longest half-life ranges from 24-27 hours, which is not much different from most subjects and is not mainly related to any specific treatment.

[1243] The mean clearance of elraglusib in subjects was 0.4268 L / h / kg or 31.14 L / h when they were treated with intravenous infusion. This clearance value is greater than the nominal human adult glomerular filtration rate of 7.2 L / h, but less than the nominal renal blood flow (~72 L / h) or the nominal hepatic blood flow (~90 L / h), and is therefore 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).

[1244] The mean elraglusib apparent (oral) clearance was 2.608 L / h / kg or 185.7 L / h after dosing in the fasted state, but was lower when administered in the fed state (0.9052 L / h / kg or 64.49 L / h), both of which are consistent with incomplete absorption from the intestine. The difference in apparent clearance between the fasted and fed states, without any change in terminal elimination, suggests that a high-fat breakfast in the fed state promotes the extent of drug absorption from the intestine compared with oral administration in the fasted state.

[1245] The mean volume of distribution of elraglusib in subjects when they received intravenous infusion therapy was 11.19 L / kg or 821.8 L. This volume is much larger than the total body volume, indicating distribution in body tissues at concentrations greater than those observed in plasma, in multiple or most tissues. The mean apparent volume of distribution after oral administration was 2 to 5 times greater than that after intravenous administration, which is consistent with incomplete absorption of elraglusib from the intestine, as was the apparent clearance. As can be seen from the apparent clearance values, the apparent volume of distribution indicates that intestinal absorption is less after administration in the fasted state than after administration in the fed state.

[1246] Comparison of relative bioavailability of elraglusib treatment

[1247] Table 5-5 summarizes the relative bioavailability of elraglusib after oral administration in the fasted and fed states compared to the absolute (100%) bioavailability after intravenous infusion, and the relative bioavailability after oral administration in the fed state compared to oral administration in the fasted state. max Elraglusib has an oral bioavailability of approximately 5-11% when calculated based on the geometric mean of the AUC values ​​in the fasting state, but last or AUC ∞ When the geometric mean of the values ​​was calculated, it was 14-21%. Administration of elraglusib in the fed state may improve oral bioavailability. When fasting IV and oral C max Administration of elraglusib in the fed state resulted in an oral bioavailability of approximately 19% to 38% when calculated based on the geometric mean of the AUC values, but last or AUC ∞ When the geometric mean of the values ​​was calculated, it ranged from 41% to 63%. Administration in the fed state produced a C max The oral bioavailability of the drug was 2.5 to 5 times that observed when administered in the fasting state and 2.4 to 3.6 times that observed in the fasting state based on the AUC metric.

[1248] Table 5-5: Evaluation of the relative bioavailability of elraglusib following oral administration compared to intravenous infusion, and comparison of oral bioavailability following administration in the fed state compared to the fasted state

[1249] (PK analysis population)

[1250]

[1251] Dosage and relative bioavailability of elraglusib

[1252] Although the dose of elraglusib in the study subjects was 3.3 mg / kg, the body weights of the subjects varied nearly 2-fold from 54.3 kg to 96.6 kg. Therefore, the total dose of elraglusib administered ranged from approximately 180 mg to 316 mg (excluding the incomplete intravenous infusion dose of approximately 10.1 mg in subject 106). Based on the individual subject's C max or AUC ∞ The linear regression of the relative bioavailability of elraglusib is shown in Fig.43 Intravenous infusion, Fig.44 Oral administration in the fasting state, and Fig.45 The bioavailability of elraglusib was approximately uniform across the 2-fold dose range tested in this study if the slope of the relationship in each case was approximately 0.0 (i.e., approximately a horizontal line). Confidence intervals (95% CI) are included in the graph to help estimate whether the regression line is statistically different from 0.0 given the limited number of available data points.

[1253] Linear regression of fasting / IV bioavailability of elraglusib versus dose ( Fig.43 ) showed that bioavailability increased with increasing dose. max When evaluating bioavailability, the slope is statistically different from 0.0 (i.e., the 95% CI of the slope does not include 0.0), but when using AUC ∞ There was no statistical difference when the values ​​were compared. Cmax The regression estimates showed that the oral bioavailability under fasting conditions increased from approximately 4% to 16% as the dose increased from 180 mg to 320 mg, while the F AUC∞ The regression estimate of increased from approximately 14% to 24%.

[1254] Linear regression of bioavailability between fed / IV and dose ( Fig.44 ) shows a similar pattern, that is, when based on C max , rather than based on AUC ∞ The bioavailability increased with dose and was statistically significant.Cmax The regression estimates showed that the oral bioavailability in the fed state increased from approximately 16% to 52% as the dose increased from 180 mg to 320 mg, while the F AUC∞ The regression estimate of elraglusib increased from approximately 41% to 71%. These trends suggest that the oral bioavailability of elraglusib may increase as the drug is absorbed from the intestine at a faster rate in subjects receiving higher doses and that this increase has an effect on the C max The impact of α is slightly greater than that of AUC.

[1255] When linear regression of fed / fasted versus dose was used to compare the 2 oral dose treatments ( Fig.45 ), the slope of the regression was negative but not statistically different from 0.0. If these trends were true, they would indicate that the difference between oral bioavailability in the fasted and fed states was greatest at lower elraglusib doses and decreased at the higher elraglusib doses used in the study.

[1256] Dose and clearance and volume of distribution of elraglusib

[1257] Linear regression was used to test the relationship between elraglusib clearance and apparent clearance and elraglusib dose. The slopes of the regression relationships for the three treatments were not statistically different from 0.0. However, the slopes after both oral doses showed a slightly negative trend, which is consistent with the bioavailability results mentioned above, that is, C max and AUC ∞ There is a regression relationship that increases with increasing dose. The regression line estimates that the apparent clearance after a 320 mg dose is one-third to one-half of the apparent clearance after a 180 mg dose.

[1258] The relationship between the volume of distribution and apparent volume of distribution of elraglusib and the dose of elraglusib was also tested using linear regression. The slopes of the regression relationships for the three treatments were not statistically different from 0.0. In addition, there was no obvious trend of sustained negative or sustained positive values ​​in the slopes after oral dose treatment. There was little evidence that the volume of distribution or apparent volume of distribution was affected by the dose of elraglusib.

[1259] This study examined the plasma pharmacokinetics of elraglusib following administration of the drug as an intravenous infusion over approximately 80 minutes, as an oral dose in the fasting state, and as an oral dose in the fed state (i.e., a high-fat, high-calorie breakfast). The pharmacokinetic objectives of the study include evaluating the pharmacokinetics of elraglusib when administered intravenously and orally and determining the relative bioavailability of elraglusib when administered orally in the fasting state or in the fed state compared to its bioavailability when administered as an intravenous infusion. In addition, the effect of oral doses administered in the fed state will be compared to that of dosing in the fasting state.

[1260] Eighteen healthy adult subjects were enrolled in a 3-period crossover study in which serial PK samples were collected 96 hours after each single-dose treatment. All subjects were evaluable for pharmacokinetics because at least one post-dose PK sample was collected, although only 16 subjects had sufficient data for 1 or more of the 3 concentration-time profiles to calculate at least C max Fourteen of these patients had sufficient pharmacokinetic information to determine the drug exposure between at least two of the three treatments (i.e., C max and AUC).

[1261] Concentration and exposure

[1262] Plasma concentrations of elraglusib decreased to near or below the assay LLOQ (0.200 ng / mL) for all 3 treatments by 96 hours post-dose, with observed AUC last Average AUC of all 3 treatments ∞ The concentration-time curves showed significant differences in the magnitude and timing of mean peak concentrations, with the greatest exposure and the most rapid rise in concentrations occurring during an intravenous infusion of approximately 80 minutes. Exposure was minimal when the oral dose was administered in the fasting state (i.e., low C max Compared with oral doses in the fasting state, oral doses in the fed state resulted in significantly increased exposure, with the 95% CI indicating that oral exposures with food (i.e., in the fed state) were 2.5 to 5 times higher than those in the fasting state, but doses taken with food resulted in C max The median delay was 3 hours.

[1263] The terminal elimination half-lives appeared to be similar in most subjects, ranging from approximately 15 to 25 hours for all 3 treatments in most subjects. However, of the 16 subjects with evaluable half-lives, 2 or 3 had elimination half-lives that were one-third to one-half of the majority of subjects, suggesting that the study population contained some subjects with a rapid clearance phenotype. These subjects had terminal elimination half-lives ranging from 7 to 11 hours and tended to have low C after oral administration in the fed or fasted state. max and AUC values. They also had the lowest AUC after intravenous infusion ∞ However, after intravenous infusion, C max Some of the subjects with shorter half-lives were those with the highest systemic clearance values ​​and smallest volumes of distribution after intravenous administration, which is consistent with the observation of shorter half-lives.

[1264] Bioavailability evaluation

[1265] Pairwise comparisons of the relative bioavailability evaluations among the 3 treatments confirmed the differences intuitively seen from their concentration-time profiles. The intravenous infusion treatment was considered to have 100% bioavailability because the drug was infused directly into the systemic circulation. The oral route of administration was expected to have lower bioavailability, which could be due to incomplete absorption from the intestine or due to elimination of the drug from the blood due to one or more first-pass effects before entering the systemic circulation. The oral bioavailability of elraglusib was significantly lower when administered in the fasted state than when administered in the fed state, suggesting that elraglusib preferentially partitions into fat or lipid materials when administered in the fed state, allowing for more efficient dispersion and easier translocation across lipid interfaces. This interpretation of high lipophilicity is consistent with the observed high volume of distribution (approximately 11 L / kg for elraglusib after administration as an intravenous infusion).

[1266] The relative bioavailability of elraglusib after oral administration also showed some evidence of correlation with the elraglusib dose, with the relative bioavailability increasing with increasing dose. This possibility suggests that there is a saturable clearance pathway that operates in parallel with the non-saturable pathways, such as saturated metabolic pathways, in the series of processes between reaching the intestinal wall and reaching the systemic circulation. This possibility explains the oral bioavailability of only 3% to 11% (based on C max Or based on AUC ∞) but at a dose that was approximately 75% higher than that used in the study, there was an increase of approximately 13% (oral bioavailability). However, these differences in relative bioavailability also varied between subjects, so it is possible that individuals with a propensity to absorb elraglusib better were coincidentally given a higher dose. This type of saturable drug elimination pathway is expected to be beneficial for C max The C value has a greater impact on the AUC value because drug absorption occurs most rapidly (i.e., after reaching C max Before and in C max ), it will be most prominent.

[1267] This saturated drug elimination pathway has less impact on elraglusib when administered in the fed state, which may be related to its higher lipophilicity, which enables it to bypass this pathway due to its location (T max later, meaning that more absorption occurs farther down the intestine compared to administration when fasting), or due to a different uptake mechanism than occurs with molecules dissolved in or carried along with fat particles.

[1268] Interestingly, one subject (105) achieved a relative bioavailability of 91% after oral administration in the fed state. This case highlights the point that if some saturation pathway operates at low doses to reduce oral bioavailability, it will have a smaller effect as the oral dose increases and will ultimately have an almost undetectable effect as the relative bioavailability of the oral dose approaches 100% (i.e., producing essentially the same total exposure as the dose administered by IV administration). This study used IV and oral doses of 3.3 mg / kg; earlier studies in this patient population have used IV elraglusib at doses ranging from 1.0 mg / kg to 15.0 mg / kg, which is almost 3 to 5 times the dose used in this study, with only a slight deviation from dose proportionality (a 15-fold dose change resulted in a 20-fold increase in AUC 24 If this deviation is real, it is also consistent with the existence of saturable drug elimination pathways operating in parallel with other non-saturable pathways.

[1269] Drug accumulation with repeated dosing

[1270] Accumulation with repeated dosing was estimated by determining the extent of carryover from the first dosing interval (i.e., the single dose used in this study to subsequent dosing intervals of 1 × τ (tau), 2 × τ, etc., to n × τ hours, when carryover is less than 1%). For IV therapy, C maxOnset is rapid, and once infusion is complete, concentrations decline rapidly over the next approximately 10 to 12 hours due to the rapid distribution phase. Concentrations decline more than 10-fold during this time interval. Accumulation is expected to be in the 1% to 5% range using the planned twice-weekly dosing schedule and even lower if a once-weekly dosing interval is used. This increase in concentration between first dose and steady state is similar to the precision of the current elraglusib assay and therefore may not be detected unless first dose and steady-state data from a large number of patients are available.

[1271] Oral administration has a lower C max values, but absorption of elraglusib from the intestine requires longer time than is typically used for elraglusib infusion in this study. When taken with food, the terminal half-life becomes dominant 18 to 24 hours after dosing, and concentrations remain at C 24 hours after the first dose. max The cumulative accumulation of elraglusib is approximately 10% to 20% of the value of elraglusib per week. Using the planned twice-weekly dosing regimen, accumulation is expected to be in the range of 1% to 10%, and will be lower if a once-weekly dosing interval is used. Repeated dosing is unlikely to produce substantial accumulation (e.g., greater than 30%) unless a dosing interval of 24 hours or less is used. Patients with a long elraglusib half-life (i.e., 20+ hours) will generally exhibit greater accumulation after steady-state is reached than patients with a short half-life (i.e., 10 hours or less).

[1272] Pharmacokinetic conclusions

[1273] Elraglusib has systemic bioavailability when administered orally, and its oral bioavailability is increased by 2.5 to 5 times when administered in the fed state (i.e., high-fat breakfast). Doses greater than 3.3 mg / kg can show higher oral bioavailability than the approximately 5% to 21% observed when administered in the fasted state and the approximately 19% to 63% observed when administered in the fed state.

[1274] The pharmacokinetics of elraglusib exhibited considerable inter-subject variability when doses were administered orally. If dosed by intravenous infusion, the variability in concentration and PK parameter estimates was much less.

[1275] The pharmacokinetics of elraglusib are in its terminal elimination phase approximately 24 hours after dosing, regardless of whether the dose is IV or oral. In most individuals, the terminal elimination phase has a half-life ranging from 15 to 25 hours, although there may be a subset of individuals who clear the drug more rapidly, exhibiting a terminal half-life ranging from 6 to 11 hours.

[1276] Elraglusib systemic clearance exceeds the nominal glomerular filtration rate in healthy adults but is consistent with renal clearance or hepatic metabolic clearance if an active secretory mechanism is present. The apparent clearance observed after oral administration appears to be a combination of incomplete absorption and first-pass metabolism. Incomplete absorption may play a greater role in the higher apparent clearance observed when dosing is performed in the fasted state.

[1277] The volume of distribution of elraglusib exceeds body weight by approximately 11 times, indicating that it is extensively distributed in tissues. Concentrations in some tissues are likely to greatly exceed plasma concentrations.

[1278] Significant accumulation of elraglusib is unlikely with repeated dosing at once or twice weekly dosing schedules. Significant accumulation may occur with dosing intervals of 24 hours or less from the first dose to steady state.

[1279] Example 6 - Preparation and Evaluation of Elraglusib ASD Containing Four Different Polymers Prepared by Acetone:Water Solvent Spray Drying

[1280] Previous formulation development work compared micronized elraglusib formulated in dry and wet granulation tablets and spray dried dispersion (ASD) in dry granulation tablets. These formulations were dosed in a PK study 3 in dogs. Based on this study, an ASD composition at a dose of 1:1 elraglusib:cellulose acetate phthalate (CAP) in a tablet was found to achieve an oral bioavailability of approximately 68% and was designated as a lead product for further development. The lead ASD tablet composition is shown in Table 6-1.

[1281] Table 6-1 - Lead Elraglusib:CAP ASD Tablet Composition Determined by Dog PK Study

[1282]

[1283] The objectives of the optimization and tableting evaluation of the elraglusib ASD were to: (1) evaluate the feasibility of avoiding tetrahydrofuran (THF) as a spray drying solvent by determining the solubility of the active pharmaceutical ingredient (API) in conventional commercial spray drying solvents and confirm the solubility in the presence of a bioavailability-enhancing polymer; (2) produce an ASD prototype and characterize its dissolution performance and physicochemical stability; and (3) evaluate the ASD prototype in a lead tablet formulation.

[1284] To this end, a series of ASD prototypes were successfully prepared and characterized. Lead ASD formulations were selected based on initial biorelevant dissolution and physical state characterization data. These lead ASD formulations then entered tablet formulation evaluation and development stability studies.

[1285] Material

[1286] The materials used in the development study of elraglusib ASD are summarized in Table 6-2 (Raw Materials) and Table 6-3 (Analytical Method Reagents). The equipment used in the development study of elraglusib ASD is shown in Table 6-4.

[1287] Table 6-2. Materials used in the development study of Elraglusib ASD

[1288]

[1289] Table 6-3. Materials used in the Elraglusib analytical method

[1290]

[1291] Table 6-4. Equipment used in the Elraglusib ASD development study

[1292]

[1293] Production method

[1294] Preparation of spray dried dispersion (ASD)

[1295] Four different elraglusib ASD formulations were prepared using four different polymers (see Table 6-5). Elraglusib and polymer were weighed and dissolved in a 90:10 mixture of acetone:water to obtain a spray solution containing 4.0% total solids weight / weight (w / w). The solution was stirred until visual inspection confirmed that the solids were completely dissolved. The B-290 Mini Spray Dryer was set up according to the configuration summarized in Table 6-6. While the equipment was heating up, the pump was calibrated with solvent to achieve a spray rate of 10-15g / min (actual rate see Table 6-6). Once the inlet temperature was reached, the outlet temperature was allowed to stabilize. The solvent was run until a stable outlet temperature of 40-45°C was achieved. After reaching steady-state conditions, spraying of the elraglusib / polymer solution was started using the calibrated pump flow and 14L / S size piping. The product was collected after spray drying and dried in an oven at 40°C for not less than (NLT) 20 hours. The complete process parameters are shown in Table 6-7.

[1296] Table 6-5. Polymer usage in ASD prototypes by batch number

[1297]

[1298] Table 6-6. B-290 Micro Spray Dryer Configuration

[1299]

[1300] Table 6-7. ASD process parameters

[1301]

[1302] a At standard temperature and pressure, a height of 30 mm on the rotor flowmeter corresponds to an actual volume flow of 439 L / hour.

[1303] Granulation

[1304] Microcrystalline cellulose (MCC), mannitol and cross-linked carboxymethyl cellulose sodium (CCS) were sieved through a 20 mesh screen (0.85 mm). The sieved ingredients and elraglusib ASD material were transferred to a 500 mL polypropylene bottle and mixed at 25 revolutions per minute (rpm) for 10 minutes. Magnesium stearate was sieved through a 30 mesh screen (0.595 mm) and added to the mixture. The intragranular ingredients were mixed for an additional 5 minutes at 25 rpm.

[1305] The premix is ​​compacted using a simulated roller pressure of 4-5 kN / cm using a MCTM-1 manual tablet press (roller simulator) and milled through a 1.25 mm screen. The mixture is collected in a 250 mL polypropylene bottle and the adjustment factor of the extragranular excipient is calculated by weighing. Extragranular CCS is added to the milled granules and mixed at 25 rpm for 5 minutes. Extragranular silicon dioxide is sieved through a 20 mesh (0.85 mm) sieve and added to the mixture, mixed at 25 rpm for 5 minutes. Then extragranular magnesium stearate is sieved through a 30 mesh (0.595 mm) sieve and added to the mixture, mixed at 25 rpm for 5 minutes to make the final mixture.

[1306] Tablet pressing

[1307] Tablets were compressed using MTCM-1 using a 9.5 x 21.0 mm flat modified oval die.

[1308] Analytical methods

[1309] Analysis of ID, detection and related substances by HPLC

[1310] High performance liquid chromatography (HPLC) was 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.

[1311] Chromatographic separation was accomplished using a Waters Atlantis T3, 4.6 x 150 mm, 3 μm column and the parameters provided in Tables 6-8. Detection was performed using an external standard of 0.2 mg / mL elraglusib (lot NB-elraglusib(NG)-A-1) prepared in diluent. Test samples of the tablet prototype were prepared by serial dilution to a target concentration of 0.2 mg / mL elraglusib. All samples were diluted in a volumetric flask.

[1312] Table 6-8. Analytical conditions for Elraglusib ID, detection, and related substances methods.

[1313]

[1314] Sedimentation dissolution

[1315] Sedimentation dissolution experiments were performed on a Sotax MD automated dissolution apparatus with online UV detection. Elraglusib standard was used for quantification of dissolution percentage using UV absorbance at 282 nm. Sedimentation dissolution tests were performed using the parameters shown in Tables 6-9.

[1316] Table 6-9. Sedimentation dissolution method parameters

[1317]

[1318] Non-sedimentation dissolution

[1319] Non-sedimenting dissolution testing was performed using manual sampling (Table 6-10) and in duplicate with the R&D HPLC method developed by Core Rx, using the same columns as the assay and related material methods (Table 6-11). Approximately 15 mg of material was weighed into a scintillation vial equipped with a cross-shaped stirring bar. To initiate the non-sedimenting dissolution test, 15 mL of either 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 shown in Table 10. Aliquots were microcentrifuged at 15,800×g for two minutes, and the supernatant was diluted directly into amber HPLC vials using a 5-fold dilution factor. At the 10- and 90-minute time points following microcentrifugation, additional samples of the supernatant were passed through a 0.2 μm microcentrifuge cutoff filter using centrifugation parameters of 15,800 × g for two minutes in an attempt to extract unbound “free” drug from dissolved colloidal species without the use of an ultracentrifuge.

[1320] Table 6-10. Non-sedimentation dissolution method parameters

[1321] Dissolution medium Simulated intestinal fluid in the fasted state (FaSSIF) or fed state (FeSSIF) Dilution 25:75 water:acetonitrile Medium volume 15mL Medium temperature 37℃ Time 0, 5, 10, 20, 30, 60, 90 minutes speed 125rpm Detector wavelength (nm) UV wavelength 438nm, bandwidth 4nm

[1322] Table 6-11. HPLC analysis parameters used for Elraglusib R&D non-sedimentation dissolution method

[1323]

[1324]

[1325] Moisture content by Karl Fischer

[1326] The water content was determined by volumetric Karl Fischer (KF) titration using a Mettler Toledo V20S KF titrator. Titration was standardized with Hydranal Composite 2 and Check P solutions. 300 mg of sample was dissolved in CompoSolver E for KF water titration.

[1327] Bulk density and tap density

[1328] To determine the bulk density, dispense the test article powder into a 25 mL graduated cylinder and record the weight of the test article. Determine the mass of powder in the measuring container and divide by the test article volume.

[1329] To determine the tap density, shake the cylinder until the volume remains constant. Record the final powder volume after shaking. Calculate the tap density by dividing the initial mass by the final volume.

[1330] Compression index and Hausner ratio according to USP <616> The calculation is described in .

[1331] hardness

[1332] According to USP <1062> The tablet hardness was measured using a Varian VK200 tablet hardness tester.

[1333] friability

[1334] According to USP <1216> A friability tester (Sotax FT2) was used for friability testing by tumbling 10 tablets at 25 rpm for 4 minutes (100 revolutions).

[1335] Compression curve

[1336] Compression curves were generated for tablets prepared using a Globe Pharma Model MTCM-1 manual tablet press with 5 / 16 inch flat upper and lower TSM-B punches.

[1337] X-ray powder diffraction

[1338] X-ray powder diffraction (XRPD) was performed using a Rigaku-Miniflex 6G benchtop X-ray diffractometer and a 2 mm deep aluminum cup. The sample was pressed into the cup using a glass slide. The X-ray source was operated at 40 kV and 15 mA. 10 degrees / min was used for elraglusib and 2.5 degrees / min was used for the ASD sample, and sample data was collected from 3-40° using a 0.02° step size. Sample rotation was turned on for all measurements.

[1339] Scanning electron microscopy

[1340] Scanning electron microscope (SEM) images were captured using a Phenom Pro in 10 kV high resolution mode. Carbon paper was used as the conductive substrate. The sample was prepared by rolling on a sample <100 mg with a plastic scraper and then carefully rolling on the double-sided adhesive carbon paper on top of the platform. Three 45° left-hand rotations of the sample holder were used to position the sample approximately 2 mm below the top of the platform for imaging.

[1341] Differential Scanning Calorimetry

[1342] A modulated differential scanning calorimeter is used with a controlled humidity chamber with a relative humidity <5% (RH) to test the glass transition temperature. Samples are prepared in differential scanning calorimetry (DSC) pans and lids. Approximately 5-10 mg of sample is weighed into each pan and placed in an appropriate equilibration chamber for at least 10 hours. The samples are removed from the chamber and the lids are crimped appropriately depending on the study design. The samples are reweighed and placed on the DSC autosampler. The samples are then run using the method parameters described in Tables 6-12.

[1343] Table 6-12.DSC method parameters

[1344] Method Parameters Target pot <![CDATA[T 零 w / holes]]> T start (℃) -20 T End (℃) 180 Scan rate (C / min) 2.5 Modulation (yes / no) yes Modulation period (sec) 60 Modulation amplitude(℃) 1.5 Drying temperature(℃) 40 Drying time (min) 30

[1345] Solubility of Elraglusib in Acetone: Water and Acetone

[1346] The solubility of elraglusib API in acetone was evaluated with and without the target polymer. Elraglusib was soluble up to 4% w / w; however, it was observed to crystallize upon standing at room temperature.

[1347] Tests using 4% w / w elraglusib and 4% w / w polymer showed that if the solution was used immediately, HPMCAS-MG, Initial spray drying was feasible at 8% w / w solids loading for L100 and Eastman cellulose acetate phthalate (CAP). It was visually observed that the HPMCAS-MG and Eastman CAP samples contained some undissolved solids, which is often observed in these polymer types due to the presence of residual levels of the insoluble high molecular weight portion of the polymer.

[1348] Prior to ASD prototype production, other solvent and polymer combinations were evaluated to determine which mixtures should be further developed and to find the appropriate elraglusib and polymer loading range to achieve suitable solution stability at a reasonable initial nebulization solution hold time (NLT 24h). Samples were prepared according to Tables 6-13.

[1349] Table 6-13.

[1350]

[1351] The samples were stirred and visually observed for 24 hours, and the observations are summarized in Tables 6-14. Precipitation of bright orange fine particles was observed in acetone (Sample 1) and 95:5 acetone:water (Sample 3) at 2 hours, while elraglusib took about 4 hours to precipitate in acetone containing HPMCAS-MG (Sample 4). Elraglusib in tetrahydrofuran (THF) remained soluble for more than 24 hours and did not crystallize when stored at 0°C overnight.

[1352] Table 6-14. Visual Observation Results of Polymer and Elraglusib Solvent Solubility Studies

[1353]

[1354] 24 hours after the solubility study was completed, the precipitated mixture was allowed to settle and an aliquot was taken and centrifuged. The supernatant was then diluted and tested by HPLC to determine the solubility of elraglusib, as shown in Tables 6-15.

[1355] Table 6-15. Elraglusib Concentrations from Polymer and Elraglusib Solvent Solubility Studies Determined by HPLC

[1356]

[1357] The measured solubility of elraglusib in acetone was 13.08 mg / mL. 34.68 mg / mL elraglusib was measured in THF solution, which is almost consistent with the theoretical concentration (i.e., 37 mg / mL) based on the partition weight of elraglusib and THF, which is consistent with the product still being in solution after 24 hours. The 1:1 elraglusib:HPMCAS-MG sample took longer to precipitate solids, but the concentration measured after 24 hours was close to that of the acetone sample.

[1358] In addition to analyzing the supernatant of the solubility study samples, the precipitate was collected and analyzed by XRPD under applicable conditions. The spectrum results showed that elraglusib had undergone transformation to the acetone solvated form.

[1359] Additional studies were performed to determine if increased water content would prevent the formation of solvate precipitates, and more dilute solutions were tested for potential ASD treatment. Sample details are summarized in Tables 6-16.

[1360] Table 6-16. Summary of samples from Elraglusib acetone:water solubility study

[1361]

[1362] The samples were stirred and visually observed for 24 hours, and the observation results are summarized in Tables 6-17.

[1363] Table 6-17. Elraglusib and Acetone: Visual Observation Results of Aqueous Solubility Studies

[1364]

[1365]

[1366] Bright orange solids precipitated from both 95:5 acetone:water and 90:10 acetone:water mixtures containing ~4% w / w solid loadings upon stirring for 2 and 3.5 hours, respectively. Elraglusib 1.5-2.0% w / w remained soluble in 95:5 acetone:water for more than 24 hours. These results support spray drying of 95:5 acetone:water solutions containing no more than 2.0% w / w drug loading.

[1367] After 24 hours, the 90:10 acetone:water sample was taken and centrifuged, and the concentration of elraglusib was determined by HPLC, as shown in Tables 6-18. The measured concentration was consistent with the initial 95:5 acetone:water sample, indicating that the additional water did not produce an increase in solubility.

[1368] Table 6-18.90:10 Acetone:Water Solubility Study Elraglusib Concentration Results

[1369]

[1370] The solubility of elraglusib in simulated intestinal fluid containing different levels of SIF powder was measured to support formulation development, facilitate the interpretation of in vitro dissolution, and support potential modeling and interpretation of in vivo pharmacokinetic data. The solubility data obtained are shown in Tables 6-19 and are generally consistent with previously collected data for elraglusib. As expected for compounds with a small number of readily ionizable sites, the equilibrium solubility is essentially independent of pH.

[1371] Table 6-19. Solubility data of Elraglusib in simulated intestinal fluid

[1372]

[1373] ASD Development

[1374] Production

[1375] Four batches of elraglusib / polymer blends were successfully spray dried with 4% w / w total solids loading and 90:10 acetone:water solvent. These batches used a variety of polymers and were completed without significant interruptions or parameters outside of the expected range. The spray drying parameters for these batches are shown in Tables 6-20 - 6-23. Table 6-24 provides a summary of the production parameters for these batches.

[1376] Table 6-20. Detailed spray drying parameters for 50% elraglusib: HPMCAS-M ASD, batch number 35044-040

[1377]

[1378] Table 6-21. Detailed spray drying parameters for 50% elraglusib: HPMCAS-H, batch number 35044-041

[1379]

[1380] Table 6-22 Detailed spray drying parameters for 50% elraglusib:EL-100*, batch number 35044-042

[1381]

[1382] *"EL100" is L100 Polymer

[1383] Table 6-23. Detailed spray drying parameters for 50% elraglusib:CAP, batch number 35044-043

[1384]

[1385] Table 6 - Summary of ASD production for 24.90:10 acetone:water and 4% w / w solids loading

[1386]

[1387] The yields for all batches were greater than 60%, which was expected for the scale and equipment used.

[1388] The ASD prototype was tested and tested for related substances, as shown in Table 6-25. The test values ​​were within the expected range.

[1389] Table 6-25. ASD prototype testing and related substances

[1390] sample Elraglusib (%) <![CDATA[Related substances of RRT 1.21 (a) > 50%elraglusib:HPMCAS-M 99.7％ 0.97％ 50%elraglusib:HPMCAS-H 99.6％ 0.96％ 50%elraglusib:L-100 99.2％ 0.95％ 50%elraglusib:CAP 100.5％ 0.96％

[1391] a The API batch number NB-elraglusib(NG)-A-1 used in the formulation contained 0.75% of RRT 1.21-related substance. According to the information provided by the sponsor, the RRT 1.21-related substance is an anhydride analog of elraglusib.

[1392] The ASD prototypes were also characterized by SEM and XRPD to evaluate the ASD particle morphology and whether any crystallization could be detected, e.g. Fig.46 and Fig.47 shown.

[1393] All ASD batches had a mixed morphology of intact, collapsed and broken spheres as observed by SEM. No surface crystallization was observed and particle size appeared to be fairly consistent between batches. Fig.46 .

[1394] Elraglusib ASD batches showed an amorphous halo with no detectable crystalline peak. The difference in the observed amorphous halo is expected to be due to the inclusion of different polymers. The aluminum background support used for the ASD material resulted in a peak observed at 37° 2-theta. See Fig.47 .

[1395] In FeSSIF pH 6.5 ( Fig.48 ) and FeSSIF pH 5.0 ( Fig.49 ) was used to evaluate the non-sedimentation biorelevant dissolution of the ASD prototype.

[1396] The ASD prototype showed approximately 10-fold higher solubility than the measured solubility of crystalline elraglusib in FaSSIF (5.7 μg / mL). The HPCMAS-M ASD sample showed the fastest dissolution rate; however, L100 and Eastman CAP ASD maintained high drug concentrations throughout the test. It was also noted that the 50:50 elraglusib:EL100 containing 500 μg / mL pre-dissolved HPMCAS-H showed poor wettability, which may have contributed to the poor performance. Table 6-26 provides the complete concentration data, where “free” represents the drug concentration remaining after filtering the colloidal species with a particle size of >200 nm.

[1397] Table 6-26. Concentration and time dissolution characteristics of Elraglusib ASD in FaSSIF pH 6.5

[1398]

[1399] Elraglusib:CAP and elraglusib:EL100 ASD prototypes exhibited similar performance for both solvated and free drug species. The HPMCAS-based formulations had lower total solvated and free drug relative to elraglusib:EL100 and elraglusib:CAP dispersions. Furthermore, the addition of HPMCAS-H to elraglusib:EL100 ASD did not result in significant differences in dissolution relative to elraglusib:EL100 ASD alone. Typically, HPMCAS-H can be added as a concentration-maintaining polymer. Tables 6-27 provide relevant data, where "free" represents the drug concentration remaining after filtering colloidal species with particle size >200 nm.

[1400] Table 6-27. Concentration and time dissolution characteristics of Elraglusib ASD in FeSSIF pH 5.0

[1401]

[1402] The final characterization was to evaluate the glass transition temperature (Tg) of the ASD prototype under dry conditions by DSC. The results of the DSC study are shown in Table 6-28.

[1403] Table 6-28. DSC results of ASD prototype

[1404]

[1405]

[1406] All ASD prototypes were observed to have a single Tg value, indicating a single amorphous phase and a uniform amorphous dispersion. Among the different ASD formulations, the Tg values ​​of the dry ASD ranged from 95-114°C, with elraglusib:CAP ASD having the highest Tg and elraglusib:EL100 ASD having Tg = 106°C. Higher Tg values ​​tend to indicate a reduced risk of physical state changes on stability.

[1407] Stability test

[1408] After three months of exposure to 40°C / 75% RH in desiccant packaging, elraglusib ASD showed no significant changes in physical appearance, physical state, or chemical state. There was no degradation in performance when evaluated under non-settling dissolution conditions.

[1409] Testing of the ASD formulation showed a trend of approximately 1% below the previous time point. In the CAP-based ASD, no change in phthalic acid content was observed after 3 months of sealing with desiccant at 40°C / 75% RH.

[1410] in conclusion

[1411] The production of four ASD prototypes was successfully completed with overall yields ranging from 63.5-68.7% and assay values ​​ranging from 99.2-100.5%. XRPD confirmed the amorphous nature of the final product and SEM imaging showed mixed morphology typical of the ASD process. All ASD prototypes showed significant solubility improvements in SIF relative to crystalline elraglusib. The elraglusib:CAP and elraglusib:EL100 ASD prototypes were selected for further development into tablet prototypes.

[1412] Granulation and mixing

[1413] Elraglusib:CAP and elraglusib:EL100 ASD were granulated and mixed according to the formulations shown in Table 6-29.

[1414] Table 6-29. Elraglusib ASD Granules Formulation (35044-052)

[1415]

[1416] The final blends of elraglusib:CAP and elraglusib:EL100 ASD were weighed and characterized. The Eastman CAP formulation achieved a final blend yield of 96.3%, The L100 formula is 96.0%. Both mixing yields are within the expected range. The compression curves of the two formulas were measured using 8mm round and flat molds, and the data are shown in Tables 6-30 and 6-31. Fig.50 As shown, the elraglusib:EL100 formulation showed significantly increased compressibility compared to the elraglusib:CAP formulation, which may be intrinsic to the polymer structure.

[1417] Table 6-30. Compression curve of Elraglusib:CAP ASD final blend formulation, batch number 35044-052-CAP-B

[1418]

[1419] Table 6-31. Compression curve of Elraglusib:EL100 ASD final blend formulation, batch number 35044-052-L100-B

[1420]

[1421] Elraglusib:EL100 raw material blend was also tested for bulk density and tap density, repeated 3 times, as shown in Table 6-32. CI and HR values ​​indicate that the final blend should have good flow properties.

[1422] Table 6-32. ASD final blend and bulk density and tap density

[1423]

[1424] Tablet pressing

[1425] Tablets were produced using a MCTM-1 tablet press according to the previously determined tablet formulations to compare the performance of the formulations. The unit dose targets were compressed using a 9.5×21.0 mm flat modified oval die at a compression pressure of 4000 psi.

[1426] The tablet prototype was subjected to physical characterization tests. The tablet characterization results are shown in Table 6-33.

[1427] Table 6-33. ASD tablet prototype characterization data

[1428]

[1429]

[1430] Based on visual inspection, the tablet cores compressed using the 9.5×21.0 mm die showed acceptable side bands and cup depth (about 24% of the total thickness), as shown in FIG. Fig.51 shown.

[1431] At the same compaction pressure (4000 psi), the elraglusib:EL100 formulation is about 1.9 MPa. The elraglusib:CAP formulation has a tensile strength of about 1.4 MPa, but has a higher friability, which may cause problems during the coating process.

[1432] The tablets were also evaluated for appearance, water content, assays, and related substances, which are summarized in Table 6-34.

[1433] Table 6-34. Tablet Characterization of elraglusib:CAP and elraglusib:EL100 Formulations

[1434]

[1435] a The API batch number NB-elraglusib(NG)-A-1 used in the formulation contained 0.75% of RRT 1.21-related substance. Information provided by the sponsor indicated that the RRT 1.21-related substance was an anhydride analog of elraglusib.

[1436] Dissolution was determined on two ASD formulation batches and compared to the previous elraglusib:CAP prototype. Fig.52 As shown. The tablet elraglusib:CAP prototype (35044-052-CAP-B) was compared with previous data generated for large-scale CAP tablet batch number 35044-03. However, the elraglusib:EL100 tablet prototype (35044-052-L100-B) had a slower dissolution release than the CAP tablet prototype. At T=15min, the CAP prototype dissolved >80%, while the elraglusib:EL100 tablet prototype dissolved more slowly (>80% at T=60 minutes). The slower release characteristics observed for the elraglusib:EL100 tablet prototype may be related to the higher tensile strength (1.9 MPa) of these tablets compared to the elraglusib:CAP tablet prototype tensile strength (1.4 MPa).

[1437] in conclusion

[1438] The solubility of elraglusib in commercially viable spray drying solvents was successfully evaluated with and without the inclusion of various pol...

Claims

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.

2. The solid dispersion of 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, polyvinyl pyrrolidone, 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 acetate phthalate.

5. The solid dispersion of claim 2, wherein the stabilizing polymer is hydroxypropyl methylcellulose phthalate.

6. The solid dispersion of claim 2, wherein the stabilizing polymer is hydroxypropylmethylcellulose acetate succinate.

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

8. The solid dispersion of claim 2, wherein the stabilizing polymer is polyvinyl pyrrolidone.

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

10. The solid dispersion of 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 L100 polymer ("EL100").

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

13. The solid dispersion of claim 1, wherein the stabilizing polymer is soluble at a pH above 5.

14. The solid dispersion of claim 1, wherein the stabilizing polymer is soluble at a pH above 5.

5.

15. The solid dispersion of claim 1, wherein the stabilizing polymer is soluble at a pH above 6.

16. A solid dispersion according to any one of the preceding claims, 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 10 wt % to about 70 wt % relative to the weight of the stabilizing polymer.

17. A solid dispersion according to any one of the preceding claims, 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 20 wt % to about 60 wt % relative to the weight of the stabilizing polymer.

18. A solid dispersion according to any one of the preceding claims, 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 wt % to about 50 wt % relative to the weight of the stabilizing polymer.

19. The solid dispersion of any one of the preceding claims, 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 the stabilizing polymer is from about 30:70 to about 50:

50.

20. The solid dispersion of any one of the preceding claims, wherein the solid dispersion has a single glass transition temperature.

21. The solid dispersion according to any one of the preceding claims, wherein the solid dispersion is stable at 60°C and 75% relative humidity for at least 48 hours.

22. The solid dispersion according to any one of the preceding claims, wherein the solid dispersion is stable for at least 4 weeks at 40°C and 75% relative humidity.

23. The solid dispersion according to any one of the preceding claims, wherein the solid dispersion is stable at 40°C and 75% relative humidity for at least 12 weeks.

24. The solid dispersion of any of the preceding claims, wherein oral administration of the solid dispersion to a patient produces an elraglusib AUC∞ that is at least 40% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

25. The solid dispersion of claim 24, wherein oral administration of the solid dispersion to a patient produces an elraglusib AUC∞ that is at least 68% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

26. The solid dispersion of claim 24, wherein oral administration of the solid dispersion to a patient produces an elraglusib AUC∞ that is at least 97% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

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

28. A method for preparing a solid dispersion according to any one of claims 1 to 23, comprising the following steps: 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.

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 of any one of claims 28-29, wherein the solvent is evaporated by spray drying.

31. The method according to any one of claims 28-29, wherein the solvent is evaporated under reduced pressure.

32. The method of any one of claims 28-29, 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]dioxolane[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (elraglusib), an emulsifier, a pharmaceutically acceptable alcohol, and a surfactant; the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, Polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene-15-hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitol fatty acid ester, polyoxyethylene alkyl ether and polyoxyethylene nonylphenol ether.

34. The liquid solution of claim 33, comprising about 4.0-6.0 wt.% of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolano[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione (elraglusib), about 75-95 wt.% of an emulsifier, about 2-17% wt.% of a pharmaceutically acceptable alcohol, and about 0.5-10% wt.% of a surfactant; the emulsifier being polyethylene glycol, mustard Lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, sodium lauryl sulfate, docusate sodium, phosphatidylcholine, benzalkonium chloride, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene-15-hydroxystearate, polyoxyethylene castor oil derivative, polyoxyethylene stearate, sorbitol fatty acid ester, polyoxyethylene alkyl ether and polyoxyethylene nonylphenol ether.

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

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

37. The liquid solution of claim 35 or claim 36, wherein the emulsifier is PEG 400.

38. The liquid solution of any one of claims 33-37, wherein the pharmaceutically acceptable alcohol is ethanol.

39. The liquid solution of any one of claims 33-38, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

40. The liquid solution of any one of claims 33-39, comprising about 4.3-5.5 wt.% elraglusib.

41. The liquid solution of any one of claims 33 to 40, wherein the concentration of elraglusib in the solution is at least 45 mg / mL.

42. The liquid solution of any one of claims 33 to 40, wherein the concentration of elraglusib in the solution is at least 50 mg / mL.

43. The solution of any one of claims 33 to 42, wherein the purity of elraglusib is greater than 97% as determined by HPLC area %.

44. The solution of claim 43, wherein the purity of elraglusib is greater than 98% as determined by HPLC area %.

45. The solution of claim 44, wherein the purity of elraglusib is greater than 99% as determined by HPLC area %.

46. ​​The solution of any one of claims 33 to 45, 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 elraglusib as determined by HPLC area %.

47. The solution of any one of claims 33 to 46, 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 elraglusib as determined by HPLC area %.

48. The solution of any one of claims 33 to 47, wherein oral administration of the solution to a patient produces an elraglusib AUC∞ that is at least 40% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

49. The solution of claim 48, wherein oral administration of the solution to a patient produces an elraglusib AUC∞ that is at least 80% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a patient.

50. The solution of any one of claims 33 to 49, wherein oral administration of the oral solution to a fed patient produces an AUC∞ of elraglusib that is at least 2.4 times greater than the AUC∞ of elraglusib produced by administration of the solution to a fasted patient.

51. The solution of any one of claims 33-50, wherein oral administration of the solution to a subject produces a plasma elraglusib Cmax (fed) that is at least 250% of the corresponding plasma elraglusib Cmax (fasting).

52. The solution of any one of claims 33-50, wherein oral administration of the solution to a subject produces a plasma elraglusib AUC∞(fed) that is at least 240% of the corresponding plasma elraglusib AUC∞(fasting).

53. A liquid suspension comprising elraglusib, an emulsifier, a pharmaceutically acceptable alcohol, a surfactant, and a pharmaceutically acceptable diluent; the emulsifier is polyethylene glycol, mustard lecithin, soy lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

54. The liquid suspension of claim 53, comprising: About 0.04-0.6wt.% of elraglusib, about 0.8-10wt.% of an emulsifier, about 0.04-1.7wt.% of a pharmaceutically acceptable alcohol, about 0.009-1wt.% of a surfactant, and about 87-99wt.% of a pharmaceutically acceptable diluent; the emulsifier is polyethylene glycol, mustard lecithin, soybean lecithin, egg lecithin, monoglyceride, diglyceride, polysorbate, stearoyl lactylate, sorbitol ester, polyglycerol ester or sucrose ester; the surfactant is sodium stearate, 4-(5-dodecyl)benzenesulfonic acid, 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.

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

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

57. A liquid suspension according to claim 55 or claim 56, wherein the emulsifier is PEG 400.

58. The liquid suspension of any one of claims 53-57, wherein the pharmaceutically acceptable alcohol is ethanol.

59. The liquid suspension of any one of claims 53-58, wherein the surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate).

60. The liquid suspension of any one of claims 53-59, comprising about 0.04 wt.% elraglusib.

61. The liquid suspension of any one of claims 53-59, comprising about 0.1 wt.% elraglusib.

62. The liquid suspension of any one of claims 53-59, comprising about 0.2 wt.% elraglusib.

63. The liquid suspension of any one of claims 53-59, comprising about 0.5 wt.% elraglusib.

64. The suspension of any one of claims 53 to 63, wherein the concentration of elraglusib in the suspension is at least 0.4 mg / mL.

65. The suspension of any one of claims 53 to 63, wherein the concentration of elraglusib in the suspension is at least 0.5 mg / mL.

66. The liquid suspension of any one of claims 53-65, wherein the pharmaceutically acceptable diluent is water, saline, an electrolyte solution, a sugar solution, or a flavored solution.

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

68. The suspension of any one of claims 53 to 67, wherein the purity of elraglusib is greater than 97% as determined by HPLC area %.

69. The suspension of any one of claims 53 to 67, wherein the purity of elraglusib is greater than 98% as determined by HPLC area %.

70. The suspension of any one of claims 53 to 67, wherein the purity of elraglusib is greater than 99% as determined by HPLC area %.

71. The suspension of any one of claims 53 to 67, 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 elraglusib as determined by HPLC area %.

72. The suspension of any one of claims 53 to 67, 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 elraglusib as determined by HPLC area %.

73. The suspension of any one of claims 53-72, wherein oral administration of the suspension to a subject produces a plasma elraglusib Cmax (fed) that is at least 250% of the corresponding plasma elraglusib Cmax (fasting).

74. The suspension of any one of claims 53-72, wherein oral administration of the suspension to a subject produces a plasma elraglusib AUC∞(fed) that is at least 240% of the corresponding plasma elraglusib AUC∞(fasting).

75. A tablet for oral administration, comprising: (i) an ASD comprising elraglusib and a stabilizing polymer; (ii) adhesives; (iii) fillers; (iv) a disintegrant; and (v) Lubricants.

76. The tablet of claim 75, comprising: (i) about 40-60 wt % ASD, the ASD comprising elraglusib and a stabilizing polymer; (ii) about 19-27% by weight of a binder; (iii) about 10-25% by weight of a filler; (iv) about 4-9% by weight of a disintegrant; and (v) about 1-3% lubricant.

77. The tablet of claim 76, comprising: (i) about 50 wt % ASD, the ASD comprising elraglusib and a stabilizing polymer; (ii) about 19.5% by weight of a binder; (iii) about 19.5% by weight of a filler; (iv) about 9% by weight of a disintegrant; and (v) about 2% lubricant.

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

79. The tablet of any one of claims 75-78, wherein the ASD comprises about 50 wt% elraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid).

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

81. The tablet of any one of claims 75-77 or 80, wherein the ASD comprises about 50 wt% elraglusib and about 50 wt% CAP.

82. A tablet according to any one of claims 75-81, wherein the binder is microcrystalline cellulose.

83. A tablet according to any one of claims 75-82, wherein the filler is mannitol.

84. The tablet of any one of claims 75-83, wherein the disintegrant is croscarmellose sodium or polyvinylpyrrolidone.

85. The tablet of any one of claims 75-84, wherein the disintegrant is croscarmellose sodium.

86. A tablet according to any one of claims 75-85, wherein the lubricant is one or more of silicon dioxide or magnesium stearate.

87. A tablet according to any one of claims 75-85, wherein the lubricant comprises silicon dioxide and magnesium stearate.

88. The tablet of claim 75, comprising: (i) an ASD comprising about 50 wt% elraglusib and about 50 wt% poly(methyl methacrylate-co-methacrylic acid); (ii) microcrystalline cellulose; (iii) mannitol; (iv) croscarmellose sodium; (v) silicon dioxide; and (vi) Magnesium stearate.

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

90. The tablet of any one of claims 75-89, wherein oral administration of the tablet to a subject produces a plasma elraglusib Cmax (fed) that is at least 250% of the corresponding plasma elraglusib Cmax (fasting).

91. The tablet of any one of claims 75-90, wherein oral administration of the tablet to a subject produces a plasma elraglusib AUC∞(fed) that is at least 240% of the corresponding plasma elraglusib AUC∞(fasted).

92. The tablet of any one of claims 75-91, wherein oral administration of the tablet to a subject produces an AUC∞ of elraglusib that is at least 40% of the AUC∞ of elraglusib produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a subject.

93. The tablet of claim 92, wherein oral administration of the tablet to a subject produces an elraglusib AUC∞ that is at least 68% of the elraglusib AUC∞ produced by intravenous administration of an equivalent dose of elraglusib (on a mg / kg basis) to a subject.

94. A capsule for oral administration, comprising: (i) an ASD comprising elraglusib and a stabilizing polymer; and (ii) one or more pharmaceutically acceptable excipients.

95. A method for achieving an elraglusib plasma concentration ranging from 1000 to 10000 ng / mL in a human, the method comprising orally administering the solid dispersion, liquid solution, liquid suspension or pharmaceutical composition of the present application to the human.

96. A method of treating a disease or disorder in a subject in need thereof, the method comprising orally administering to the subject a solid dispersion as described in any one of claims 1 to 26, a pharmaceutical composition as described in claim 27, a solution as described in any one of claims 33-52, a suspension as described in any one of claims 53-74, a tablet as described in any one of claims 75-93, or a capsule as described in claim 94.

97. The method of claim 96, wherein the disease or disorder is cancer.

98. The method of claim 97, wherein the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, pancreatic cancer, or glioblastoma.

99. The method of claim 97, wherein the cancer is glioblastoma.

100. The method of claim 96, wherein the disease or disorder is a lymphoproliferative disease.

101. The method of claim 100, wherein the lymphoproliferative disorder is a malignant lymphoproliferative disorder.

102. The method of claim 101, wherein the malignant lymphoproliferative disorder is a malignant B-cell lymphoproliferative disorder.

103. The method of claim 102, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma, acute lymphocytic leukemia, chronic myeloid leukemia in the lymphoblastic stage, 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 disorder, plasma cell neoplasm, primary mediastinal B-cell lymphoma, Hodgkin's disease, or Castleman's disease.

104. The method of claim 103, wherein the malignant B-cell lymphoproliferative disorder is diffuse large B-cell lymphoma.

105. The method of claim 104, wherein the diffuse large B-cell lymphoma is double hit lymphoma.

106. The method of claim 101, wherein the lymphoproliferative disorder is a malignant T-cell lymphoproliferative disorder.

107. The method of claim 106, wherein the malignant T-cell lymphoproliferative disorder is 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 / naked cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, lymphoblastic chronic myeloid leukemia, post-transplant lymphoproliferative syndrome, human T-cell leukemia virus type 1 positive (HTLV-1 + ) Adult T-cell leukemia / lymphoma (ATL), T-prolymphocytic leukemia (T-PLL), or unspecified T-cell lymphoma.

108. The method of claim 96, wherein the disease or disorder is traumatic brain injury.

109. The method of claim 96, wherein the disease or disorder is idiopathic pulmonary fibrosis.

110. The method of claim 96, wherein the disease or disorder is pleural fibrosis.

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