Formulations of MNK inhibitors

Abstract

The present disclosure provides compositions and formulations of a MNK inhibitor compound, as well as uses thereof for the treatment of MNK-associated diseases, disorders, and conditions.

Description

FORMULATIONS OF MNK INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 664,407, filed June 26, 2024, the contents of which are hereby incorporated by reference.STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under grant No. 1U44NS115692 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Inadequate treatment of pain is a devastating health problem in the United States. One third of all Americans suffer from some form of chronic pain and a third of these have pain that is resistant to current medical therapies. The economic impact of pain is equally large at approximately $100 billion annually. Opioid or narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance which requires escalating doses to achieve equivalent pain relief. Furthermore, opioids and narcotic analgesics are often ineffective for neuropathic pain treatment, and patients using these drugs often experience worse quality of life due to the resulting drug-induced sedation, reduced physical activity, constipation, respiratory depression, high potential for addiction, and other side effects.

[0004] Inhibitors of mitogen-activated protein kinase interacting protein kinase (MNK) are a promising alternative to opioid and narcotic analgesics for treatment of neuropathic pain and other indications. Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signals to the eukaryotic translation initiation factor (elF) 4E complex to regulate the sensitization of nociceptors. MNKs phosphorylate the eukaryotic translation initiation factor 4E(eIF4E). Inhibition of MNK has been shown to disrupt the MAPK pathway, thereby decreasing sensitization of nociceptors, which may achieve a therapeutic effect on neuropathic pain.SUMMARY

[0005] The present disclosure provides compositions comprising a MNK inhibitor, as well as uses thereof for the treatment of MNK-associated diseases, disorders, and conditions, such as neuropathic pain and migraine. In some embodiments, provided compositions are suitable for fdling into a capsule. In some embodiments, provided compositions are suitable for oral administration (e.g., to human subjects).

[0006] The present disclosure encompasses the recognition that particular excipients, ratios, and methods of preparation may be important for providing a formulation of a MNK inhibitor that is suitable for clinical use in humans (e.g., for oral administration to humans). For example, it may be important for an oral formulation to have suitable dissolution properties in order to, e.g., ensure consistent delivery of the dose of active agent to a subject. In some aspects, it may be important for an oral formulation to have a certain water content, e.g., so as to maintain the active agent in a particular solid form that displays suitable dissolution and / or PK properties.

[0007] As discussed further herein, in some embodiments, the present disclosure encompasses the recognition that compositions comprising a disintegrant (such as croscarmellose sodium), and / or a particular weight percentage of active agent (e.g., Compound 1 disclosed herein) may display particular characteristics that make them suitable for oral administration to humans. In some embodiments, the present disclosure also recognizes that a dry granulation process for preparing a provided formulation may impart certain benefits, such as a particular water content in the resulting composition, as compared to wet granulation processes.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 shows the results of dissolution studies of Formulations 2, 3, 4, 6, and 7.

[0009] FIG. 2 shows the results of dissolution studies of Formulations 4A, 8, 9, and 10.

[0010] FIG. 3 is a graph showing the particle size distribution of the 15 mg-dose dry granulation blend.

[0011] FIG. 4 is a graph showing the particle size distribution of the 15 mg-dose capsule blend.

[0012] FIG. 5 is a graph showing the particle size distribution of the 50 mg-dose dry granulation blend.

[0013] FIG. 6 is a graph showing the particle size distribution of the 50 mg-dose capsule blend.

[0014] FIG. 7 is a series of XRPD spectrum (from top to bottom: Formulation 4, 15 mg-dose engineering batch, and 50 mg-dose engineering batch).

[0015] FIG. 8 shows the results of dissolution studies of the 15 mg-dose and 50 mg-dose engineering batches at 50 rpm and 75 rpm.

[0016] FIG. 9 shows the results of dissolution studies of Formulation 4A, Formulation 4, and the 50 mg-dose engineering batch at 75 rpm.

[0017] FIG. 10 shows the results of dissolution studies of the 15 mg-dose and 50 mg-dose engineering batches at 50 rpm and 75 rpm.

[0018] FIG. 11 shows the results of dissolution studies of 40 mg capsules filled with the 15 mg-dose engineering batch.

[0019] FIG. 12 shows the particle size distribution of the micronized batch dry granulation blend, compared with the 50-mg dose engineering batch dry granulation blend.

[0020] FIG. 13 shows the particle size distribution of the micronized batch capsule blend, compared with the 50-mg dose engineering batch capsule blend.

[0021] FIG. 14 shows the dissolution profile of the micronized batch capsules.DETAILED DESCRIPTIONCompounds and Definitions

[0022] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5lhEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0023] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0024] The term “about” or “approximately”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context.

[0025] As used herein, the term “administering” or “administration” typically refers to administration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and / or a site of responsive processes, cells, tissues, etc.) As will be understood by those skilled in the art, reading the present disclosure, in some embodiments, one or more particular routes of administration may be feasible and / or useful in the practice of the present disclosure. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing.

[0026] The term “pharmaceutically acceptable salt,” as used herein, refers to a form of a relevant compound as a salt appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0027] As used herein, the term “subject” refers an organism, typically a mammal (e.g., a human). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In someembodiments, a subject is at risk of (e g., susceptible to), e.g., at elevated risk of relative to an appropriate control individual or population thereof, a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is an individual to whom diagnosis and / or therapy and / or prophylaxis is and / or has been administered. The terms “subject” and “patient” are used interchangeably herein.

[0028] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.Compound 1

[0029] Compound 1, i.e., 6"-((6-aminopyrimidin-4-yl)amino)-8"-methyl-2" / f- dispiro[cyclopropane-l,r-cyclohexane-4',3"-imidazo[l,5-rz]pyridine]-l",5"-dione:1 is a MNK inhibitor and is described in WO 2023 / 278686. Compound 1 has been shown to inhibit MNK in various assays described therein. Accordingly, Compound 1 is useful for treating diseases, disorders, or conditions associated with MNK, such as neuropathic pain and migraine. Compound 1 has also been shown to have minimal blood-brain barrier penetration, making it particularlysuitable for treating indications that do not require blood-brain barrier penetration for efficacy (e.g., indications where treatment of brain neurons or other brain tissues is not required) and / or for minimizing central nervous system side effects.

[0030] In some embodiments, Compound 1 is provided and / or utilized in accordance with the present disclosure in a free base form. Compound 1 can exist in a variety of polymorphic crystalline free base forms, including solvate, hydrate, or unsolvated forms. In some embodiments, Compound 1 is a hemihydrate. In some embodiments, Compound 1 is a hemihydrate characterized by having substantially the following peaks at 2-theta angles (± 0.2°) in its XRPD spectrum: 5.6°, 8.0°, 8.4°, 9.2°, 10.9°, 11.2°, 13.2°, 14.3°, 15.3°, 16.2°, 16.5°, 16.9°, 17.4°, 18.2°, 18.6°, 19.9°, 20.2°, 20.5°, 21.9°, 22.3°, 22.5°, 23.3°, 23.6°, 24.7°, 25.2°, 25.8°, 26.2°, 27.0°, 27.3°, 27.8°, 28.5°, and 28.8°. In some embodiments, Compound 1 is characterized by having at least two of the following peaks at 2-theta angles in its XRPD spectrum: 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°. In some embodiments, Compound 1 is characterized by having at least three of the following peaks at 2-theta angles in its XRPD spectrum: 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°. In some embodiments, Compound 1 is characterized by having the following peaks at 2-theta angles in its XRPD spectrum: 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

[0031] In some embodiments, Compound 1 is provided and / or utilized in accordance with the present disclosure in a salt form. Pharmaceutically acceptable salts are well known in the art.

[0032] Unless otherwise indicated, as used herein, “Compound 1” refers to Compound 1 in any available form, such as, e g., a free base hydrated form or salt form. It will be understood, therefore, that reference to an amount (e.g., in mg) of Compound 1 means the amount of Compound 1 in free base, unsolvated, form.Provided Compositions

[0033] The present disclosure provides compositions comprising a MNK inhibitor (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more excipients selected from fdlers, surfactants, effervescents, disintegrants, glidants, and lubricants.

[0034] In some embodiments, the present disclosure provides a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a disintegrant; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants.

[0035] In some embodiments, the present disclosure provides a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a filler; a surfactant and / or an effervescent; optionally a disintegrant; a glidant; and a lubricant.

[0036] In some embodiments, the present disclosure provides a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a filler; a surfactant; a disintegrant; a glidant; and a lubricant.

[0037] In some embodiments, provided compositions comprise about 5% to about 20% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% to about 15% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% to about 10% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% to about 9% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% to about 8% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% to about 7% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% to about 6% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 5.7% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 6% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 7% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 8% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 9% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15% w / w Compound 1, or a pharmaceutically acceptable salt thereof. In someembodiments, provided compositions comprise about 19% w / w Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20% w / w Compound 1, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, provided compositions comprise about 10 mg to about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10 mg to about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15 mg to about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10 mg to about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 30 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 35 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 45 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, provided compositions comprise one or more fdlers. In some embodiments, a fdler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, and combinations thereof. In some embodiments, a filler is microcrystalline cellulose (e.g., Avicel PH 101). In some embodiments, a filler is silicified microcrystalline cellulose (e.g., Prosol v SMCC HD 90).

[0040] In some embodiments, provided compositions comprise about 45% to about 85% w / w filler. In some embodiments, provided compositions comprise about 65% to about 85% w / w filler. In some embodiments, provided compositions comprise about 75% to about 85% w / w filler. In some embodiments, provided compositions comprise about 65% to about 80% w / w filler. In someembodiments, provided compositions comprise about 69% to about 80% w / w fdler. In some embodiments, provided compositions comprise about 70% to about 80% w / w fdler. In some embodiments, provided compositions comprise about 75% to about 80% w / w fdler. In some embodiments, provided compositions comprise about 45% w / w fdler. In some embodiments, provided compositions comprise about 50% w / w fdler. In some embodiments, provided compositions comprise about 55% w / w fdler. In some embodiments, provided compositions comprise about 60% w / w fdler. In some embodiments, provided compositions comprise about 65% w / w fdler. In some embodiments, provided compositions comprise about 68% w / w fdler. In some embodiments, provided compositions comprise about 69% w / w fdler. In some embodiments, provided compositions comprise about 70% w / w fdler. In some embodiments, provided compositions comprise about 75% w / w fdler. In some embodiments, provided compositions comprise about 78% w / w fdler. In some embodiments, provided compositions comprise about 79% w / w fdler. In some embodiments, provided compositions comprise about 79.5% w / w fdler. In some embodiments, provided compositions comprise about 80% w / w fdler. In some embodiments, provided compositions comprise about 85% w / w fdler.

[0041] In some embodiments, provided compositions comprise one or more surfactants. In some embodiments, a surfactant is selected from sodium lauryl sulfate, a poloxamer, and combinations thereof. In some embodiments, a surfactant is sodium lauryl sulfate (e.g., Kolliphor SLS). In some embodiments, a surfactant is a poloxamer (e.g., poloxamer 188, e.g., Kolliphor P188). In some embodiments, provided compositions comprise both sodium lauryl sulfate and a poloxamer (e.g., in about a 1 : 1, 2: 1, or 1 :2 ratio). In some embodiments, provided compositions comprise only one of sodium lauryl sulfate or poloxamer. In some embodiments, provided compositions do not comprise a surfactant.

[0042] Poloxamers are typically block copolymers comprising a hydrophobic chain of poly oxypropylene (e.g., polypropylene glycol, PPG, and / or polypropylene oxide), PPO) flanked by two hydrophilic chains of polyoxyethylene (e.g., polyethylene glycol, PEG, and / or poly(ethylene oxide), PEG). Poloxamers are known by the trade names Synperonic, Pluronic, and / or Kolliphor. Poloxamers are commonly named with the letter P (for poloxamer) followed by three digits: the first two digits multiplied by 100 give the approximate molecular mass of the polyoxypropylene chain, and the last digit multiplied by 10 gives the percentage polyoxyethylene content.

[0043] In some embodiments, provided compositions comprise about 1.5% to about 6% w / w surfactant. In some embodiments, provided compositions comprise about 2% to about 6% w / w surfactant. In some embodiments, provided compositions comprise about 2% to about 4% w / w surfactant. In some embodiments, provided compositions comprise about 3% to about 4% w / w surfactant. In some embodiments, provided compositions comprise about 1.5% w / w surfactant. In some embodiments, provided compositions comprise about 2% w / w surfactant. In some embodiments, provided compositions comprise about 3% w / w surfactant. In some embodiments, provided compositions comprise about 3.8% w / w surfactant. In some embodiments, provided compositions comprise about 4% w / w surfactant. In some embodiments, provided compositions comprise about 5% w / w surfactant. In some embodiments, provided compositions comprise about 6% w / w surfactant.

[0044] In some embodiments, provided compositions comprise one or more effervescents. In some embodiments, an effervescent is selected from citric acid, sodium bicarbonate, and combinations thereof. In some embodiments, an effervescent is citric acid. In some embodiments, an effervescent is sodium bicarbonate. In some embodiments, provided compositions comprise both citric acid and sodium bicarbonate (e.g., in about a 1: 1, 2:3, or 3:2 ratio). In some embodiments, provided compositions do not comprise an effervescent.

[0045] In some embodiments, provided compositions comprise about 15% to about 30% w / w effervescent. In some embodiments, provided compositions comprise about 15% to about 27% w / w effervescent. In some embodiments, provided compositions comprise about 15% to about 20% w / w effervescent. In some embodiments, provided compositions comprise about 20% to about 30% w / w effervescent. In some embodiments, provided compositions comprise about 15% w / w effervescent. In some embodiments, provided compositions comprise about 20% w / w effervescent. In some embodiments, provided compositions comprise about 27% w / w effervescent. In some embodiments, provided compositions comprise about 30% w / w effervescent.

[0046] In some embodiments, provided compositions comprise a surfactant and do not comprise an effervescent. In some embodiments, provided compositions comprise an effervescent and do not comprise a surfactant. In some embodiments, provided compositions comprise both a surfactant and an effervescent.

[0047] In some embodiments, provided compositions comprise one or more disintegrants. In some embodiments, a disintegrant is selected from croscarmellose sodium, crospovidone, and combinations thereof. In some embodiments, provided compositions comprise croscarmellose sodium (e.g., Ac-Di-Sol SD-711). In some embodiments, provided compositions comprise crospovidone (e.g., Polyplasdone XL). In some embodiments, provided compositions comprise both croscarmellose sodium and crospovidone. In some embodiments, provided compositions do not comprise a disintegrant other than croscarmellose sodium. In some embodiments, provided compositions do not comprise crospovidone.

[0048] In some embodiments, provided compositions comprise about 5% to about 10% w / w disintegrant. In some embodiments, provided compositions comprise about 5% to about 8% w / w disintegrant. In some embodiments, provided compositions comprise about 8% to about 10% w / w disintegrant. In some embodiments, provided compositions comprise about 9% to about 10% w / w disintegrant. In some embodiments, provided compositions comprise about 5% w / w disintegrant. In some embodiments, provided compositions comprise about 6% w / w disintegrant. In some embodiments, provided compositions comprise about 7% w / w disintegrant. In some embodiments, provided compositions comprise about 8% w / w disintegrant. In some embodiments, provided compositions comprise about 9% w / w disintegrant. In some embodiments, provided compositions comprise about 9.6% w / w disintegrant. In some embodiments, provided compositions comprise about 10% w / w disintegrant.

[0049] In some embodiments, provided compositions comprise one or more glidants. In some embodiments, provided compositions comprise fumed silica (e.g., Aerosil 200).

[0050] In some embodiments, provided compositions comprise about 0.25% to about 1.0% w / w glidant. In some embodiments, provided compositions comprise about 0.5% to about 1.0% w / w glidant. In some embodiments, provided compositions comprise about 0.5% to about 0.75% w / w glidant. In some embodiments, provided compositions comprise about 0.75% to about 1.0% w / w glidant. In some embodiments, provided compositions comprise about 0.25% w / w glidant. In some embodiments, provided compositions comprise about 0.5% w / w glidant. In some embodiments, provided compositions comprise about 0.75% w / w glidant. In some embodiments, provided compositions comprise about 1.0% w / w glidant.

[0051] In some embodiments, provided compositions comprise one or more lubricants. In some embodiments, provided compositions comprise magnesium stearate.

[0052] In some embodiments, provided compositions comprise about 0.25% to about 1.0% w / w lubricant. In some embodiments, provided compositions comprise about 0.5% to about 1.0% w / w lubricant. In some embodiments, provided compositions comprise about 0.5% to about 0.75% w / w lubricant. In some embodiments, provided compositions comprise about 0.75% to about 1.0% w / w lubricant. In some embodiments, provided compositions comprise about 0.25% w / w lubricant. In some embodiments, provided compositions comprise about 0.5% w / w lubricant. In some embodiments, provided compositions comprise about 0.75% w / w lubricant. In some embodiments, provided compositions comprise about 1.0% w / w lubricant.

[0053] In some embodiments, the total weight of a provided composition is about 50 mg to about 700 mg. In some embodiments, the total weight of a provided composition is about 250 mg to about 700 mg. In some embodiments, the total weight of a provided composition is about 200 mg to about 300 mg. In some embodiments, the total weight of a provided composition is about 500 mg to about 700 mg. In some embodiments, the total weight of a provided composition is about 50 mg. In some embodiments, the total weight of a provided composition is about 100 mg. In some embodiments, the total weight of a provided composition is about 200 mg. In some embodiments, the total weight of a provided composition is about 250 mg. In some embodiments, the total weight of a provided composition is about 262.5 mg. In some embodiments, the total weight of a provided composition is about 300 mg. In some embodiments, the total weight of a provided composition is about 500 mg. In some embodiments, the total weight of a provided composition is about 700 mg.

[0054] In some embodiments, provided compositions comprise: about 5% to about 20% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 5% to about 10% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants.

[0055] In some embodiments, provided compositions comprise: about 5% to about 10% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 8% to about 10% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants.

[0056] In some embodiments, provided compositions comprise:about 5% to about 20% w / w Compound 1 , or a pharmaceutically acceptable salt thereof; about 45% to about 85% w / w filler; about 1.5% to about 6% w / w surfactant; about 5% to about 10% w / w disintegrant; about 0.5% to about 1.0% w / w glidant; and about 0.5% to about 1.0% w / w lubricant.

[0057] In some embodiments, provided compositions comprise: about 5% to about 10% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 65% to about 85% w / w filler; about 2% to about 4% w / w surfactant; about 8% to about 10% w / w disintegrant; about 0.5% to about 1.0% w / w glidant; and about 0.5% to about 1.0% w / w lubricant.

[0058] In some embodiments, the present disclosure provides a composition comprising: about 5.7% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 9.6% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants.

[0059] In some embodiments, the present disclosure provides a composition comprising: about 5.7% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 79.5% w / w filler; about 3.8% w / w surfactant; about 9.6% w / w disintegrant; about 0.5% w / w glidant; and about 1.0% w / w lubricant.

[0060] In some embodiments, the present disclosure provides a composition comprising: about 5.7% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 79.5% w / w silicified microcrystalline cellulose; about 3.8% w / w pol oxamer (e.g., pol oxamer Pl 88); about 9.6% w / w croscarmellose sodium; about 0.5% w / w fumed silica; andabout 1 .0% w / w magnesium stearate.

[0061] In some embodiments, the present disclosure provides a composition comprising: about 15 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 25 mg croscarmellose sodium; and one or more pharmaceutically acceptable excipients selected from fdlers, surfactants, lubricants, and glidants, optionally, wherein the total weight of the composition is 262.5 mg.

[0062] In some embodiments, the present disclosure provides a composition comprising: about 15 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 208.75 mg silicified microcrystalline cellulose; about 10 mg pol oxamer; about 25 mg croscarmellose sodium; about 1.25 mg fumed silica; and about 2.5 mg magnesium stearate, optionally, wherein the total weight of the composition is 262.5 mg.

[0063] In some embodiments, the present disclosure provides a composition comprising: about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 66.7 mg croscarmellose sodium; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants, optionally, wherein the total weight of the composition is 700 mg.

[0064] In some embodiments, the present disclosure provides a composition comprising: about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 556.7 mg silicified microcrystalline cellulose; about 26.7 mg poloxamer; about 66.7 mg croscarmellose sodium; about 3.3 mg fumed silica; and about 6.6 mg magnesium stearate, optionally, wherein the total weight of the composition is 700 mg.

[0065] In some embodiments, the present disclosure provides a composition comprising: about 19% w / w Compound 1, or a pharmaceutically acceptable salt thereof;about 9.6% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants.

[0066] In some embodiments, the present disclosure provides a composition comprising: about 19% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 66.2% w / w filler; about 3.8% w / w surfactant; about 9.6% w / w disintegrant; about 0.5% w / w glidant; and about 1.0% w / w lubricant.

[0067] In some embodiments, the present disclosure provides a composition comprising: about 19% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 66.2% w / w silicified microcrystalline cellulose; about 3.8% w / w pol oxamer; about 9.6% w / w croscarmellose sodium; about 0.5% w / w fumed silica; and about 1.0% w / w magnesium stearate.

[0068] In some embodiments, the present disclosure provides a composition comprising: about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 25 mg croscarmellose sodium; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants, optionally, wherein the total weight of the composition is 262.5 mg.

[0069] In some embodiments, the present disclosure provides a composition comprising: about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 173.75 mg silicified microcrystalline cellulose; about 10 mg pol oxamer; about 25 mg croscarmellose sodium; about 1.25 mg fumed silica; and about 2.5 mg magnesium stearate, optionally, wherein the total weight of the composition is 262.5 mg.

[0070] In some embodiments, the present disclosure provides a composition selected from those described in the Examples section herein.

[0071] In some embodiments, provided compositions display one or more desirable characteristics, such as good dissolution profiles, flow properties, particle size, and / or water content.

[0072] In some embodiments, the present disclosure provides a composition as described herein, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL 0.1N aqueous HC1 with paddle stirring at about 75 rpm, at least about 95% release of Compound 1 is observed within about 90 min. In some embodiments, the present disclosure provides a composition as described herein, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL 0.1N aqueous HC1 with paddle stirring at about 75 rpm, at least about 90% release of Compound 1 is observed within about 90 min. In some embodiments, the present disclosure provides a composition as described herein, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL 0. IN aqueous HC1 with paddle stirring at about 75 rpm, at least about 85% release of Compound 1 is observed within about 90 min.

[0073] In some embodiments, the present disclosure provides a composition as described herein, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL of 100 mM citrate in 0. IN aqueous HC1 with paddle stirring at about 75 rpm, at least about 95% release of Compound 1 is observed within about 90 min. In some embodiments, the present disclosure provides a composition as described herein, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL of 100 mM citrate in 0.1N aqueous HC1 with paddle stirring at about 75 rpm, at least about 90% release of Compound 1 is observed within about 90 min. In some embodiments, the present disclosure provides a composition as described herein, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL of 100 mM citrate in 0. IN aqueous HC1 with paddle stirring at about 75 rpm, at least about 85% release of Compound 1 is observed within about 90 min.

[0074] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition comprises less than about 5 wt% water. In some embodiments, the present disclosure provides a composition as described herein, wherein the compositioncomprises less than about 4 wt% water. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition comprises less than about 3 wt% water.

[0075] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 8 mm to about 24 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 12 mm to about 22 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 8 mm to about 16 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 16 mm to about 24 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 12 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 16 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a flowability index of about 22 mm, when measured using a Flodex test (e.g., as described in Example 4).

[0076] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has an angle of repose of about 40° to about 44°, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has an angle of repose of about 41° to about 43°, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has an angle of repose of about 41° (e.g., about 41.3°), when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has an angle of repose of about 43° (e.g., about 42.9°), when measured using a Flodex test (e.g., as described in Example 4).

[0077] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a bulk density of about 0.49 to about 0.55 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a bulk density of about 0.53 to about 0.55 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a bulk density of about 0.50 to about 0.53 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a bulk density of about 0.54 g / mL (e.g., about 0.536 g / mL), when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a bulk density of about 0.55 g / mL (e.g., about 0.548 g / mL), when measured as described in Example 4.

[0078] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a tapped density of about 0.69 to about 0.80 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a tapped density of about 0.72 to about 0.78 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a tapped density of about 0.69 to about 0.74 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a tapped density of about 0.73 g / mL (e.g., about 0.724 g / mL), when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a tapped density of about 0.78 g / mL (e.g., about 0.780 g / mL), when measured as described in Example 4.

[0079] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a Hausner ratio of about 1.3 to about 1.5, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a Hausner ratio of about 1.34 to about 1.44, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a Hausner ratio of about 1.34 to about 1.40, when measured as described in Example 4. In some embodiments, the presentdisclosure provides a composition as described herein, wherein the composition has a Hausner ratio of about 1.42 to about 1.44, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a Hausner ratio of about 1.35 (e.g., about 1.349), when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a Hausner ratio of about 1.42 (e.g., about 1.422), when measured as described in Example 4.

[0080] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a compressibility index of about 25 to about 30, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a compressibility index of about 25 to about 27, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a compressibility index of about 28 to about 30, when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a compressibility index of about 26 (e.g., about 25.9), when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a compressibility index of about 30 (e.g., about 29.7), when measured as described in Example 4.

[0081] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a particle size distribution substantially similar to that in FIG. 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a particle size distribution substantially similar to that in FIG. 6. In some embodiments, the present disclosure provides a composition as described herein, wherein the particle size of about 80-83% of the composition is less than about 560 pm, e.g., when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the particle size of about 65-69% of the composition is less than about 425 pm, e.g., when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the particle size of about 55-56% of the composition is less than about 250 pm, e.g., when measured as described in Example 4.

[0082] In some embodiments, provided compositions are filled into a capsule, e g., for oral administration to a subject. In some embodiments, provided compositions are filled into a size 00 capsule. In some embodiments, provided compositions are filled into a size 0 capsule. In some embodiments, provided compositions are filled into a size 1 capsule. In some embodiments, provided compositions are filled into a size 2 capsule. In some embodiments, provided compositions are filled into a size 3 capsule.

[0083] In some embodiments, the present disclosure provides a capsule comprising a composition described herein.Methods of Preparing Provided Compositions

[0084] The present disclosure also provides methods of preparing compositions comprising a MNK inhibitor and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides methods of preparing compositions provided herein.

[0085] In some embodiments, the present disclosure provides a composition prepared by a method described herein.

[0086] In some embodiments, the present disclosure provides a method of preparing a composition described herein, the method comprising: (i) dry granulating an intragranular blend comprising Compound 1 , or a pharmaceutically acceptable salt thereof, and intragranular materials to provide a dry granulation blend; and (ii) blending the dry granulation blend with extragranular materials to provide the composition. In some embodiments, step (ii) comprises (1) blending the dry granulation blend with the second disintegrant and the glidant to provide an extragranular blend; and (2) blending the second lubricant and the extragranular blend to provide the composition.

[0087] In some embodiments, the method further comprises a step of blending Compound 1, or a pharmaceutically acceptable salt thereof, with the intragranular materials to provide the intragranular blend. In some such embodiments, the method comprises steps of (a) blending Compound 1 or a pharmaceutically acceptable salt thereof, the filler, the surfactant, and the first disintegrant to provide a first blend; and (b) blending a first lubricant and the first blend to provide the intragranular blend.

[0088] In some embodiments, the present disclosure provides a method of preparing a composition described herein, the method comprising:(i) blending Compound 1 or a pharmaceutically acceptable salt thereof, the filler, the surfactant, and a first disintegrant to provide a first blend;(ii) blending a first lubricant and the first blend to provide an intragranular blend;(iii) dry granulating the intragranular blend to provide a dry granulation blend;(iv) blending the dry granulation blend with a second disintegrant and a glidant to provide an extragranular blend; and(v) blending a second lubricant and the extragranular blend to provide the composition.

[0089] In some embodiments, intragranular materials comprise one or more fillers, surfactants, effervescents, disintegrants, and / or lubricants, e.g., fillers, surfactants, effervescents, disintegrants, and lubricants described herein. In some embodiments, intragranular materials comprise one or more fillers, surfactants, disintegrants, and lubricants. In some embodiments, intragranular materials comprise a filler, a surfactant, a first disintegrant, and a first lubricant. In some embodiments, intragranular materials comprise silicified microcrystalline cellulose, poloxamer (e.g., poloxamer 188), croscarmellose sodium, and magnesium stearate.

[0090] In some embodiments, extragranular materials comprise one or more disintegrants, glidants, and / or lubricants. In some embodiments, extragranular materials comprise a second disintegrant, a glidant, and a second lubricant. In some embodiments, extragranular materials comprise croscarmellose sodium, fumed silica, and magnesium stearate.

[0091] In some embodiments, a first disintegrant and a second disintegrant are the same (e.g., are both croscarmellose sodium in, e.g., approximately equal amounts). In some embodiments, a first lubricant and a second lubricant are the same (e.g., are both magnesium stearate in, e.g., approximately equal amounts).

[0092] In some embodiments, intragranular materials comprise, relative to the total weight of the composition: about 45% to about 85% w / w filler; about 1.5% to about 6% w / w surfactant; about 2.5% to about 5% w / w disintegrant; and about 0.25% to about 0.5% w / w lubricant; and extragranular materials comprise, relative to the total weight of the composition: about 2.5% to about 5% w / w disintegrant; about 0.5% to about 1.0% w / w glidant; andabout 0.25% to about 0.5% w / w lubricant.

[0093] In some embodiments, intragranular materials comprise, relative to the total weight of the composition: about 65% to about 85% w / w filler; about 2% to about 4% w / w surfactant; about 4% to about 5% w / w disintegrant; and about 0.25% to about 0.5% w / w lubricant; and extragranular materials comprise, relative to the total weight of the composition: about 4% to about 5% w / w disintegrant about 0.5% to about 1.0% w / w glidant; and about 0.25% to about 0.5% w / w lubricant.

[0094] In some embodiments, intragranular materials comprise, relative to the total weight of the composition: about 79.5% w / w filler; about 3.8% w / w surfactant; about 4.8% w / w disintegrant; and about 0.5% w / w lubricant; and extragranular materials comprise, relative to the total weight of the composition: about 4.8% w / w disintegrant about 0.5% w / w glidant; and about 0.5% w / w lubricant.

[0095] In some embodiments, intragranular materials comprise, relative to the total weight of the composition: about 79.5% w / w silicified microcrystalline cellulose; about 3.8% w / w poloxamer (e.g., pol oxamer Pl 88); about 4.8% w / w croscarmellose sodium; and about 0.5% w / w magnesium stearate; and extragranular materials comprise, relative to the total weight of the composition: about 4.8% w / w croscarmellose sodium; about 0.5% w / w fumed silica; and about 0.5% w / w magnesium stearate.

[0096] In some embodiments, intragranular materials comprise, relative to the total weight of the composition: about 66.2% w / w filler; about 3.8% w / w surfactant; about 4.8% w / w disintegrant; and about 0.5% w / w lubricant; and extragranular materials comprise, relative to the total weight of the composition: about 4.8% w / w disintegrant; about 0.5% w / w glidant; and about 0.5% w / w lubricant.

[0097] In some embodiments, intragranular materials comprise, relative to the total weight of the composition: about 66.2% w / w silicified microcrystalline cellulose; about 3.8% w / w pol oxamer; about 4.8% w / w croscarmellose sodium; and about 0.5% w / w magnesium stearate; and extragranular materials comprise, relative to the total weight of the composition: about 4.8% w / w croscarmellose sodium; about 0.5% w / w fumed silica; and about 0.5% w / w magnesium stearate.

[0098] In some embodiments, the present disclosure provides a dry granulation blend, e.g., prepared by and / or for use in a process described herein. In some embodiments, a composition (i.e., a dry granulation blend) provided herein comprises Compound 1, or a pharmaceutically acceptable salt thereof; a disintegrant; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants. In some embodiments, a composition (i.e., a dry granulation blend) provided herein comprises Compound 1, or a pharmaceutically acceptable salt thereof; a filler; a surfactant and / or an effervescent; optionally a disintegrant; and a lubricant. In some embodiments, a composition (i.e., a dry granulation blend) provided herein comprises Compound 1, or a pharmaceutically acceptable salt thereof; a filler; a surfactant; a disintegrant; and a lubricant.

[0099] In some embodiments, a composition (i.e., a dry granulation blend) comprises:about 6% to about 20% w / w Compound 1 , or a pharmaceutically acceptable salt thereof; about 2.5% to about 6% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants.

[0100] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 6% to about 10% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 4% to about 5% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants.

[0101] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 6% to about 20% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 45% to about 85% w / w filler; about 1.5% to about 6% w / w surfactant; about 2.5% to about 6% w / w disintegrant; and about 0.5% w / w lubricant.

[0102] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 6% to about 10% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 65% to about 85% w / w filler; about 2% to about 5% w / w surfactant; about 4% to about 5% w / w disintegrant; and about 0.5% w / w lubricant.

[0103] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 6% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 5.1% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants.

[0104] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 6% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 84.3% w / w filler; about 4% w / w surfactant; about 5.1% w / w disintegrant; andabout 0.5% w / w lubricant.

[0105] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 6.0% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 84.3% w / w silicified microcrystalline cellulose; about 4.0% w / w poloxamer (e.g., pol oxamer Pl 88); about 5.1% w / w croscarmellose sodium; and about 0.5% w / w magnesium stearate.

[0106] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 15 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 12.5 mg croscarmellose sodium; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants, optionally, wherein the total weight of the composition is 247.5 mg.

[0107] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 15 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 208.75 mg silicified microcrystalline cellulose; about 10 mg poloxamer (e.g., poloxamer Pl 88); about 12.5 mg croscarmellose sodium; and about 1.25 mg magnesium stearate, optionally, wherein the total weight of the composition is 247.5 mg.

[0108] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 33.3 mg croscarmellose sodium; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants, optionally, wherein the total weight of the composition is 660 mg.

[0109] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 556.7 mg silicified microcrystalline cellulose; about 26.7 mg poloxamer (e.g., poloxamer Pl 88); about 33.3 mg croscarmellose sodium; andabout 3.3 mg magnesium stearate, optionally, wherein the total weight of the composition is 660 mg.

[0110] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 20.1% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 5.1% w / w disintegrant (e.g., croscarmellose sodium); and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants.[0U1] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 20.1% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 70.2% w / w filler; about 4.0% w / w surfactant; about 5.1% w / w disintegrant; and about 0.5% w / w lubricant.

[0112] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 20.1% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 70.2% w / w silicified microcrystalline cellulose; about 4.0% w / w poloxamer (e.g., pol oxamer Pl 88); about 5.1% w / w croscarmellose sodium; and about 0.5% w / w magnesium stearate.

[0113] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 12.5 mg croscarmellose sodium; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, and lubricants, optionally, wherein the total weight of the composition is 247.5 mg.

[0114] In some embodiments, a composition (i.e., a dry granulation blend) comprises: about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 173.75 mg silicified microcrystalline cellulose; about 10 mg poloxamer; about 12.5 mg croscarmellose sodium; and about 1.25 mg magnesium stearate,optionally, wherein the total weight of the composition is 247.5 mg.

[0115] In some embodiments, provided dry granulation blend compositions display one or more desirable characteristics, such as good flow properties and / or particle size.

[0116] In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 8 mm to about 24 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 12 mm to about 22 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 8 mm to about 16 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 16 mm to about 24 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 8 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 18 mm, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a flowability index of about 22 mm, when measured using a Flodex test (e.g., as described in Example 4).

[0117] In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has an angle of repose of about 38° to about 45°, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has an angle of repose of about 40° to about 44°, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has an angle of repose of about 41° to about 43°, when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blendcomposition as described herein, wherein the composition has an angle of repose of about 40° (e.g., about 40.1°), when measured using a Flodex test (e.g., as described in Example 4). In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has an angle of repose of about 43° (e.g., about 43.4°), when measured using a Flodex test (e.g., as described in Example 4).

[0118] In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a bulk density of about 0.45 to about 0.65 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a bulk density of about 0.49 to about 0.55 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a bulk density of about 0.48 to about 0.53 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a bulk density of about 0.50 g / mL (e.g., about 0.496 g / mL), when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a bulk density of about 0.52 g / mL (e.g., about 0.521 g / mL), when measured as described in Example 4.

[0119] In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a tapped density of about 0.59 to about 0.92 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a tapped density of about 0.69 to about 0.80 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a tapped density of about 0.69 to about 0.74 g / mL, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a tapped density of about 0.70 g / mL (e.g., about 0.696 g / mL), when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a tapped density of about 0.74 g / mL (e.g., about 0.739 g / mL), when measured as described in Example 4.

[0120] In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a Hausner ratio of about 1.25 to about 1.5, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a Hausner ratio of about 1.3 to about 1.5, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a Hausner ratio of about 1.4 to about 1.45, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a Hausner ratio of about 1.40 (e.g., about 1.402), when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a Hausner ratio of about 1.42 (e g., about 1.417), when measured as described in Example 4.

[0121] In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a compressibility index of about 21 to about 33, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a compressibility index of about 25 to about 30, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a compressibility index of about 28 to about 30, when measured as described in Example 4. In some embodiments, the present disclosure provides a dry granulation blend composition as described herein, wherein the composition has a compressibility index of about 29 (e.g., about 28.7 or about 29.4), when measured as described in Example 4.

[0122] In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a particle size distribution substantially similar to that in FIG. 3. In some embodiments, the present disclosure provides a composition as described herein, wherein the composition has a particle size distribution substantially similar to that in FIG. 5. In some embodiments, the present disclosure provides a composition as described herein, wherein the particle size of about 82-87% of the composition is less than about 560 pm, e.g., when measured as described in Example 4. In some embodiments, the present disclosure provides acomposition as described herein, wherein the particle size of about 65-73% of the composition is less than about 425 pm, e.g., when measured as described in Example 4. In some embodiments, the present disclosure provides a composition as described herein, wherein the particle size of about 54-59% of the composition is less than about 250 pm, e.g., when measured as described in Example 4.Uses

[0123] The present disclosure also encompasses uses of provided compositions. In some embodiments, provided compositions are useful in methods of treating MNK-associated diseases, disorders, or conditions.

[0124] In some embodiments, the present disclosure provides methods of administering provided compositions or capsules to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compositions or capsules to a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK.

[0125] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with MNK, comprising administering a provided composition or capsule to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided composition or capsule to a subject in need thereof.

[0126] In some embodiments, provided methods are for treating neuropathic pain. In some embodiments, the present disclosure provides a method of treating neuropathic pain, the method comprising administering a provided composition or capsule to a subject in need thereof.

[0127] Neuropathic pain typically develops over time and may benefit from therapies that interfere with pathways involved in its development and / or continuation. Disease or damage causing neuropathic pain may affect the central nervous system (CNS), the peripheral nervous system, or both (as opposed to causes of nociceptive pain, which affect the peripheral nervous system only). Common causes of neuropathic pain include spinal cord injury, multiple sclerosis, central nervous system ischemia, spinal nerve disease, diabetes, other metabolic disorders, herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders, physical trauma to a nerve trunk such as during surgery, peripheral ischemia, peripheral nerve lesions, nerve compression, chemotherapy or otherdrug-induced nerve damage, radiation injury, arthritis, autoimmune disease, and infection in an area near the affected nerves.

[0128] Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptors are specialized neurons that detect pain. Nociceptor sensitivity is not fixed; it can change over time. Some causes of neuropathic pain affect nociceptor sensitivity by inducing “peripheral sensitization.” Peripheral sensitization includes spontaneous pathological activity, abnormal excitability, heightened sensitivity to chemical stimuli, heightened sensitivity to thermal stimuli, heightened sensitivity to mechanical stimuli, and any combinations of these. Disruption of peripheral sensitization, either by reducing or preventing such peripheral sensitization in the first place or by reducing the degree of already-developed peripheral sensitization, may therefore treat neuropathic pain. Although the disclosure is not limited to one mechanism of action, MNK inhibitors as disclosed herein (e.g., Compound 1) may disrupt peripheral sensitization.

[0129] MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). MNKs are a subfamily of Ser / Thr kinases, phylogenetically considered Ca2 / calmodulin-dependent kinases (CaMKs). MNKs are activated through phosphorylation by the growth factor-stimulated Ras / extracellular signal -regulated kinase pathway and the stress-induced p38 pathway. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signal to the eukaryotic translation initiation factor (elF) 4E complex to regulate the sensitization of nociceptors.

[0130] In some embodiments, provided methods are for treating migraine. In some embodiments, the present disclosure provides a method of treating migraine, the method comprising administering a provided composition or capsule to a subject in need thereof.

[0131] In some embodiments, provided methods are for treating or preventing pain associated with rheumatoid arthritis. In some embodiments, the present disclosure provides a method of treating or preventing pain associated with rheumatoid arthritis, the method comprising administering a provided composition to a subject in need thereof.

[0132] In some embodiments, provided methods are for treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome. In some embodiments, thepresent disclosure provides a method of treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome, the method comprising administering a provided composition or capsule to a subject in need thereof.

[0133] In some embodiments, provided compositions are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., Compound 1) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for a solid pharmaceutical composition (e.g., a capsule as described herein) containing a predetermined amount of an active agent (e.g., Compound 1).

[0134] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example, as described herein.

[0135] In some embodiments, provided compositions are administered orally.EXAMPLESExample 1. Preparation of Compound 1

[0136] Compound 1 was prepared generally as described in WO 2023 / 278686. The final step to generate Compound 1 was performed as follows:

[0137] To a suspension of Int-A (1 equiv.) in EtOH / THF / ThO (2:1 : 1 , N / N / N, 25 vol.), an aqueous solution of potassium hydroxide (7.5 equiv. in 1 vol. of water) was added dropwise at 25 ± 5 °C. The reaction mixture was stirred for 20 minutes at 25 ± 5 °C, then heated to 45 ± 5 °C and stirred for 4-5 h at 45 ± 5 °C. The reaction mixture was then cooled to 25 ± 5 °C and stirred for10 min at 25 ± 5 °C, then filtered through a bed of Celite®, followed by rinsing the filter cake with EtOH / THF / TEO (2 V). If IPC analysis of the crude reaction mixture showed incomplete consumption of Int-A, additional stirring was performed for 2 h at 45 ± 5 °C, followed by cooling to 25 ± 5 °C. SilametThiourea (60 Angstroms; 1.02 w / w on Int-A) was added to the reaction mixture and stirred for 1 h at 25 ± 5 °C, followed by the addition of activated charcoal (1 :0.05 w / w on Int-A) as a slurry in THF (1 :1 w / v on Int-A). The mixture was stirred for 1 h at 25 ± 5 °C, and the suspension was filtered through a bed of Celite®, followed by rinsing the filter cake with EtOH / THF / FEO (2 V). The pH of the reaction mixture was adjusted to 7.5-8 using 1.5 N aq. HC1, and the mixture was stirred for 1 h at 0-5 °C. The precipitate was collected by filtration and washed with water. The isolated solid was slurried with purified water (10 V) for 30 min at 25 ± 5 °C, and then the solid was collected by filtration and washed with purified water (2 V). The collected solid was dried at 45-50 °C under reduced pressure for 3 h to afford Compound 1.

[0138] Compound 1 prepared in this manner was a hemihydrate and was characterized by having substantially the following peaks at 2-theta angles (± 0.2°) in its XRPD spectrum: 5.6°, 8.0°, 8.4°, 9.2°, 10.9°, 11.2°, 13.2°, 14.3°, 15.3°, 16.2°, 16.5°, 16.9°, 17.4°, 18.2°, 18.6°, 19.9°,20.2°, 20.5°, 21.9°, 22.3°, 22.5°, 23.3°, 23.6°, 24.7°, 25.2°, 25.8°, 26.2°, 27.0°, 27.3°, 27.8°, 28.5°, and 28.8°.

[0139] If XPRD analysis indicated the presence of a mixture of polymorphs and / or higher order hydrates (i.e., forms other than the form described above with ~3% w / w water content), an additional water slurry was performed as follows: Compound 1 in water (10 V) was stirred via overhead stirrer (150 rpm) at 25 ± 5 °C for 16 h. Stirring was stopped, and the solid was collected by fdtration and washed with purified water (2 V). The obtained solid was dried at 45-50 °C for 48 h under reduced pressure to give Compound 1 with approx. 3% w / w water content. Compound 1 prepared in this manner was characterized by having substantially the following peaks at 2-theta angles (± 0.2°) in its XRPD spectrum: 5.6°, 8.0°, 8.4°, 9.2°, 10.9°, 11.2°, 13.2°, 14.3°, 15.3°, 16.2°, 16.5°, 16.9°, 17.4°, 18.2°, 18.6°, 19.9°, 20.2°, 20.5°, 21.9°, 22.3°, 22.5°, 23.3°, 23.6°, 24.7°, 25.2°, 25.8°, 26.2°, 27.0°, 27.3°, 27.8°, 28.5°, and 28.8°.Example 2. Exemplary Formulation Prepared with Wet Granulation

[0140] Formulation 1 was prepared using wet granulation as follows: Required quantities of raw materials were dispensed. All intragranular raw materials were passed through a US 20 Mesh sieve, added to a 1 L bowl, and dry mixed for 2 min. Treated water was added through a tube using a pump into the bowl with intragranular raw materials while mixing was maintained. After the water was added, the wet granulated materials were dried in an oven overnight or for 24 hours. The oven-dried wet granulated materials were milled using a comil. All extragranular materials were passed through a US 20 Mesh sieve. Then, the milled wet granulated materials and the sieved extragranular materials were added to a V-Blender shell and blended for 2 min. The blend was discharged, and capsules were filled with the blend.Table 2.1. Formulation 1aAdjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0141] Formulation 1 was manufactured using a wet granulation technique. The water content of Formulation 1, however, was less than satisfactory. The solid state form of Compound 1 was altered during the wet granulation process and some change in color (to yellow) was observed. Additionally, difficulties were experienced with the fill level of this formulation in different-sized capsules. Dry granulation techniques were explored next.Example 3. Exemplary Formulations Prepared with Dry Granulation

[0142] Formulations 2-10 were prepared using dry granulation using a TFC-Lab Micro Roller Compactor as follows:

[0143] The required quantities of all intragranular raw materials were dispensed. Compound 1 was passed through a US 60 Mesh sieve and added to a V-blender. The intragranular excipients except the lubricant were passed through a US 20 Mesh sieve, added to a V-blender, and blended for 10 min. The lubricant was passed through a US 20 Mesh sieve, added to the V-blender containing the other intragranular excipients, and blended for 2 min. The intragranular blend was then discharged. A Vector TFC-Lab Micro roller compactor was set up with the following settings:The intragranular blend was then dry granulated using the roller compactor to give the dry granulation blend. An oscillating granulator was set up with a US 20 Mesh screen size, and a V- blender was set up. All extragranular raw materials were dispensed and, other than the lubricant, were passed through a US 20 Mesh sieve. About half of the dry granulation blend was added to the V-blender, followed by the extragranular raw materials, except the lubricant, and then the remaining half of the dry granulation blend. The mixture was blended for 10 min. The lubricant was passed through a US 20 Mesh sieve, added to the V-blender, and blended for 2 min. The capsule blend was discharged, and capsules were filled with the capsule blend.Table 3.1. Formulation 2a Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0144] Formulation 2 was manufactured using a dry granulation technique. Intact ribbons and granules were formed with the dry granulation process. The thickness of the ribbons ranged between 1.40 - 2.10 mm.Table 3.2. Formulation 3Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0145] In Formulation 3, citric acid and sodium bicarbonate were replaced with 2% SLS in the intragranular portion. Intact ribbons were formed during the dry granulation process. The thickness of the ribbons ranged between 1.40 - 1.52 mm.Table 3.3. Formulation 4a Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0146] In Formulation 4, SLS was replaced with poloxamer in the intragranular portion. Soft ribbons were formed with a thickness of 1.08-1.25 mm.Table 3.4. Formulation 5a Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0147] In Formulation 5, both SLS and poloxamer were added in the intragranular portion. No intact ribbons were formed during the dry granulation process. Small and soft ribbons were produced with a thickness between 0.98 - 1.15 mm, which were fragile. No improvement was seen despite increasing the pressure.Table 3.5. Formulation 6“ Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0148] In Formulation 6, citric acid replaced SLS and poloxamer. Intact ribbons and granules were formed during the dry granulation process with a ribbon thickness of 1.34 - 1.62 mm.Table 3.6. Formulation 7a Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0149] Formulation 7 comprised a 1:1 ratio of SLS and poloxamer. For Formulation 7, both SLS and poloxamer were added in the intragranular portion with 1 : 1 ratio. No intact ribbons wereformed during the dry granulation process. Soft ribbons were produced with a thickness between 1.10 - 1.41 mm. No improvement was seen despite increasing the compaction force.Table 3.7. Formulation 8’ Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0150] In Formulation 8, the drug load was decreased from 20.0% to 10.0%. Ribbons were produced but were more brittle. The thickness of the ribbons ranged between 1.25 - 1.34 mm.Table 3.8. Formulation 9Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0151] In Formulation 9, 5% of crospovidone was added to the formulation. Dry granulation produced ribbons but they were softer. The thickness of the ribbons ranged between 1.04 - 1.42 mm.Table 3.9. Formulation 10a Adjusted for purity (96.2%) and free base (100.0%) content to deliver 10 mg & 50 mg of Compound 1 free base.

[0152] For Formulation 10, crospovidone was removed from the formulation and Ac-Di-Sol SD 711 concentration was increased to 10%. Dry granulation produced ribbons but they were softer. The thickness of the ribbons ranged between 1.08 - 1.39 mm.

[0153] A variation of Formulation 4 was also prepared and is referred to herein as “Formulation 4A ” Formulation 4A was prepared by adding 5% Ac-Di-Sol SD 711 (croscarmellose sodium) to Formulation 4.Example 4. Characterization of Dry Granulation Blends from Formulations

[0154] The dry granulation blends for each formulation were characterized for flow properties, density, and compressibility according to the following general procedures:

[0155] Flodex Powder Flow ability Test: For powders of unknown Flodex measurement, testing was started with a 16 mm flow disk. Powder was carefully loaded into a funnel. The funnel was tapped lightly as necessary to fill the cylinder without packing. Powder sufficient to fill the cylinder within 1 cm of the top was used. The release lever was turned until the closure plate dropped open. The Flodex apparatus was not shaken or tapped during the test. A positive result was achieved if sufficient powder flowed out of the cylinder so that the hole at the bottom of the cylinder was visible. A negative result was achieved if sufficient powder did not flow out of thecylinder, leaving the hole at the bottom of the cylinder not visible. If a positive result was achieved, testing was repeated with smaller flow disks until the test result was negative. If a negative result was achieved, testing was repeated with larger disks until the test result was positive. The cylinder was emptied between tests and change of the flow disk. The flowability index from the Flodex test was the diameter of the smallest hole through which the sample passed three successive tests.

[0156] Angle of Repose: Angle of repose was measured using the Flodex apparatus. The apparatus was assumed with only the funnel and base (no disk installed). Atrial was performed to determine the funnel height using 100 g of powder. The funnel height should be 2-4 cm above the cone formed from the powder flow; if needed, the funnel height was adjusted. Then, the funnel, base, and surrounding area were cleaned. Approximately 100 g of powder sample was allowed to pass through the funnel and create a cone-shaped pile of material on a flat surface. The height and base of material collected beneath the funnel was measured, and the measured values were used to calculate the angle of repose using the following equation: 0 = Tan-1(h / r), where 0 is angle of repose; h is height of pile; and r is radius of pile. Table 4.2 describes what flow property is associated with angle of repose.

[0157] Bulk Density, Tapped Density, Hausner Ratio, and Compressibility Index: A dry granulated cylinder was tared on a balance and a mass (M) of the test sample was added without any compacting. The weight was recorded. As necessary, the powder was leveled without compacting and the unsettled apparent volume (Vo) was recorded. The graduated cylinder was secured to a tapped density tester. The tapped density tester was used to carry out 10, 500, and 1250 taps of the powder sample, and Vio, V500, and V1250 were recorded to the nearest graduated unit. If the difference between V500 and V1250 was greater than 2 mL, tapping was repeated in 1250- tap increments until the difference between successive readings was less than or equal to 2 mL. This value was recorded as VF. Bulk density, tapped density, Hausner ratio, and compressibility index were calculated as follows:• Bulk density (g / mL) = M / Vo• Tapped density (g / mL) = M / VF• Hausner ratio = VO / VF• Compressibility index = 1OO(VO-VF) / VOTable 4.3 describes what flow character is associated with Hausner ratio and compressibility index.

[0158] Results from these characterization studies are summarized in Table 4.1.Table 4.1.Table 4.2. Flow Properties and Corresponding Angles of Repose USP <1174>Table 4.3. Scale of Flowability USP <1174>

[0159] Particle Size Distribution: A sonic sifter instrument and methodology were used that were a variation on USP general chapter <786>. Sieve sizes were selected to collect material over a range of particle sizes for the material being characterized. The tare weight of the fines collector and each sieve were recorded. The sieves were then assembled with the smallest size on the bottom and the largest size on the top. The sieve stack was placed on top of the fines collector and affixed with a column lock. Approximately 10 g of sample material was weighed out and placed on the top sieve. The diaphragm was then affixed. The assembled column was slid into the sonic sifter, and the column lock was unlocked for a tight fit. Sift and pulse settings were adjusted (5-8 was typical), and the timer was set (2-5 min was typical). When the test was complete, the gross weight of each sieve and the fines collector was measured, and the net weight of the powder retained on each sieve was calculated. From these values, % retained and average particle size were calculated.Example 5. Dissolution Profiles of Formulations

[0160] The dissolution profiles of Formulations 2, 3, 4, 6, 7, 8, 9, and 10 were assessed under the following conditions:• Volume: 900 mL• Dissolution Media: 0. IN HC1• Apparatus: paddles• RPM: 75 rpm

[0161] FIG. 1 shows the results of dissolution studies of Formulations 2, 3, 4, 6, and 7.

[0162] FIG. 2 shows the results of dissolution studies of Formulations 4A, 8, 9, and 10.Example 6. Engineering Batches

[0163] Based on the results from dissolution testing, Formulation 4A was chosen fortesting in engineering batches with 15 mg and 50 mg doses, having approx. 5% and 20% drug load, respectively.

[0164] The engineering batches were prepared as follows: the required quantities of all intragranular raw materials were dispensed. Compound 1 was passed through a US 60 Mesh sieve and added to a V-blender. The intragranular excipients except the lubricant were passed through a US 20 Mesh sieve, added to a V-blender, and blended for 10 min. The lubricant was passed through a US 20 Mesh sieve, added to the V-blender containing the other intragranular excipients, and blended for 2 min. The blend was then discharged. A Gerties roller compactor was set up with the following settings:The intragranular blend was then dry granulated using the roller compactor to give the dry granulation blend. All extragranular raw materials were dispensed and, other than the lubricant, were passed through a US 20 Mesh sieve. About half of the dry granulation blend was added to the V-blender, followed by the extragranular raw materials, except the lubricant, and then the remaining half of the dry granulation blend. The mixture was blended for 10 min. The lubricant was passed through a US 20 Mesh sieve, added to the V-blender, and blended for 2 min. The capsule blend was discharged, and capsules were filled with the capsule blend.

[0165] The 15 mg-dose batch is described in Table 6.1, and the 50 mg-dose batch is described in Table 6.2.Table 6.1.“Adjusted for purity (95.3%) and free base (100.0%) content to deliver 15 mg of Compound 1 freeTable 6.2.aAdjusted for purity (95.3%) and free base (100.0%) content to deliver 15 mg of Compound 1 free base.

[0166] The dry granulation blends and capsule blends from the 15 mg-dose and 50 mg-dose engineering batches were characterized for flow properties, density, and compressibility, as summarized in Table 6.3.Table 6.3.

[0167] The particle size distribution of the 15 mg-dose dry granulation blend, 15 mg-dose capsule blend, 50 mg-dose dry granulation blend, and 50 mg-dose capsule blend are shown in FIGs. 3-6. Particle size distributions were measured as described above in Example 4.

[0168] XRPD analysis for the two engineering batches and Formulation 4 are shown in FIG.7.Example 7. Dissolution Profiles of the Engineering Batches

[0169] The dissolution profdes of the two engineering batches were assessed under the following conditions:• Volume: 900 mL• Dissolution Media: 0. IN HC1• Apparatus: paddles• RPM: 50 & 75 rpm

[0170] The results from the dissolution studies of the engineering batches are shown in FIG.8.

[0171] A comparison of the 50 mg-dose engineering batch to Formulation 4 and Formulation 4 A is shown in FIG. 9.

[0172] Additional dissolution studies were performed under the following conditions:• Volume: 900 mL• Dissolution Media: 100 mM citrate with 0. IN HC1 (media) pH 1.07• Apparatus: paddles• RPM: 50 & 75 rpm

[0173] The results are shown in FIG. 10.

[0174] As shown in FIGs. 8-10, the 15 mg capsules achieved greater than 95% drug release in 90 min, while the dissolution results of the 50 mg capsules were less consistent and showed less than 90% drug release in 90 min.

[0175] The 15-mg engineering batch capsule blend was used to fill size 00 capsules in proportion to a dose of 40 mg. Dissolution results for these 40 mg capsules are shown in FIG. 11 (run six times). Greater than 95% drug release was achieved in 90 min.Example 8. Exemplary Formulation Prepared with Micronized Compound 1

[0176] Micronized Compound 1 was prepared as follows: Compound 1 was micronized using an air jet miller targeting D90 < 20 microns. The following conditions were used: primary nitrogen pressure of 6 kg / cm2; secondary nitrogen pressure of 6 kg / cm2; nitrogen atmosphere; room temperature; 75 g input quantity; and 62 g output quantity after micronization. After micronization, a particle size target of D90 < 20 microns was achieved.

[0177] The 50-mg dose engineering batch was prepared using the micronized Compound 1, as summarized in Table 8.1. Intact ribbons were not observed during the dry granulation process. The capsule blend was filled into size 2 capsules.Table 8.1aAdjusted for purity value of 94.8%.

[0178] The batch prepared using micronized Compound 1 was characterized for flow properties, density, and compressibility, as shown in Table 8.2.Table 8.2.

[0179] The particle size distribution of the micronized batch dry granulation blend, compared with the 50-mg dose engineering batch dry granulation blend is shown in FIG. 12.

[0180] The particle size distribution of the micronized batch capsule blend, compared with the 50-mg dose engineering batch capsule blend is shown in FIG. 13.

[0181] The dissolution profile of the micronized batch capsules is shown in FIG. 14 (run six times). The dissolution profile was similar to the 50-mg engineering batch.

[0182] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize compositions and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS1. A compositi on compri sin :Compound 1:1 or a pharmaceutically acceptable salt thereof; a di si nt egrant; and one or more pharmaceutically acceptable excipients selected from fillers, surfactants, lubricants, and glidants.

2. A compositi on compri sing :Compound 1 :1 or a pharmaceutically acceptable salt thereof; a filler; a surfactant and / or an effervescent; optionally a disintegrant; a glidant; and a lubricant.

3. The composition of claim 1 or 2, wherein the composition comprises about 5% to about 20% w / w Compound 1.

4. The composition of claim 3, wherein the composition comprises about 5.7% w / w Compound 1.

5. The composition of claim 3, wherein the composition comprises about 10% w / w Compound 1.

6. The composition of claim 3, wherein the composition comprises about 19% or about 20% w / w Compound 1.

7. The composition of any one of claims 1-6, wherein the composition comprises about 10 mg to about 50 mg Compound 1.

8. The composition of claim 7, wherein the composition comprises about 10 mg Compound 1.

9. The composition of claim 7, wherein the composition comprises about 15 mg Compound 1.

10. The composition of claim 7, wherein the composition comprises about 40 mg Compound 1.

11. The composition of claim 7, wherein the composition comprises about 50 mg Compound 1.

12. The composition of any one of claims 1-11, wherein Compound 1 is in a free base form.

13. The composition of any one of claims 1-12, wherein Compound 1 is a hemihydrate.

14. The composition of any one of claims 2-13, wherein the composition comprises a disintegrant.

15. The composition of any one of claims 1-14, wherein the composition comprises about 5% to about 10% w / w disintegrant.

16. The composition of claim 15, wherein the composition comprises about 9% to about 10% w / w disintegrant.

17. The composition of claim 16, wherein the composition comprises about 9.6% w / w disintegrant.

18. The composition of any one of claims 1-17, wherein the disintegrant is croscarmellose sodium or crospovidone, or a combination thereof.

19. The composition of any one of claims 1-17, wherein the disintegrant is croscarmellose sodium.

20. The composition of claim 19, wherein the composition comprises no disintegrant other than croscarmellose sodium.

21. The composition of any one of claims 1 or 3-20, wherein the composition comprises a filler.

22. The composition of any one of claims 1-21, wherein the composition comprises about 45% to about 85% w / w filler.

23. The composition of claim 22, wherein the composition comprises about 69% to about 80% w / w filler.

24. The composition of claim 23, wherein the composition comprises about 75% to about 80% w / w filler.

25. The composition of claim 24, wherein the composition comprises about 79.5% w / w filler.

26. The composition of any one of claims 1-25, wherein the filler is microcrystalline cellulose or silicified microcrystalline cellulose.

27. The composition of any one of claims 1-26, wherein the composition comprises a surfactant.

28. The composition of claim 27, wherein the composition comprises about 1.5% to about 6% w / w surfactant.

29. The composition of claim 28, wherein the composition comprises about 2% to about 4% w / w surfactant.

30. The composition of claim 29, wherein the composition comprises about 3.8% w / w surfactant.

31. The composition of any one of claims 1-30, wherein the surfactant is sodium lauryl sulfate or poloxamer, or a combination thereof.

32. The composition of claim 31, wherein the surfactant is poloxamer (e.g., poloxamer 188).

33. The composition of any one of claims 2-32, wherein the composition comprises an effervescent.

34. The composition of claim 33, wherein the composition comprises about 15% to about 27% w / w effervescent.

35. The composition of claim 34, wherein the effervescent is citric acid or sodium bicarbonate, or a combination thereof.

36. The composition of any one of claims 1 or 3-35, wherein the composition comprises a glidant.

37. The composition of any one of claims 1-36, wherein the composition comprises about 0.5% to about 1.0% w / w glidant.

38. The composition of claim 37, wherein the composition comprises about 0.5% w / w glidant.

39. The composition of any one of claims 1-38, wherein the glidant is fumed silica.

40. The composition of any one of claims 1 or 3-39, wherein the composition comprises a lubricant.

41. The composition of any one of claims 1-40, wherein the composition comprises about 0.5% to about 1.0% w / w lubricant.

42. The composition of claim 41, wherein the composition comprises about 1.0% w / w lubricant.

43. The composition of any one of claims 1-42, wherein the lubricant is magnesium stearate.

44. The composition of claim 1 or 2, wherein the composition comprises: about 5.7% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 79.5% w / w filler; about 3.8% w / w surfactant; about 9.6% w / w disintegrant; about 0.5% w / w glidant; and about 1.0% w / w lubricant.

45. The composition of claim 1 or 2, wherein the composition comprises: about 5.7% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 79.5% w / w silicified microcrystalline cellulose; about 3.8% w / w pol oxamer; about 9.6% w / w croscarmellose sodium;about 0.5% w / w fumed silica; and about 1.0% w / w magnesium stearate.

46. The composition of claim 1 or 2, wherein the composition comprises: about 15 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 208.75 mg silicified microcrystalline cellulose; about 10 mg pol oxamer; about 25 mg croscarmellose sodium; about 1.25 mg fumed silica; and about 2.5 mg magnesium stearate.

47. The composition of claim 1 or 2, wherein the composition comprises: about 40 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 556.7 mg silicified microcrystalline cellulose; about 26.7 mg poloxamer; about 66.7 mg croscarmellose sodium; about 3.3 mg fumed silica; and about 6.6 mg magnesium stearate.

48. The composition of claim 1 or 2, wherein the composition comprises: about 19% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 66.2% w / w filler; about 3.8% w / w surfactant; about 9.6% w / w disintegrant; about 0.5% w / w glidant; and about 1.0% w / w lubricant.

49. The composition of claim 1 or 2, wherein the composition comprises: about 19% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 66.2% w / w silicified microcrystalline cellulose; about 3.8% w / w poloxamer;about 9.6% w / w croscarmellose sodium; about 0.5% w / w fumed silica; and about 1.0% w / w magnesium stearate.

50. The composition of claim 1 or 2, wherein the composition comprises: about 50 mg Compound 1, or a pharmaceutically acceptable salt thereof; about 173.75 mg silicified microcrystalline cellulose; about 10 mg pol oxamer; about 25 mg croscarmellose sodium; about 1.25 mg fumed silica; and about 2.5 mg magnesium stearate.

51. The composition of any one of claims 1-50, wherein the total weight of the composition is about 50 mg to about 700 mg.

52. The composition of claim 51, wherein the total weight of the composition is about 262.5 mg.

53. The composition of claim 51, wherein the total weight of the composition is about 700 mg.

54. The composition of any one of claims 1-53, wherein when the composition is filled into a capsule and the capsule is placed into about 900 mL 0.1N aqueous HC1 or about 900 mb of 100 mM citrate in 0.1N aqueous HC1 with paddle stirring at about 75 rpm, at least about 95% release of Compound 1 is observed within about 90 min.

55. The composition of any one of claims 1-54, wherein the composition has one or more of the following characteristics:(i) a Flodex test of about 8 mm to about 24 mm;(ii) an angle of repose of about 40° to about 44°;(iii) a bulk density of about 0.49 g / mL to about 0.55 g / mL;(iv)a tapped density of about 0.69 g / mL to about 0.80 g / mL;(v) a Hausner ratio of about 1 .3 to about 1 .5; or(vi)a compressibility index of about 25 to about 30.

56. The composition of any one of claims 1-55, wherein: the particle size of about 80-83% of the composition is less than about 560 pm, e.g., when measured as described in Example 4; the particle size of about 65-69% of the composition is less than about 425 pm, e.g., when measured as described in Example 4; or the particle size of about 55-56% of the composition is less than about 250 pm, e.g., when measured as described in Example 4.

57. The composition of any one of claims 1-56, wherein the composition has a water content of less than about 5%.

58. A capsule comprising the composition of any one of claims 1-57.

59. A method of preparing the composition of any one of claims 1-57, the method comprising: dry granulating an intragranular blend comprising Compound 1, or a pharmaceutically acceptable salt thereof, and intragranular materials to provide a dry granulation blend; and blending the dry granulation blend with extragranular materials to provide the composition.

60. The method of claim 59, comprising a step of blending Compound 1, or a pharmaceutically acceptable salt thereof, with the intragranular materials to provide the intragranular blend.

61. The method of claim 59 or 60, wherein the intragranular materials comprise a fdler, a surfactant, a first disintegrant, and a first lubricant.

62. The method of claim 61, comprising steps of blending Compound 1 or a pharmaceutically acceptable salt thereof, the filler, the surfactant, and the first disintegrant to provide a first blend; and blending the first lubricant and the first blend to provide the intragranular blend.

63. The method of any one of claims 59-62, wherein the extragranular materials comprise a second disintegrant, a glidant, and a second lubricant.

64. The method of claim 63, comprising steps of:(i) blending the dry granulation blend with the second disintegrant and the glidant to provide an extragranular blend; and(ii) blending the second lubricant and the extragranular blend to provide the composition.

65. The method of claim 63 or 64, wherein the first disintegrant and the second disintegrant are the same (e.g., croscarmellose sodium).

66. The method of claim 63 or 64, wherein the first lubricant and the second lubricant are the same (e.g., magnesium stearate).

67. A method of preparing the capsule of claim 58, comprising filling a capsule shell with the composition of any one of claims 1-57.

68. A composition comprising:Compound 1 :1 or a pharmaceutically acceptable salt thereof; a filler; a surfactant and / or an effervescent; optionally a disintegrant; and a lubricant.

9. The composition of claim 68, wherein the composition comprises: about 6% to about 20% w / w Compound 1, or a pharmaceutically acceptable salt thereof; about 45% to about 85% w / w filler; about 1.5% to about 6% w / w surfactant; about 5% to about 10% w / w disintegrant; and about 0.5% w / w lubricant.

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