WO2016025567A1 - Oral formulations and uses thereof - Google Patents

Oral formulations and uses thereof Download PDF

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Publication number
WO2016025567A1
WO2016025567A1 PCT/US2015/044793 US2015044793W WO2016025567A1 WO 2016025567 A1 WO2016025567 A1 WO 2016025567A1 US 2015044793 W US2015044793 W US 2015044793W WO 2016025567 A1 WO2016025567 A1 WO 2016025567A1
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Prior art keywords
compound
formulation
cancer
composition
formulation according
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PCT/US2015/044793
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French (fr)
Inventor
Lianfeng Huang
Jiping Liu
Steven Richard Witowski
Daozhong Zou
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Celgene Avilomics Research, Inc.
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Publication of WO2016025567A1 publication Critical patent/WO2016025567A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention provides various formulations and compositions comprising a compound useful as an inhibitor of ER kinases, for example one or both of ER 1 and ERK2 kinases.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • the processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells.
  • the ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras.
  • Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase.
  • Raf Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates one or both of ERKl and ERK2.
  • MEK1/2 When activated, one or both of ERKl and ERK2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation.
  • the ERK MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors.
  • Ras genes which are upstream of one or both of ERKl and ERK2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors.
  • BRAF a serine- threonine kinase of the Raf family
  • kinase activity is associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers.
  • Compound 1 is active in a variety of assays and therapeutic models demonstrating covalent, irreversible inhibition of one or both of ERKl and ERK2 kinases (see, e.g., Table A of the '230 publication). Accordingly, compound 1 is useful for treating one or more disorders associated with activity of one or both of ERKl and ERK2.
  • the present invention provides formulations for oral administration comprising a composition which comprises compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, such formulations for oral administration are capsule formulations.
  • compositions for oral administration comprise a composition which comprises compound 1, or a pharmaceutically acceptable salt thereof, and further comprises one or more excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof, as discussed below.
  • excipients such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof, as discussed below.
  • the present invention provides a unit dosage form comprising a provided formulation.
  • the present invention provides a pharmaceutically acceptable salt of compound 1.
  • the present invention provides a phosphate salt of compound 1, depicted below and referred to herein as com ound 2:
  • the present invention provides an amorphous form of compound 2. In some embodiments, the present invention provides a crystalline form of compound 2. In certain embodiments, such crystalline forms are selected from Form A, Form B, Form C, or Form D of compound 2. In certain embodiments, such a crystalline form is Form A of compound 2.
  • the present invention also provides methods of preparing provided formulations. Such formulations are useful, among other things, for administration of compound 1, or a pharmaceutically acceptable salt thereof, in any context in which such delivery is desirable.
  • provided formulations are useful for treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with one or both of ER 1 and ERK2. Such formulations are also useful for administration to subjects suffering from a disease or disorder associated with one or both of ERK1 and ERK2.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with one or both of ERKl and ERK2 comprising the step of administering to the subject a provided formulation, as described herein.
  • disorders or conditions include, among others, proliferative diseases such as cancer.
  • Figure 1 depicts an XRPD pattern of Form A of compound 2.
  • Figure 2 depicts an XRPD pattern of Form B of compound 2.
  • Figure 3 depicts an XRPD pattern of Form C of compound 2.
  • Figure 4 depicts an XRPD pattern of Form D of compound 2.
  • Figure 5 contains a graph depicting the solubility enhancement of Compound 2 in the presence of SBE betacyclodextrin (e.g., Captisol ® ).
  • SBE betacyclodextrin e.g., Captisol ®
  • Figure 6 contains a graph depicting the solubility enhancement of Compound 2 in the presence of sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • Figure 7 contains graphed PK data for dogs under fed state.
  • Figure 8 contains a graph depicting the effect of sodium bicarbonate on dissolution of a 150 mg capsule containing a Compound 2 formulation.
  • amorphous substantially free of crystalline forms refers to a composition containing compound 1 or compound 2, in which less than 20% (w/w) of the compound 1 or compound 2 is present in a crystalline form (e.g., less than 15%, 12%, 10%, 8%, 5%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.01% (w/w) of Compound 1 or Compound 2 is present in a crystalline form).
  • the crystalline content of a composition can be assessed using x-ray diffraction techniques.
  • a "disease or disorder associated with one or both of ERKl and ERK2" means any disease or other deleterious condition in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role.
  • another embodiment of the present invention relates to preventing, treating, stabilizing or lessening the severity or progression of one or more diseases in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role.
  • the present invention relates to a method of treating or lessening the severity of a proliferative disorder, wherein said method comprises administering to a patient in need thereof compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.
  • non-functional coating is a coating that does not significantly affect release characteristic(s) of a therapeutically active compound or compounds from a formulation when administered.
  • examples of a non-functional coat include a seal coat (e.g., hydroxypropyl cellulose, hypromellose or polyvinyl alcohol).
  • a non-functional coating is a polish coat or seal coat.
  • polymorph refers to the different crystal structures (of unsolvated forms) in which a compound can crystallize.
  • solvate refers to a crystal form with either a stoichiometric or non-stoichiometric amount of solvent that is incorporated into the crystal structure.
  • hydrate refers to a crystal form with either a stoichiometric or non-stoichiometric amount of water that is incorporated into the crystal structure.
  • subject means a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.).
  • domestic animals e.g., horses, dogs, cats, etc.
  • shocker or “suffering” as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have.
  • Therapeutically active agent refers to a substance, including a biologically active substance, that is useful for therapy (e.g., human therapy, veterinary therapy), including prophylactic and therapeutic treatment.
  • Therapeutically active agents include organic molecules that are drug compounds, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, small molecules linked to a protein, glycoprotein, steroid, nucleic acid, DNA, RNA, nucleotide, nucleoside, oligonucleotides, antisense oligonucleotides, lipid, hormone, and vitamin.
  • Therapeutically active agents include any substance used as a medicine for treatment, prevention, delay, reduction or amelioration of a disease, condition, or disorder.
  • therapeutically active agents useful in the formulations of the present invention are BTK inhibitors, and the like. Further detailed description of compounds useful as therapeutically active agents is provided below.
  • a therapeutically active agent includes a compound that increases the effect or effectiveness of a second compound, for example, by enhancing potency or reducing adverse effects of a second compound.
  • a "therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
  • a "therapeutically effective amount" is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms of a disorder or condition associated with one or both of ER 1 and ERK2.
  • treat refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition.
  • treatment refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • treating includes preventing relapse or recurrence of a disease or disorder.
  • unit dosage form refers to a physically discrete unit of a provided formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • compositions, and formulations thereof comprise the phosphate salt of compound 1, which salt is depicted below and referred to herein as com ound 2:
  • compound 2 can exist in a variety of physical forms.
  • compound 2 can be in solution, suspension, or in solid form.
  • compound 2 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof.
  • compound 2 is anhydrous.
  • compound 2 is a hydrate.
  • compound 2 is a solvate.
  • compound 2 is a dehydrate.
  • compound 2 is a desolvate. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 2 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess phosphoric acid, excess compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2.
  • extraneous matter may include excess phosphoric acid, excess compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2.
  • at least about 95% by weight of compound 2 is present.
  • at least about 99% by weight of compound 2 is present.
  • compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 2 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 2 contains no more than about 1.0% are percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 2 is also meant to include all tautomeric forms of compound 2. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
  • compound 2 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound contains no significant amount of amorphous compound 2. In certain embodiments, at least about 95% by weight of crystalline compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 2 is present.
  • compound 2 can exist in at least four distinct polymorphic forms.
  • the present invention provides a polymorphic form of compound 2 referred to herein as Form A.
  • the present invention provides a polymorphic form of compound 2 referred to herein as Form B.
  • the present invention provides a polymorphic form of compound 2 referred to herein as Form C.
  • the present invention provides a polymorphic form of compound 2 referred to herein as Form D.
  • compound 2 is amorphous. In some embodiments, compound 2 is amorphous, and is substantially free of crystalline compound 2.
  • Such solid forms, or polymorphs include Forms A-D, described below.
  • Form A of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
  • the position 2d? is within ⁇ 0.2.
  • Form A of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1 , and 20.8. In some embodiments, Form A of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1 , and 20.8. In some embodiments, Form A of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1 , and 20.8.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1.
  • Form B of Compound 2 is substantially similar to the XRPD provided in Figure 1.
  • Form B of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
  • the position 2d? is within ⁇ 0.2.
  • Form B of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0. In some embodiments, Form B of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0. In some embodiments, Form B of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 2.
  • Form C of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
  • the position 2d? is within ⁇ 0.2.
  • Form C of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5. In some embodiments, Form C of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5. In some embodiments, Form C of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 3.
  • Form D of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
  • the position 2d? is within ⁇ 0.2.
  • Form D of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.1 , 10.4, and 25.1. In some embodiments, Form D of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.1 , 10.4, and 25.1. In some embodiments, Form D of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 9.1 , 10.4, and 25.1.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 4.
  • a provided composition, or formulation thereof comprises from about 1% to about 60% compound 2, based upon total weight of given composition or formulation (wt %). In some embodiments, a provided composition, or formulation thereof, comprises from about 1 wt% to about 50 wt% compound 2.
  • a provided composition, or formulation thereof comprises from about 1 wt% to about 20 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 2 wt% to about 18 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 4 wt% to about 12 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 5 wt% to about 10 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 6 wt% to about 9 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 7 wt% to about 8 wt% compound 2. In certain embodiments, a provided composition, or formulation thereof, comprises about 7.59 wt% compound 2.
  • a provided composition, or formulation thereof comprises from about 20 wt% to about 60 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 25 wt% to about 55 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 30 wt% to about 50 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 35 wt% to about 50 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 40 wt% to about 50 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 41 wt% to about 49 wt% compound 2.
  • a provided composition, or formulation thereof comprises from about 42 wt% to about 48 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 43 wt% to about 47 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 44 wt% to about 46 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 45 wt% to about 46 wt% compound 2. In certain embodiments, a provided composition, or formulation thereof, comprises about 45.53 wt% compound 2.
  • the present invention provides a solid formulation comprising compound 2 and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof, as discussed below.
  • pharmaceutically acceptable excipients such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof, as discussed below.
  • the present invention provides a composition comprising compound 2 Form A and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • a pharmaceutically acceptable composition is a blended powder.
  • the present invention provides a composition comprising compound 2 Form B and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • the pharmaceutically acceptable composition is a blended powder.
  • the present invention provides a composition comprising compound 2 Form C and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • the pharmaceutically acceptable composition is a blended powder.
  • the present invention provides a composition comprising compound 2 Form D and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • the pharmaceutically acceptable composition is a blended powder.
  • the present invention provides a composition comprising compound 1 (free base) and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • the pharmaceutically acceptable composition is a blended powder.
  • the present invention provides a composition comprising a salt form of compound 1 other than compound 2, and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants.
  • exemplary such salt forms of compound 1 include HCl salt forms, HBr salt forms, bis-phosphate salt forms, sulfate salt forms, bis-sulfate salt forms, tosylate salt forms, mesylate salt forms, besylate salt forms, maleate salt forms, and oxalate salt forms.
  • provided formulations may comprise one or more solubilizers.
  • Solubilizers include, by way of example and without limitation, cyclodextrins such as alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, hydroxymethyl cyclodextrin, hydroxyethyl cyclodextrin, and hydroxybutyl cyclodextrin, carboxymethyl cyclodextrin, carboxyethyl cyclodextrin, carboxypropyl cyclodextrin, carboxybutyl cyclodextrin, methylcarboxymethyl cyclodextrin; amino cyclodextrin, sulfobutyl-ether- -cyclodextrin sodium salt ("SBECD", also referred to herein as betadex sulfobutyl ether
  • provided compositions comprise from about 1% to about 50% solubilizer, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 1% to about 45%, or about 1% to about 40%, or about 1%) to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20% solubilizer based on the total weight of the composition.
  • provided compositions comprise about 1% to about 10% solubilizer, based on the total weight of composition. In certain embodiments, provided compositions comprise about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%), or about 1% to about 6%, or about 1% to about 5%, or about 2% to about 4% solubilizer based on the total weight of the composition.
  • provided compositions comprise a solubilizer in an amount of about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%), about 2.9%, about 3.0%>, about 3.1%>, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%), about 3.7%, about 3.8%, about 3.9%>, or about 4.0%.
  • provided compositions comprise a solubilizer in an amount of about 3.33%.
  • provided compositions comprise about 10%> to about 30%) solubilizer, based on the total weight of composition. In certain embodiments, provided compositions comprise about 10%> to about 25%, or about 15% to about 25%, or about 17% to about 23%), or about 18% to about 22%, or about 19% to about 21% solubilizer based on the total weight of the composition.
  • provided compositions comprise a solubilizer in an amount of about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%), about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%), about 38%), about 39%, or about 40%.
  • provided compositions comprise a solubilizer in an amount of about 20%.
  • compositions comprise sulfobutyl-ether- ⁇ - cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 45%, or about 1%) to about 40%), or about 1% to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20% solubilizer based on the total weight of the composition.
  • provided compositions comprise sulfobutyl-ether- ⁇ - cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 10%. In some embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%), or about 1% to about 6%, or about 1% to about 5%, or about 2% to about 4%. In certain embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 3.33%.
  • provided compositions comprise sulfobutyl-ether- ⁇ - cyclodextrin sodium salt as a solubilizer in an amount of about 10% to about 30%. In some embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt in an amount of about 10% to about 25%, or about 15% to about 25%, or about 17% to about 23%, or about 18% to about 22%, or about 19% to about 21%. In certain embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 20%. ii. Surfactants/Wetting Agents
  • Surfactants/wetting agents are well known in the art and typically facilitate drug release and absorption by enhancing the solubility of poorly-soluble drugs.
  • Representative surfactants/wetting agents include, but are not limited to, poloxamers, polyoxyethylene ethers (e.g., polyethylene glycol), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g., triacetin, glycerol monostearate, and the like), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, Vitamin E TPGS, copovidone, polyvinyl alcohol (P
  • compositions comprise from about 0.1% to about 10%), or from about 0.1 %> to about 9%>, or from about 0.1 %> to about 8%>, or from about 0.1 %> to about 7%), or from about 0.1 %> to about 6%>, or from about 0.1 %> to about 5%>, or from about 0.1% to about 4%, or from about 0.1% to about 3%, or from about 0.1% to about 2% wetting agent, or from about 0.1% to about 1%, or from about 0.1% to about 0.5%, or from about 0.2% to about 0.4% wetting agent based upon total weight of the formulation.
  • provided compositions comprise from about 0.1 %> to about 10%), or from about 0.2%> to about 8%>, or from about 0.5%> to about 5%>, or from about 1%> to about 5%, or from about 1% to about 4%, or from about 1% to about 3%, or from about 1.5% to about 2.5% wetting agent based upon total weight of the formulation.
  • a provide composition comprises about 2%> wetting agent.
  • provided compositions comprise about 0.1 %>, about 0.2%>, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0% wetting agent.
  • a provide composition comprises about 0.33% wetting agent.
  • a surfactant/wetting agent is a surfactant/wetting agent such as sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.1% to about 10%, or from about 0.1% to about 9%, or from about 0.1% to about 8%, or from about 0.1% to about 7%), or from about 0.1 % to about 6%, or from about 0.1 % to about 5%, or from about 0.1% to about 4%, or from about 0.1% to about 3%.
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 2%.
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0%.
  • a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.33%.
  • provided formulations may comprise one or more dispersing agents.
  • Dispersing agents are substances added to a formulation to prevent settling, clumping, or gelling.
  • compound 2 in certain formulations has a tendency to gel in the presence of moisture. It has been found that the use of certain dispersing agents can minimize such gelling.
  • Dispersing agents include, by way of example and without limitation, salts such as sodium carbonate, sodium bicarbonate, sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, potassium chloride, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, and sodium chloride, sugars such as mannitol, fructose, sucrose, xylitol maleic acid, sorbitol, and dextrose, and acids such as D,L-malic acid, and the like, and combinations thereof.
  • salts such as sodium carbonate, sodium bicarbonate, sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, potassium chloride, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, and sodium chloride
  • sugars such as mannitol, fructose, sucrose, xylitol maleic acid, sorbitol, and dextrose
  • acids such as D,L-malic acid
  • provided compositions comprise from about 0.1 % to about 20%) dispersing agent, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 15%, or about 0.1% to about 10%, or about 0.1% to about 8%, or about 0.1% to about 7%, or about 0.1% to about 6%, or about 0.1% to about 5%, or about 0.1% to about 4%, or about 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.2% to about 0.8%, or about 0.2% to about 0.6%), or about 0.3% to about 0.5% dispersing agent.
  • compositions comprise from about 0.5% to about 10%), or about 0.5%> to about 5%, or about 1% to about 5%, or about 1% to about 4%, or about 1%) to about 3.5%, or about 1.5% to about 3.5%, or about 2% to about 3% dispersing agent.
  • compositions comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%), about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0% dispersing agent.
  • provided compositions comprise about 0.4% dispersing agent. In certain embodiments, provided compositions comprise about 0.5% dispersing agent. In certain embodiments, provided compositions comprise about 0.42% dispersing agent.
  • provided compositions comprise about 2.0% dispersing agent. In certain embodiments, provided compositions comprise about 3.0%> dispersing agent In certain embodiments, provided compositions comprise about 2.5% dispersing agent.
  • a dispersing is a bicarbonate salt, such as sodium bicarbonate.
  • provided compositions comprise sodium bicarbonate as a dispersing agent in an amount of about 0.1% to about 15%, or about 0.1% to about 10%, or about 0.1%) to about 8%, or about 0.1% to about 7%, or about 0.1% to about 6%, or about 0.1%) to about 5%), or about 0.1% to about 4%, or about 0.1% to about 3%.
  • compositions comprise sodium bicarbonate as a dispersing agent in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%), about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0%.
  • provided compositions comprise about 0.4% sodium bicarbonate. In certain embodiments, provided compositions comprise about 0.5% sodium bicarbonate. In certain embodiments, provided compositions comprise about 0.42% sodium bicarbonate.
  • provided compositions comprise about 2.0%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 3.0%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 2.5% sodium bicarbonate. iv. Fillers
  • compositions for use in the present invention may comprise one or more fillers. Fillers are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix.
  • Suitable fillers are known in the art.
  • suitable fillers include but are not limited to starch, PVP (polyvinyl pyrrolidone), celluloses such as low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (e.g., Avicel ® ), silicified microcrystalline cellulose (Prosolv 50), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose) and ethylcellulose, pregelatimzed starch, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, lactose (e.g., lactose monohydrate), mannitol, magnesium aluminum silicate, and polymethacrylates.
  • PVP polyvinyl pyrrolidone
  • HPC hydroxypropyl cellulose
  • microcrystalline cellulose e.g., Avicel ®
  • silicified microcrystalline cellulose Prosolv
  • Fillers include agents selected from the group consisting of silicic acid, microcrystalline cellulose (e.g., Avicel®), starch, pregelatimzed starch, sugars such as lactose, sucrose, glucose, dextrose, fructose, maltose, a suitable inorganic calcium salts such as dibasic calcium phosphate and calcium sulfate, polyols such as sorbitol, mannitol, lactitol, malitol and xylitol, or a combination thereof.
  • silicic acid e.g., Avicel®
  • starch pregelatimzed starch
  • sugars such as lactose, sucrose, glucose, dextrose, fructose, maltose
  • a suitable inorganic calcium salts such as dibasic calcium phosphate and calcium sulfate
  • polyols such as sorbitol, mannitol, lactitol, malitol and
  • a filler is selected from the group consisting of microcrystalline cellulose, starch, pregelatimzed starch, dextrose, sucrose, dibasic calcium phosphate, calcium sulfate, mannitol, or a combination thereof.
  • provided compositions comprise from about 10%> to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 85% filler, based upon total weight of the formulation.
  • provided compositions comprise from about 10%> to about 50%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10%> to about 40%> filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 30% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 25% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 20% to about 25% filler, based upon total weight of the formulation.
  • provided compositions comprise about 14%, about 15%, about 16%>, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29% or about 30% filler.
  • provided compositions comprise from about 40% to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 50% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 60% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 70% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 75% to about 85% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 78% to about 82% filler, based upon total weight of the formulation.
  • provided compositions comprise about 70%, about 71%), about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% filler.
  • the filler is microcrystalline cellulose.
  • provided compositions comprise from about 10% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 85% microcrystalline cellulose, based upon total weight of the formulation.
  • provided compositions comprise from about 10% to about 50% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 40% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 30% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 25% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 20% to about 25% microcrystalline cellulose, based upon total weight of the formulation.
  • provided compositions comprise about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%o, about 26%, about 27%, about 28%, about 29% or about 30% microcrystalline cellulose.
  • provided compositions comprise from about 40% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 50% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 60% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 70% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 75% to about 85% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 78% to about 82% microcrystalline cellulose, based upon total weight of the formulation.
  • provided compositions comprise about 70%, about 71%, about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%), about 89%), or about 90% microcrystalline cellulose.
  • Disintegrants comprise about 70%, about 71%, about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%), about 89%), or about 90% microcrystalline cellulose.
  • compositions for use in the present invention may further comprise one or more disintegrants.
  • Incorporation of suitable disintegrant(s) into provided compositions may facilitate breakdown of provided compositions.
  • inclusion of disintegrants may be particularly desired in provided compositions that contain active compound(s).
  • Suitable disintegrants include, but are not limited to, clays, agar, calcium carbonate, sodium carbonate, sodium bicarbonate, cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), starch, sodium carboxymethyl starch (sodium starch glycolate), calcium carboxymethyl cellulose, pregelatinized starch, microcrystalline cellulose, cross-linked polyvinylpyrrolidone (e.g., crospovidone), potato or tapioca starch, alginic acid, certain silicates, microcrystalline starch, water insoluble starch, magnesium aluminum silicate (Veegum) or a combination thereof.
  • a suitable disintegrants is selected from cross-linked polyvinylpyrrolidone, starch, pregelatinized starch, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, clay, or a combination thereof.
  • provided formulations comprise from about 1% to about 30% disintegrant, based upon total weight of the formulation. In some embodiments, provided formulations comprise from about 1% to about 25%, about 1% to about 20% disintegrant, about 1% to about 15% disintegrant, about 1% to about 10% disintegrant, about 2%) to about 8%) disintegrant, about 3% to about 7% disintegrant, or about 4% to about 6% disintegrant. In some embodiments, provided formulations comprise about 1%, about 2%, about 3%), about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% disintegrant, based upon total weight of the formulation. In certain embodiments, provided formulations comprise about 5% disintegrant, based upon total weight of the formulation.
  • a disintegrant in a provided composition is a cross-linked polymer such as cross-linked polyvinylpyrrolidone.
  • a disintegrant is cross-linked polyvinylpyrrolidone.
  • a disintegrant is cross-linked polyvinylpyrrolidone in an amount of about 1% to about 25%, about 1% to about 20% disintegrant, about 1% to about 15% disintegrant, about 1% to about 10% disintegrant, about 2%) to about 8%) disintegrant, about 3% to about 7% disintegrant, or about 4% to about 6%.
  • provided formulations comprise about 1%, about 2%, about 3%, about 4%), about 5%), about 6%, about 7%, about 8%, about 9%, or about 10% cross-linked polyvinylpyrrolidone, based upon total weight of the formulation.
  • compositions of the present invention may further comprise one or more glidants.
  • a glidant is a substance that is added to a powder to improve its flowability.
  • Such compounds include, without limitation, colloidal silica (also referred to as colloidal silicon dioxide), fumed silica, talc, starch, DL-leucine, metallic stearates such as sodium stearate, calcium stearate, zinc stearate and magnesium stearate, sodium lauryl sulfate, and the like, and combinations thereof.
  • provided compositions comprise from about 0.1% to about 3%) glidant, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 2.5%, or about 0.1% to about 2.0%>, or about 0.1%) to about 1.5%, or about 0.5% to about 1.5%, or about 0.8% to about 1.2% glidant. In certain embodiments, provided compositions comprise about 0.1%, about 0.2%>, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% glidant.
  • a glidant is colloidal silica.
  • provided compositions comprise from about 0.1 % to about 2.5%, or about 0.1 % to about 2.0%), or about 0.1 % to about 1.5%, or about 0.5% to about 1.5% colloidal silica, based on the total weight of the composition.
  • provided compositions comprise from about 0.5% to about 1.5% colloidal silica.
  • provided compositions comprise 1.0% colloidal silica. vii. Lubricants
  • compositions of the present invention may further comprise one or more lubricants.
  • Lubricants are agents added in small quantities to formulations to improve certain processing characteristics. For example, lubricants prevent the formulation mixture from sticking to the compression machinery and enhance product flow by reducing interparticulate friction.
  • Such compounds include, by way of example and without limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, boric acid, mineral oil, stearic acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, glyceryl behenate, magnesium lauryl sulfate, sodium lauryl sulfate, hydrogenated vegetable oil, glyceryl distearate, sodium stearyl fumarate, sodium oleate, fatty acids (e.g., palmitic and stearic acids) and other materials known to one of ordinary skill in the art.
  • fatty acids e.g., palmitic and stearic acids
  • provided compositions comprise from about 0.1% to about 3%) lubricant, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 2.5%, or about 0.1% to about 2.0%>, or about 0.1%) to about 1.5%, or about 0.5% to about 1.5%, or about 0.8% to about 1.2% lubricant. In certain embodiments, provided compositions comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% lubricant.
  • a lubricant is magnesium stearate.
  • provided compositions comprise from about 0.1% to about 2.5% magnesium stearate.
  • provided compositions comprise from about 0.1% to about 2.0% magnesium stearate.
  • provided compositions comprise from about 0.5%) to about 1.5% magnesium stearate.
  • provided compositions comprise about 1% magnesium stearate.
  • a provided composition comprises the following components:
  • a provided composition is any of those described below and herein, wherein the composition comprises compound 2. In certain embodiments, a provided composition is any of those described below and herein, wherein the composition comprises Form A of compound 2.
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components: (a) about 7.59% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • a provided composition comprises the following components:
  • provided formulations are prepared by dry blending compound 2 and excipients. Exemplary such methods are described below and in the Examples section.
  • a provided formulation is prepared by a process comprising:
  • provided formulations are prepared by dry blending compound 2 and excipients.
  • a provided formulation is prepared by a process comprising:
  • capsules are filled with the final blended powder.
  • the above procedure is used to prepare a capsule containing compound 2 in an amount of about 1 wt% to about 20 wt%, or from about 2 wt% to about 18 wt%, or from about 4 wt% to about 12 wt%, or from about 5 wt% to about 10 wt%, or from about 6 wt% to about 9 wt%, or from about 7 wt% to about 8 wt%. In certain embodiments, the above procedure is used to prepare a capsule containing compound 2 in an amount of about 7.59 wt%.
  • a provided formulation is prepared by a process comprising:
  • a provided formulation is prepared by a process comprising:
  • a provided formulation is prepared by a process comprising:
  • a provided formulation is prepared by a process comprising:
  • capsules are filled with the final blended powder.
  • the above procedure is used to prepare a capsule containing compound 2 in an amount of about 20 wt% to about 60 wt%, or from about 25 wt% to about 55 wt%, or from about 30 wt% to about 50 wt%, or from about 35 wt% to about 50 wt%, or from about 40 wt% to about 50 wt%, or from about 41 wt% to about 49 wt%, or from about 42 wt% to 48 wt%, or from about 43 wt% to 47 wt%, or from about 44 wt% to about 46 wt%, or from about 45 wt% to about 46 wt%.
  • the above procedure is used to prepare a capsule containing compound 2 in an amount of about 45.53 wt%.
  • a tablet or capsule is typically a unit dosage form.
  • the unit dosage forms described herein refer to an amount of compound 1, i.e. the free base form of the active pharmaceutical ingredient, which may be provided as the free base or as a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprises a salt form of compound 1, for example the phosphate salt form referred to herein as compound 2
  • the amount of the salt form present in the composition is an amount that is equivalent to a unit dose of free base compound 1.
  • a pharmaceutical composition comprising compound 2 would contain 6.07 mg of compound 2 necessary to deliver an equivalent 5 mg unit dose of the free base compound 1.
  • a unit dosage form contains 5 mg compound 1.
  • a unit dosage form contains 30 mg compound 1.
  • a unit dosage form contains 150 mg compound 1.
  • Provided formulations may be administered to a patient one or more times daily, as required to provide an effective amount of compound 1.
  • one or more unit dosage forms of a provided formulation may be administered to a patient in a single day.
  • a unit dose of compound 1, or a pharmaceutically acceptable salt thereof is administered once a day (QD).
  • a unit dose of compound 1, or a pharmaceutically acceptable salt thereof is administered twice a day (BID).
  • two or more different unit doses are administered to provide a therapeutically effective amount of compound 1.
  • a 180 mg dose of compound 1 can be administered as one 150 mg unit dose and one 30 mg unit dose. It will be appreciated that such unit doses can be administered at the same time or at different times during a day.
  • the present invention provides a method for treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more unit doses of a provided formulation.
  • the present invention provides a method of treating an ERKl and/or ERK2- mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides about 5, 30, or 150 mg of compound 1.
  • the amount of compound 1 is provided in the form of compound 2, e.g., Form A of compound 2.
  • the present invention provides a method of treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides any amount of compound 1 described above and herein.
  • the present invention provides a method for treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more unit doses of a provided formulation. In some embodiments, the present invention provides a method of treating an ERKl and/or ERK2- mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides about 5 mg to about 1000 mg of compound 1.
  • a formulation of the present invention provides about 1 mg, 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650
  • the present invention provides a method of treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides about 5 mg, 30 mg, or 150 mg of compound 1.
  • a capsule formulation of the present invention provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of compound 1.
  • the present invention provides a method of treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules comprising compound 1 in the form of compound 2, Form A.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that it is effective to measurably inhibit one or both of ERKl and ERK2, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • a "pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of one or both of ERKl and ERK2, or a mutant thereof.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • compound 1, and pharmaceutically acceptable salts thereof described herein is an inhibitor of one or both of ERKl and ERK2.
  • ERK is one of the key components in the RAS-RAF-MEK- ERK MAPK pathway and that ERKl and ERK2 are downstream nodes within the MAPK pathway.
  • an ERK inhibitor can treat disease or disorders in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERKl and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek).
  • ERK is a downstream target
  • ERK inhibitors are believed to be able to overcome, in some instances, drug resistance induced by inhibitors of targets upstream of ERK within the MAPK pathway.
  • RAF or MEK utilized in the treatment of K-RAS and B-RAF mutant tumors have resulted in such drug resistance.
  • drug resistance has been associated with other tumors driven by hyperactivation of the MAPK pathway (such as NF1 mutant tumors).
  • Kinase selectivity was achieved through silencing the selective Cys in a combination of the interactions between the covalent inhibitors of the invention and unique amino acids in the ATP binding pocket. Targeting the selective Cys provides for prolonged pharmacodynamics in silencing ERK activity, as well as potential lower doses in cancer treatment, compared to reversible inhibitors.
  • the activity of compound 1, and pharmaceutically acceptable salts thereof, as an inhibitor of one or both of an ERKl and ERK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of downstream phosphorylation, changes in gene expression, subsequent functional markers and consequences, and/or kinase activity of one or both of activated ER 1 and ERK2 kinase, or a mutant thereof. Alternate in vitro assays quantitate the ability of the test compound to bind to one or both of ER 1 and ERK2.
  • Test compound binding may be measured by radiolabeling the test compound prior to binding, isolating one or both of the compound / ERK1 complex and the compound / ERK2 complex, and determining the amount of radiolabel bound.
  • test compound binding may be determined by running a competition experiment where test compounds are incubated with one or both of ERK1 and ERK2 kinase bound to known radioligands.
  • Test compound binding may be determined by competition with an ERK covalent probe that is amenable to further functionalization with a detection probe, such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification
  • the term "measurably inhibit”, as used herein means a measurable change in one or both of ERKl and ERK2 protein kinase activity between a sample comprising a provided composition, and one or both of an ERKl and ERK2 protein kinase and an equivalent sample comprising one or both of ERKl and ERK2 protein kinase in the absence of a provided composition.
  • Such measurements of protein kinase activity are known to one of ordinary skill in the art and include those methods set forth herein below and/or in the Examples of the '230 publication.
  • compound 1, and pharmaceutically acceptable salts thereof is an inhibitor of one or both of ERKl and ERK2 protein kinases, and ERKl and ERK2 are downstream targets within the MAPK pathway.
  • such compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role.
  • Such disease, condition, or disorder may be referred to herein as associated with the MAPK pathway or alternatively as associated with one or both of ERKl and ERK2.
  • Such diseases, conditions, or disorders may also be referred to herein as an "ERKl- or ERK2 -mediated disease, condition, or disorder.”
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK), including one or both of ERKl and ERK2 protein kinases, is implicated in said disease, condition, or disorder, wherein said method comprises administering to a patient in need thereof a compound of the present invention.
  • the present invention relates to a method of inhibiting one or both of ER 1 and ERK2 protein kinase activity in a patient comprising the step of administering to said patient a composition comprising a compound of the present invention.
  • the present invention provides a method for treating a disease, condition, or disorder mediated by one or both of ERK1 and ERK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound of the present invention.
  • the present invention provides a method for overcoming drug resistance to Raf or MEK inhibitors, comprising the step of administering to a patient an inhibitor compound of one or both of ER l and ERK2, such as a compound of the present invention.
  • the mechanism of drug resistance is through mutation of a target protein or reactivation of the MAPK pathway.
  • the term “resistance” may refer to changes in a wild-type nucleic acid sequence coding a target protein, and/or to the amino acid sequence of the target protein and/or to the amino acid sequence of another protein, which changes, decreases or abolishes the inhibitory effect of the inhibitor on the target protein.
  • the term “resistance” may also refer to overexpression or silencing of a protein differing from a target protein that can reactivate the MAPK pathway or other survival pathways.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment is administered after one or more symptoms have developed.
  • treatment is administered in the absence of symptoms.
  • treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2 comprising administering to a patient in need thereof a composition comprising a compound of the present invention.
  • General diseases, conditions, or disorders treated by a compound of the present invention include cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, liver disease, a cardiac disorder, schizophrenia, or a bone-related disorder.
  • the present invention relates to a method of treating or lessening the severity of a disease, condition, or disorder selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone- related diseases, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention.
  • the cancer is recurring.
  • the cancer is refractory.
  • the cancer is metastatic.
  • the cancer is locally advanced.
  • the cancer is a RAF inhibitor-resistant cancer.
  • the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
  • the cancer is a MEK inhibitor-resistant cancer.
  • the cancer is a MAPK pathway-mediated cancer.
  • the cancer is a BRAF -mutated cancer.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF
  • the cancer is a RAS-mutated cancer.
  • the RAS-mutated involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS , KRAS G13C/D , or KRAsQeiL/H/R Jn certain embodiments, the RAS-mutated cancer is an
  • NRAS-mutated cancer including, but not limited to, NRAS Q61R , NRAS Q61K , NRAS Q61L , or NRAS ⁇ 61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular carcinoma (HCC)) and biliary passage carcinoma), kidney carcinoma,
  • HCC hepato
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-hodgkins lymphoma.
  • a lymphoma is large cell immunoblastic lymphoma.
  • the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; esophogeal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung,
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non- small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia.
  • a leukemia is acute lymphoblastic leukemia.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is melanoma.
  • the melanoma is uveal melanoma.
  • the melanoma is a melanoma of the skin.
  • the melanoma is locally advanced.
  • the melanoma is metastatic.
  • the melanoma is recurring.
  • the melanoma is BRAF v60 °- mutated melanoma.
  • the melanoma is a RAS-mutated melanoma. In some embodiments, the melanoma is NRAS-mutated melanoma. In certain embodiments, the melanoma is wild type for KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAF inhibitor-resistant (e.g., Vemurfenib-resistant, dabrafenib-resistant, etc.) melanoma. In certain embodiments, the cancer is a VemR (i.e., Vemurfenib-resistant) BRAF-mutated melanoma. In some embodiments, the melanoma is relapsed. In some embodiments, the melanoma is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is colorectal cancer.
  • the colorectal cancer is locally advanced.
  • the colorectal cancer is metastatic.
  • the colorectal cancer is a BRAF-mutated colorectal cancer.
  • the colorectal cancer is a BRAF v600 -mutated colorectal cancer.
  • the colorectal cancer is a RAS-mutated colorectal cancer.
  • the colorectal cancer is a KRAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a NRAS-mutated colorectal cancer. In some embodiments, the colorectal cancer is relapsed. In some embodiments, the colorectal cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is pancreatic cancer.
  • the pancreatic cancer is locally advanced.
  • the pancreatic cancer is metastatic.
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
  • the pancreatic cancer is a RAS-mutated pancreatic cancer.
  • the pancreatic cancer is a KRAS-mutated pancreatic cancer.
  • the pancreatic cancer is KRAS-mutated pancreatic cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the pancreatic cancer is relapsed.
  • the pancreatic cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a papillary thyroid cancer.
  • the papillary thyroid cancer is locally advanced.
  • the papillary thyroid cancer is metastatic.
  • the papillary thyroid cancer is recurring.
  • the papillary thyroid cancer is BRAF-mutated papillary thyroid cancer.
  • the papillary thyroid cancer is BRAF v600 -mutated papillary thyroid cancer.
  • the papillary thyroid cancer is relapsed.
  • the papillary thyroid cancer is refractory.
  • the papillary thyroid cancer includes undifferentiated or dedifferentiated histology.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is locally advanced.
  • the lung cancer is metastatic.
  • the lung cancer is a RAS-mutated lung cancer.
  • the lung cancer is KRAS-mutated lung cancer.
  • the lung cancer is a KRAS-mutated lung cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the lung cancer is relapsed.
  • the lung cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a leukemia.
  • a leukemia is a chronic leukemia.
  • a leukemia is chronic myeloid leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia (AML).
  • AML acute monocytic leukemia
  • AML-M5 acute lymphoblastic leukemia
  • a leukemia is acute T cell leukemia. In certain embodiments, a leukemia is myelomonoblastic leukemia. In certain embodiments, a leukemia is human B cell precursor leukemia. In certain embodiments, a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a CNS cancer, for instance CNS tumors.
  • a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is multiple myeloma (MM).
  • the multiple myeloma is locally advanced.
  • the multiple myeloma is metastatic.
  • the multiple myeloma is a RAS-mutated multiple myeloma.
  • the multiple myeloma is KRAS-mutated multiple myeloma.
  • the multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS , KRAS ⁇ u , or KRAS y
  • the multiple myeloma is relapsed. In some embodiments, the multiple myeloma is refractory.
  • the present invention relates to a method of treating a cancer, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the HCC is locally advanced.
  • the HCC is metastatic.
  • the HCC is a RAS- mutated HCC.
  • the HCC is KRAS-mutated HCC.
  • the HCC is a KRAS-mutated HCC, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the hepatocellular carcinoma is relapsed.
  • the hepatocellular carcinoma is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • a composition comprising a compound of the present invention, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • Step 1 N-(2-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)5- methylphenyl)acrylamide (Intermediate 1)
  • Step 2 can be carried out by adding Intermediate 1 to a suitable coupling partner in the presence of Na 2 C0 3 , a degassed solvent (e.g., tert-amyl alcohol), a suitable palladium catalyst (e.g., tris-dibenzylamino dipalladium) and a suitable phosphine ligand (e.g., Dave Phos) under conditions suitable to effect coupling.
  • a degassed solvent e.g., tert-amyl alcohol
  • a suitable palladium catalyst e.g., tris-dibenzylamino dipalladium
  • a suitable phosphine ligand e.g., Dave Phos
  • the present invention provides, inter alia, oral dosage forms (e.g., capsules) of compound 2. It has been unexpectedly found that the inclusion of certain ingredients in oral dosage forms of compound 2 significantly improve capsule performance by, for instance, improving, solubility of compound 2, minimizing gelling tendency of compound 2 in wet environments, and/or improving dispersion of compound 2.
  • solubility and dispersion are improved by adding an amount of each of Captisol USP, sodium lauryl sulfate, and sodium bicarbonate in a capsule.
  • Exemplary such formulations are described further below and herein.
  • Form A of compound 2 was prepared as follows.
  • Procedure A Compound 1 was dissolved in 15x tetrahydrofuran. One molar equivalent of 2 molar phosphoric acid in acetonitrile was charged. The batch was slurried at 20 °C for 1 to 2 hours. The solvent was removed under reduced pressure. The resulting solids were slurried in acetone for about 16 hours at 20 °C, filtered and dried.
  • Procedure B Compound 1 was dissolved in THF. Equal molar equivalent of 1.08 M phosphoric acid in acetonitrile was charged. The sample was shaken at ambient temperature at 200 RPM for 1 hour. The solvent was removed under nitrogen purge. The resulting solids were slurried in acetone with a stirring bar at ambient temperature overnight, then filtered and dried in vacuum oven at 30 °C overnight.
  • Procedure C Compound 1 was dissolved in THF (20x vol) at 20 °C. Seeds of compound 2 Form A (5% wt) were charged. A I M solution of phosphoric acid (1 mol eq.) in ethanol was charged. The batch was left under vigorous agitation for two hours. Solvent exchange to isopropyl acetate was carried out with a constant volume distillation under reduced pressure, with temperature not exceeding 40 °C. The batch was cooled to 20 °C. The solvent was removed under nitrogen purge. The batch was filtered, washed two times with isopropyl acetate and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure D Compound 1 was dissolved in 9x vol THF/ H 2 0 (95:5 vol). A solution of H 3 PO 4 (1.2 mol eq.) in ethanol was charged to a second flask, seeds of compound 2 form A (5%) were charged and vigorous agitation was started. The solution of compound 1 was charged to the H 3 PO 4 solution (reverse addition) over one hour. The slurry was aged for one hour. Solvent exchange to ethanol was started (constant volume vacuum distillation with continuous addition of ethanol, final THF NMT 0.5%). The batch was cooled to 20 °C, filtered and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure E Compound 1 was dissolved in lOx vol THF/H 2 0 (95:5 vol). Isopropyl alcohol (5x vol) was charged. Constant volume distillation, with continuous addition of isopropyl alcohol was started at atmospheric pressure. Solvent exchange was carried out until THF content was below 5%. Compound 1 recrystallized during the solvent exchange. The batch was cooled to 30 °C. A 1M solution of H 3 PO 4 in IPA was charged over 2 hours. Seeds of compound 2 Form A (1%) were then charged. The batch was stirred vigorously overnight. The batch was filtered and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure F Compound 1 was dissolved in 9x vol THF/H 2 0 (95:5 vol). After polish filtration, distillation to reduce volume from 9x to 5x was performed, followed by addition of 8x ethyl acetate to bring the total volume to 13x. Solvent exchange to ethyl acetate, with constant volume distillation was carried out (final THF NMT 2%). The temperature was then reduced to 30 °C. Seeds of compound 2 (1% wt) were charged. A solution of H 3 PO 4 (1.2 eq.) in ethanol (5x) was then dosed in over 2 hours. The temperature was reduced to 20 °C, the batch was aged for 12 hours under vigorous stirring, then filtered, washed two times with ethyl acetate and dried in a vacuum oven at ⁇ 40 °C overnight, under vacuum with nitrogen bleed.
  • Procedure G Compound 1 was charged to a reactor, then ethanol (4x vol) and ethyl acetate (6x), were charged. The batch was agitated at 30 °C. A solution of H 3 PO 4 (1.2 mol eq.) in ethanol (2x vol) was charged over 2 hours. Seeds of compound 2 Form A (1%) were charged. The batch was filtered, washed two times with ethyl acetate, dried overnight at -40 °C, under vacuum with nitrogen bleed.
  • Figure 1 depicts an XRPD pattern of Form A of compound 2.
  • a first formulation comprising compound 1 (freebase) in a vehicle of 5% SBE betacyclodextrin (e.g., Captisol ® ) and 0.2% polysorbate 80 (Tween 80) was developed. This formulation provided sufficient exposure of compound 1 in dogs. After salt selection, it was found that the compound 2 (phosphate salt) had much better solubility in Captisol solution and sodium lauryl sulfate (SLS) solution. (See Figures 5 and 6)
  • Table 5 shows the pharmacokinetic results of (1) compound 2 in two different vehicles when administered to dogs at fasted state (see columns 3 and 4); (2) compound 2 formulated with different concentrations of SBE betacyclodextrin (see columns 5 and 6); and (3) food effects when compound 2 is administered in an SBE betacyclodextrin formulation to either fasted or fed dogs (columns 4 and 5).
  • the first formulation was a capsule containing only compound 2.
  • the second formulation contained SBE betacyclodextrin (Captisol ® ) (see Table 6, below).
  • the third formulation contained citric acid (see Table 6, below). Both the SBE betacyclodextrin formulation and citric acid formulation were prepared using a wet granulation process.
  • a liquid phase was prepared for each formulation by weighing out SLS and PVP (SBE betacyclodextrin formulation) or citric acid and PVP (citric acid formulation) into a 6 mL vial and adding to each an amount of 0.5 mL water.
  • SLS and PVP SBE betacyclodextrin formulation
  • citric acid and PVP citric acid formulation
  • a solid phase was prepared for each formulation by weighing out and mixing compound 2 and all remaining excipients except for magnesium stearate. Each dry blend was then sieved three times through a 35 mesh (500 ⁇ ) and transferred to its own mortar.
  • a liquid phase was added to each mortar, with constant stirring. Once the liquid and solid phases were well mixed, the resulting mixtures were sieved through a 14 mesh (1410 ⁇ ) and dried at 60 °C for one hour. The dried mixtures were then sieved through a 20 mesh (841 ⁇ ). Magnesium stearate was then added to each formulation and mixed lightly. 400 mgs of each formulation were then weighed into separate capsules.
  • Example 3 Formulations for Dog PK Study [00226] As the citric acid formulation had poor dissolution, citric acid was replaced with sodium chloride in the formulations for dog PK comparison study. Three formulations were prepared according to the method described above. The first formulation contained only compound 2 in a capsule. The second formulation contained SBE betacyclodextrin (e.g., Captisol ®) (see Table 7, below). The third formulation contained sodium chloride (see Table 7, below).
  • SBE betacyclodextrin e.g., Captisol ®
  • the third formulation contained sodium chloride (see Table 7, below).
  • Dosing group 1 tests a suspension of compound 2 in 5% SBE betacyclodextrin and 0.2% polysorbate; dosing group 2 tests a suspension of compound 2 in 5% SBE betacyclodextrm and 0.2% polysorbate; dosing group 3 tests a capsule of compound 2 only; dosing group 4 tests a capsule of compound 2 and 20% SBE betacyclodextrm as described in Table 7; and dosing group 5 tests a capsule of compound 2 and 10%> NaCl as described in Table 7.
  • Table 7 The results shown in Figure 7 are also displayed in Tables 8 and 9.
  • lipid Phospholipon 90H
  • Table 12 Based on positive food effect information, a lipid (Phospholipon 90H) was added to the formulation, and the formulation was again prepared using a wet granulation process and a dry process for comparative purposes as shown in Table 12.
  • Sodium lauryl sulfate, sodium bicarbonate and betadex sulfobutyl ether sodium were combined together and mixed. Blended into this mixture was compound 2, Crospovidone, microcrystalline cellulose, and colloidal silicon dioxide. The resulting mixture was blended in a blender for about 250 revolutions and then screened. The screened mixture was again blended in a blender for about 400 revolutions. Magnesium stearate was added to the blend and blended for about 60 revolutions. 80 mg of the final blend were added into each size 4 gelatin capsule.
  • Sodium lauryl sulfate, sodium bicarbonate and Crospovidone were combined together and mixed. Blended into this mixture was compound 2, betadex sulfobutyl ether sodium, microcrystalline cellulose, and colloidal silicon dioxide. The resulting mixture was blended in a blender for about 250 revolutions and then screened. The screened mixture was again blended in a blender for about 400 revolutions. Magnesium stearate was added to the blend and blended for about 60 revolutions. 80 mg of the final blend were added into each size 4 gelatin capsule.
  • Sodium lauryl sulfate, sodium bicarbonate and Crospovidone were combined together and mixed. Blended into this mixture was compound 2, betadex sulfobutyl ether sodium, microcrystalline cellulose, and colloidal silicon dioxide. The resulting mixture was blended in a blender for about 250 revolutions and then screened. The screened mixture was again blended in a blender for about 400 revolutions. Magnesium stearate was added to the blend and blended for about 60 revolutions. 400 mg of final blend were added into each size 0 gelatin capsule.

Abstract

The present invention provides pharmaceutical formulations comprising an ERK inhibitor.

Description

ORAL FORMULATIONS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. provisional application number 62/037,078, filed August 13, 2014, the entirety of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention provides various formulations and compositions comprising a compound useful as an inhibitor of ER kinases, for example one or both of ER 1 and ERK2 kinases.
BACKGROUND OF THE INVENTION
[0003] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.
[0004] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
[0005] The processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase. Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates one or both of ERKl and ERK2. When activated, one or both of ERKl and ERK2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation. The ERK MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors. Ras genes, which are upstream of one or both of ERKl and ERK2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors. In addition, mutations of BRAF, a serine- threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers.
[0006] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.
SUMMARY OF THE INVENTION
[0007] PCT patent application serial number PCT/US14/15256, filed February 7, 2014 and published as WO 2014/124230 on August 14, 2014 ("the '230 publication," the entirety of which is hereby incorporated herein by reference), describes certain ERK inhibitor compounds which covalently and irreversibly inhibit activity of one or both of ERKl and ERK2 kinases. Such compounds include compound 1:
Figure imgf000003_0001
1 or a pharmaceutically acceptable salt thereof.
[0008] Compound 1, N-(2-((2-((2-methoxy-5-methylpyridin-4-yl)amino)-5-
(trifluoromethyl)pyrimidin-4-yl)amino)-5-methylphenyl)acrylamide, is designated as compound number 1-90 in the '230 publication and the synthesis of compound 1 is described in detail at Example 94 of the '230 publication, and is reproduced herein for ease of reference.
[0009] Compound 1 is active in a variety of assays and therapeutic models demonstrating covalent, irreversible inhibition of one or both of ERKl and ERK2 kinases (see, e.g., Table A of the '230 publication). Accordingly, compound 1 is useful for treating one or more disorders associated with activity of one or both of ERKl and ERK2. [0010] In some embodiments, the present invention provides formulations for oral administration comprising a composition which comprises compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, such formulations for oral administration are capsule formulations.
[0011] In general, provided formulations for oral administration comprise a composition which comprises compound 1, or a pharmaceutically acceptable salt thereof, and further comprises one or more excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof, as discussed below.
[0012] In some embodiments, the present invention provides a unit dosage form comprising a provided formulation.
[0013] As described above and herein, in some embodiments, the present invention provides a pharmaceutically acceptable salt of compound 1. For instance, in some embodiments the present invention provides a phosphate salt of compound 1, depicted below and referred to herein as com ound 2:
Figure imgf000004_0001
compound 2
[0014] In some embodiments, the present invention provides an amorphous form of compound 2. In some embodiments, the present invention provides a crystalline form of compound 2. In certain embodiments, such crystalline forms are selected from Form A, Form B, Form C, or Form D of compound 2. In certain embodiments, such a crystalline form is Form A of compound 2.
[0015] The present invention also provides methods of preparing provided formulations. Such formulations are useful, among other things, for administration of compound 1, or a pharmaceutically acceptable salt thereof, in any context in which such delivery is desirable.
[0016] For example, provided formulations are useful for treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with one or both of ER 1 and ERK2. Such formulations are also useful for administration to subjects suffering from a disease or disorder associated with one or both of ERK1 and ERK2. [0017] In certain embodiments, the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases and conditions associated with one or both of ERKl and ERK2 comprising the step of administering to the subject a provided formulation, as described herein. Such disorders or conditions include, among others, proliferative diseases such as cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 depicts an XRPD pattern of Form A of compound 2.
[0019] Figure 2 depicts an XRPD pattern of Form B of compound 2.
[0020] Figure 3 depicts an XRPD pattern of Form C of compound 2.
[0021] Figure 4 depicts an XRPD pattern of Form D of compound 2.
[0022] Figure 5 contains a graph depicting the solubility enhancement of Compound 2 in the presence of SBE betacyclodextrin (e.g., Captisol®).
[0023] Figure 6 contains a graph depicting the solubility enhancement of Compound 2 in the presence of sodium lauryl sulfate (SLS).
[0024] Figure 7 contains graphed PK data for dogs under fed state.
[0025] Figure 8 contains a graph depicting the effect of sodium bicarbonate on dissolution of a 150 mg capsule containing a Compound 2 formulation.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
Definitions:
[0026] As used herein, the term "about", when used in reference to the amount of one or more components in a provided formulation, refers to the stated value ± 10%.
[0027] As used herein, the term "amorphous substantially free of crystalline forms" refers to a composition containing compound 1 or compound 2, in which less than 20% (w/w) of the compound 1 or compound 2 is present in a crystalline form (e.g., less than 15%, 12%, 10%, 8%, 5%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.01% (w/w) of Compound 1 or Compound 2 is present in a crystalline form). The crystalline content of a composition can be assessed using x-ray diffraction techniques.
[0028] As used herein, a "disease or disorder associated with one or both of ERKl and ERK2" means any disease or other deleterious condition in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role. Accordingly, another embodiment of the present invention relates to preventing, treating, stabilizing or lessening the severity or progression of one or more diseases in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role. Specifically, the present invention relates to a method of treating or lessening the severity of a proliferative disorder, wherein said method comprises administering to a patient in need thereof compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.
[0029] As used herein the term "non-functional coating" is a coating that does not significantly affect release characteristic(s) of a therapeutically active compound or compounds from a formulation when administered. Examples of a non-functional coat include a seal coat (e.g., hydroxypropyl cellulose, hypromellose or polyvinyl alcohol). In certain embodiments, a non-functional coating is a polish coat or seal coat.
[0030] As used herein, the term "polymorph" refers to the different crystal structures (of unsolvated forms) in which a compound can crystallize. As used herein, the term "solvate" refers to a crystal form with either a stoichiometric or non-stoichiometric amount of solvent that is incorporated into the crystal structure. Similarly, the term "hydrate" refers to a crystal form with either a stoichiometric or non-stoichiometric amount of water that is incorporated into the crystal structure.
[0031] The term "subject", as used herein, means a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.).
[0032] The terms "suffer" or "suffering" as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have.
[0033] "Therapeutically active agent" or "active agent" refers to a substance, including a biologically active substance, that is useful for therapy (e.g., human therapy, veterinary therapy), including prophylactic and therapeutic treatment. Therapeutically active agents include organic molecules that are drug compounds, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, small molecules linked to a protein, glycoprotein, steroid, nucleic acid, DNA, RNA, nucleotide, nucleoside, oligonucleotides, antisense oligonucleotides, lipid, hormone, and vitamin. Therapeutically active agents include any substance used as a medicine for treatment, prevention, delay, reduction or amelioration of a disease, condition, or disorder. Among therapeutically active agents useful in the formulations of the present invention are BTK inhibitors, and the like. Further detailed description of compounds useful as therapeutically active agents is provided below. A therapeutically active agent includes a compound that increases the effect or effectiveness of a second compound, for example, by enhancing potency or reducing adverse effects of a second compound.
[0034] As used herein, a "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition. In some embodiments, a "therapeutically effective amount" is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms of a disorder or condition associated with one or both of ER 1 and ERK2.
[0035] The terms "treat" or "treating," as used herein, refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition. As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.
[0036] The expression "unit dosage form" as used herein refers to a physically discrete unit of a provided formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
/. Solid Forms of Compound 2
A. Compound 2
[0037] As described above, in some embodiments provided compositions, and formulations thereof, comprise the phosphate salt of compound 1, which salt is depicted below and referred to herein as com ound 2:
Figure imgf000008_0001
compound 2.
[0038] It will be appreciated by one of ordinary skill in the art that the phosphoric acid and compound 1 are ionically bonded to form compound 2. It is contemplated that compound 2 can exist in a variety of physical forms. For example, compound 2 can be in solution, suspension, or in solid form. In certain embodiments, compound 2 is in solid form. When compound 2 is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. In some embodiments, compound 2 is anhydrous. In some embodiments, compound 2 is a hydrate. In some embodiments, compound 2 is a solvate. In some embodiments, compound 2 is a dehydrate. In some embodiments, compound 2 is a desolvate. Exemplary solid forms are described in more detail below.
[0039] In some embodiments, the present invention provides compound 2 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess phosphoric acid, excess compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2. In certain embodiments, at least about 95% by weight of compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of compound 2 is present.
[0040] According to one embodiment, compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 2 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, compound 2 contains no more than about 1.0% are percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[0041] The structure depicted for compound 2 is also meant to include all tautomeric forms of compound 2. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
[0042] It has been found that compound 2 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
[0043] In certain embodiments, compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound contains no significant amount of amorphous compound 2. In certain embodiments, at least about 95% by weight of crystalline compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 2 is present.
[0044] It has been found that compound 2 can exist in at least four distinct polymorphic forms. In some embodiments, the present invention provides a polymorphic form of compound 2 referred to herein as Form A. In certain embodiments, the present invention provides a polymorphic form of compound 2 referred to herein as Form B. In certain embodiments, the present invention provides a polymorphic form of compound 2 referred to herein as Form C. In certain embodiments, the present invention provides a polymorphic form of compound 2 referred to herein as Form D.
[0045] In some embodiments, compound 2 is amorphous. In some embodiments, compound 2 is amorphous, and is substantially free of crystalline compound 2.
[0046] Such solid forms, or polymorphs, include Forms A-D, described below.
Form A of Compound 2
[0047] In some embodiments, Form A of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
Table 1 - XRPD Peak Positions for Form A of Compound 2
Figure imgf000010_0001
1 In this and all subsequent tables,
the position 2d? is within ± 0.2.
[0048] In some embodiments, Form A of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1 , and 20.8. In some embodiments, Form A of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1 , and 20.8. In some embodiments, Form A of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 6.8, 10.1 , and 20.8.
[0049] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1. Form B of Compound 2
[0050] In some embodiments, Form B of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
Table 2 - XRPD Peak Positions for Form B of Compound 2
Figure imgf000011_0001
1 In this and all subsequent tables,
the position 2d? is within ± 0.2.
[0051] In some embodiments, Form B of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0. In some embodiments, Form B of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0. In some embodiments, Form B of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 3.6, 7.3, and 15.0.
[0052] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 2.
Form C of Compound 2
[0053] In some embodiments, Form C of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below. Table 3 - XRPD Peak Positions for Form C of Compound 2
Figure imgf000012_0001
1 In this and all subsequent tables,
the position 2d? is within ± 0.2.
[0054] In some embodiments, Form C of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5. In some embodiments, Form C of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5. In some embodiments, Form C of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 8.4, 9.3, and 16.5.
[0055] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 3.
Form D of Compound 2
[0056] In some embodiments, Form D of compound 2 has at least 1 , 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
Table 4 - XRPD Peak Positions for Form D of Compound 2
Figure imgf000013_0001
1 In this and all subsequent tables,
the position 2d? is within ± 0.2.
[0057] In some embodiments, Form D of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.1 , 10.4, and 25.1. In some embodiments, Form D of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.1 , 10.4, and 25.1. In some embodiments, Form D of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 9.1 , 10.4, and 25.1.
[0058] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 4.
77. Oral Formulations
A. Compound 2
[0059] In some embodiments, a provided composition, or formulation thereof, comprises from about 1% to about 60% compound 2, based upon total weight of given composition or formulation (wt %). In some embodiments, a provided composition, or formulation thereof, comprises from about 1 wt% to about 50 wt% compound 2.
[0060] In some embodiments, a provided composition, or formulation thereof, comprises from about 1 wt% to about 20 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 2 wt% to about 18 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 4 wt% to about 12 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 5 wt% to about 10 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 6 wt% to about 9 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 7 wt% to about 8 wt% compound 2. In certain embodiments, a provided composition, or formulation thereof, comprises about 7.59 wt% compound 2.
[0061] In some embodiments, a provided composition, or formulation thereof, comprises from about 20 wt% to about 60 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 25 wt% to about 55 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 30 wt% to about 50 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 35 wt% to about 50 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 40 wt% to about 50 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 41 wt% to about 49 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 42 wt% to about 48 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 43 wt% to about 47 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 44 wt% to about 46 wt% compound 2. In some embodiments, a provided composition, or formulation thereof, comprises from about 45 wt% to about 46 wt% compound 2. In certain embodiments, a provided composition, or formulation thereof, comprises about 45.53 wt% compound 2.
[0062] In some embodiments, the present invention provides a solid formulation comprising compound 2 and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, or combinations thereof, as discussed below. B. Other Components
[0063] In certain embodiments, the present invention provides a composition comprising compound 2 Form A and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants. In some embodiments, a pharmaceutically acceptable composition is a blended powder.
[0064] In certain embodiments, the present invention provides a composition comprising compound 2 Form B and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants. In some embodiments, the pharmaceutically acceptable composition is a blended powder.
[0065] In certain embodiments, the present invention provides a composition comprising compound 2 Form C and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants. In some embodiments, the pharmaceutically acceptable composition is a blended powder.
[0066] In certain embodiments, the present invention provides a composition comprising compound 2 Form D and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants. In some embodiments, the pharmaceutically acceptable composition is a blended powder.
[0067] In certain embodiments, the present invention provides a composition comprising compound 1 (free base) and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants. In some embodiments, the pharmaceutically acceptable composition is a blended powder.
[0068] In certain embodiments, the present invention provides a composition comprising a salt form of compound 1 other than compound 2, and one or more pharmaceutically acceptable excipients, such as, for example, one or more solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants and lubricants. Exemplary such salt forms of compound 1 include HCl salt forms, HBr salt forms, bis-phosphate salt forms, sulfate salt forms, bis-sulfate salt forms, tosylate salt forms, mesylate salt forms, besylate salt forms, maleate salt forms, and oxalate salt forms. [0069] One skilled in the art will readily appreciate that the category under which a particular component is listed is not intended to be limiting; in some cases a particular component might appropriately fit in more than one category. Also, as will be appreciated, the same component can sometimes perform different functions, or can perform more than one function, in the context of a particular formulation, for example depending upon the amount of the ingredient and/or the presence of other ingredients and/or active compound(s). i. Solubilizers
[0070] In certain embodiments, provided formulations may comprise one or more solubilizers. Solubilizers include, by way of example and without limitation, cyclodextrins such as alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, hydroxymethyl cyclodextrin, hydroxyethyl cyclodextrin, and hydroxybutyl cyclodextrin, carboxymethyl cyclodextrin, carboxyethyl cyclodextrin, carboxypropyl cyclodextrin, carboxybutyl cyclodextrin, methylcarboxymethyl cyclodextrin; amino cyclodextrin, sulfobutyl-ether- -cyclodextrin sodium salt ("SBECD", also referred to herein as betadex sulfobutyl ether sodium, sulfobutylether betacyclodextrin, or SBE betacyclodextrin), and the like, and combinations thereof. In certain embodiments, the solubilizer is sulfobutyl-ether- -cyclodextrin sodium salt.
[0071] In some embodiments, provided compositions comprise from about 1% to about 50% solubilizer, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 1% to about 45%, or about 1% to about 40%, or about 1%) to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20% solubilizer based on the total weight of the composition.
[0072] In certain embodiments, provided compositions comprise about 1% to about 10% solubilizer, based on the total weight of composition. In certain embodiments, provided compositions comprise about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%), or about 1% to about 6%, or about 1% to about 5%, or about 2% to about 4% solubilizer based on the total weight of the composition. In some embodiments, provided compositions comprise a solubilizer in an amount of about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%), about 2.9%, about 3.0%>, about 3.1%>, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%), about 3.7%, about 3.8%, about 3.9%>, or about 4.0%. In certain embodiments, provided compositions comprise a solubilizer in an amount of about 3.33%.
[0073] In certain embodiments, provided compositions comprise about 10%> to about 30%) solubilizer, based on the total weight of composition. In certain embodiments, provided compositions comprise about 10%> to about 25%, or about 15% to about 25%, or about 17% to about 23%), or about 18% to about 22%, or about 19% to about 21% solubilizer based on the total weight of the composition. In some embodiments, provided compositions comprise a solubilizer in an amount of about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%), about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%), about 38%), about 39%, or about 40%. In certain embodiments, provided compositions comprise a solubilizer in an amount of about 20%.
[0074] In some embodiments, provided compositions comprise sulfobutyl-ether-β- cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 45%, or about 1%) to about 40%), or about 1% to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20% solubilizer based on the total weight of the composition.
[0075] In some embodiments, provided compositions comprise sulfobutyl-ether-β- cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 10%. In some embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%), or about 1% to about 6%, or about 1% to about 5%, or about 2% to about 4%. In certain embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 3.33%.
[0076] In some embodiments, provided compositions comprise sulfobutyl-ether-β- cyclodextrin sodium salt as a solubilizer in an amount of about 10% to about 30%. In some embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt in an amount of about 10% to about 25%, or about 15% to about 25%, or about 17% to about 23%, or about 18% to about 22%, or about 19% to about 21%. In certain embodiments, provided compositions comprise sulfobutyl-ether- -cyclodextrin sodium salt as a solubilizer in an amount of about 20%. ii. Surfactants/Wetting Agents
[0077] Surfactants/wetting agents are well known in the art and typically facilitate drug release and absorption by enhancing the solubility of poorly-soluble drugs. Representative surfactants/wetting agents include, but are not limited to, poloxamers, polyoxyethylene ethers (e.g., polyethylene glycol), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g., triacetin, glycerol monostearate, and the like), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, Vitamin E TPGS, copovidone, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cellulose such as methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose (CMC), hydroxyethylmethyl cellulose (HEMC), phospholipids (e.g., lecithin), hydrogenated phospholipids, Soluplus® (i.e., polyvinyl caprolactam/polyvinyl acetate/polyethylene glycol graft copolymer) and the like, and combinations thereof.
[0078] In some embodiments, provided compositions comprise from about 0.1% to about 10%), or from about 0.1 %> to about 9%>, or from about 0.1 %> to about 8%>, or from about 0.1 %> to about 7%), or from about 0.1 %> to about 6%>, or from about 0.1 %> to about 5%>, or from about 0.1% to about 4%, or from about 0.1% to about 3%, or from about 0.1% to about 2% wetting agent, or from about 0.1% to about 1%, or from about 0.1% to about 0.5%, or from about 0.2% to about 0.4% wetting agent based upon total weight of the formulation.
[0079] In some embodiments, provided compositions comprise from about 0.1 %> to about 10%), or from about 0.2%> to about 8%>, or from about 0.5%> to about 5%>, or from about 1%> to about 5%, or from about 1% to about 4%, or from about 1% to about 3%, or from about 1.5% to about 2.5% wetting agent based upon total weight of the formulation. In certain embodiments, a provide composition comprises about 2%> wetting agent.
[0080] In some embodiments, provided compositions comprise about 0.1 %>, about 0.2%>, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0% wetting agent. In certain embodiments, a provide composition comprises about 0.33% wetting agent. [0081] In certain embodiments, a surfactant/wetting agent is a surfactant/wetting agent such as sodium lauryl sulfate (SLS). For instance, in certain embodiments, a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.1% to about 10%, or from about 0.1% to about 9%, or from about 0.1% to about 8%, or from about 0.1% to about 7%), or from about 0.1 % to about 6%, or from about 0.1 % to about 5%, or from about 0.1% to about 4%, or from about 0.1% to about 3%. In certain embodiments, a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 2%.
[0082] In certain embodiments, a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0%. In certain embodiments, a surfactant/wetting agent is sodium lauryl sulfate in an amount of about 0.33%.
Hi. Dispersing Agents
[0083] In certain embodiments, provided formulations may comprise one or more dispersing agents. Dispersing agents are substances added to a formulation to prevent settling, clumping, or gelling. For instance, compound 2 in certain formulations has a tendency to gel in the presence of moisture. It has been found that the use of certain dispersing agents can minimize such gelling. Dispersing agents include, by way of example and without limitation, salts such as sodium carbonate, sodium bicarbonate, sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, potassium chloride, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, and sodium chloride, sugars such as mannitol, fructose, sucrose, xylitol maleic acid, sorbitol, and dextrose, and acids such as D,L-malic acid, and the like, and combinations thereof.
[0084] In some embodiments, provided compositions comprise from about 0.1 % to about 20%) dispersing agent, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 15%, or about 0.1% to about 10%, or about 0.1% to about 8%, or about 0.1% to about 7%, or about 0.1% to about 6%, or about 0.1% to about 5%, or about 0.1% to about 4%, or about 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.2% to about 0.8%, or about 0.2% to about 0.6%), or about 0.3% to about 0.5% dispersing agent. [0085] In some embodiments, provided compositions comprise from about 0.5% to about 10%), or about 0.5%> to about 5%, or about 1% to about 5%, or about 1% to about 4%, or about 1%) to about 3.5%, or about 1.5% to about 3.5%, or about 2% to about 3% dispersing agent.
[0086] In certain embodiments, provided compositions comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%), about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0% dispersing agent.
[0087] In certain embodiments, provided compositions comprise about 0.4% dispersing agent. In certain embodiments, provided compositions comprise about 0.5% dispersing agent. In certain embodiments, provided compositions comprise about 0.42% dispersing agent.
[0088] In certain embodiments, provided compositions comprise about 2.0% dispersing agent. In certain embodiments, provided compositions comprise about 3.0%> dispersing agent In certain embodiments, provided compositions comprise about 2.5% dispersing agent.
[0089] In some embodiments, a dispersing is a bicarbonate salt, such as sodium bicarbonate. In some embodiments, provided compositions comprise sodium bicarbonate as a dispersing agent in an amount of about 0.1% to about 15%, or about 0.1% to about 10%, or about 0.1%) to about 8%, or about 0.1% to about 7%, or about 0.1% to about 6%, or about 0.1%) to about 5%), or about 0.1% to about 4%, or about 0.1% to about 3%. In some embodiments, provided compositions comprise sodium bicarbonate as a dispersing agent in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%), about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9% or about 3.0%.
[0090] In certain embodiments, provided compositions comprise about 0.4% sodium bicarbonate. In certain embodiments, provided compositions comprise about 0.5% sodium bicarbonate. In certain embodiments, provided compositions comprise about 0.42% sodium bicarbonate.
[0091] In certain embodiments, provided compositions comprise about 2.0%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 3.0%> sodium bicarbonate. In certain embodiments, provided compositions comprise about 2.5% sodium bicarbonate. iv. Fillers
[0092] Compositions for use in the present invention may comprise one or more fillers. Fillers are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix.
[0093] Suitable fillers (also referred to as "diluents" and/or "binders") are known in the art. For example, suitable fillers include but are not limited to starch, PVP (polyvinyl pyrrolidone), celluloses such as low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (e.g., Avicel®), silicified microcrystalline cellulose (Prosolv 50), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose) and ethylcellulose, pregelatimzed starch, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, lactose (e.g., lactose monohydrate), mannitol, magnesium aluminum silicate, and polymethacrylates.
[0094] Fillers include agents selected from the group consisting of silicic acid, microcrystalline cellulose (e.g., Avicel®), starch, pregelatimzed starch, sugars such as lactose, sucrose, glucose, dextrose, fructose, maltose, a suitable inorganic calcium salts such as dibasic calcium phosphate and calcium sulfate, polyols such as sorbitol, mannitol, lactitol, malitol and xylitol, or a combination thereof.
[0095] In certain embodiments, a filler is selected from the group consisting of microcrystalline cellulose, starch, pregelatimzed starch, dextrose, sucrose, dibasic calcium phosphate, calcium sulfate, mannitol, or a combination thereof.
[0096] In some embodiments, provided compositions comprise from about 10%> to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 85% filler, based upon total weight of the formulation.
[0097] In some embodiments, provided compositions comprise from about 10%> to about 50%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10%> to about 40%> filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 30% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 25% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 20% to about 25% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise about 14%, about 15%, about 16%>, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29% or about 30% filler.
[0098] In some embodiments, provided compositions comprise from about 40% to about 90%) filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 50% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 60% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 70% to about 90% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 75% to about 85% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 78% to about 82% filler, based upon total weight of the formulation. In some embodiments, provided compositions comprise about 70%, about 71%), about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% filler.
[0099] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, provided compositions comprise from about 10% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 85% microcrystalline cellulose, based upon total weight of the formulation.
[00100] In some embodiments, provided compositions comprise from about 10% to about 50% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 40% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 10% to about 30% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 15% to about 25% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 20% to about 25% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%o, about 26%, about 27%, about 28%, about 29% or about 30% microcrystalline cellulose.
[00101] In some embodiments, provided compositions comprise from about 40% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 50% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 60% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 70% to about 90% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 75% to about 85% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise from about 78% to about 82% microcrystalline cellulose, based upon total weight of the formulation. In some embodiments, provided compositions comprise about 70%, about 71%, about 73%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%), about 89%), or about 90% microcrystalline cellulose. v. Disintegrants
[00102] Pharmaceutical compositions for use in the present invention may further comprise one or more disintegrants. Incorporation of suitable disintegrant(s) into provided compositions may facilitate breakdown of provided compositions. Thus, inclusion of disintegrants may be particularly desired in provided compositions that contain active compound(s). Suitable disintegrants are known in the art and include, but are not limited to, clays, agar, calcium carbonate, sodium carbonate, sodium bicarbonate, cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), starch, sodium carboxymethyl starch (sodium starch glycolate), calcium carboxymethyl cellulose, pregelatinized starch, microcrystalline cellulose, cross-linked polyvinylpyrrolidone (e.g., crospovidone), potato or tapioca starch, alginic acid, certain silicates, microcrystalline starch, water insoluble starch, magnesium aluminum silicate (Veegum) or a combination thereof. [00103] In some embodiments, a suitable disintegrants is selected from cross-linked polyvinylpyrrolidone, starch, pregelatinized starch, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, clay, or a combination thereof.
[00104] In some embodiments, provided formulations comprise from about 1% to about 30% disintegrant, based upon total weight of the formulation. In some embodiments, provided formulations comprise from about 1% to about 25%, about 1% to about 20% disintegrant, about 1% to about 15% disintegrant, about 1% to about 10% disintegrant, about 2%) to about 8%) disintegrant, about 3% to about 7% disintegrant, or about 4% to about 6% disintegrant. In some embodiments, provided formulations comprise about 1%, about 2%, about 3%), about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% disintegrant, based upon total weight of the formulation. In certain embodiments, provided formulations comprise about 5% disintegrant, based upon total weight of the formulation.
[00105] In some embodiments, a disintegrant in a provided composition is a cross-linked polymer such as cross-linked polyvinylpyrrolidone. In some embodiments, a disintegrant is cross-linked polyvinylpyrrolidone. In certain embodiments, a disintegrant is cross-linked polyvinylpyrrolidone in an amount of about 1% to about 25%, about 1% to about 20% disintegrant, about 1% to about 15% disintegrant, about 1% to about 10% disintegrant, about 2%) to about 8%) disintegrant, about 3% to about 7% disintegrant, or about 4% to about 6%. In some embodiments, provided formulations comprise about 1%, about 2%, about 3%, about 4%), about 5%), about 6%, about 7%, about 8%, about 9%, or about 10% cross-linked polyvinylpyrrolidone, based upon total weight of the formulation. vi. Glidants
[00106] Pharmaceutical compositions of the present invention may further comprise one or more glidants. A glidant is a substance that is added to a powder to improve its flowability. Such compounds include, without limitation, colloidal silica (also referred to as colloidal silicon dioxide), fumed silica, talc, starch, DL-leucine, metallic stearates such as sodium stearate, calcium stearate, zinc stearate and magnesium stearate, sodium lauryl sulfate, and the like, and combinations thereof.
[00107] In some embodiments, provided compositions comprise from about 0.1% to about 3%) glidant, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 2.5%, or about 0.1% to about 2.0%>, or about 0.1%) to about 1.5%, or about 0.5% to about 1.5%, or about 0.8% to about 1.2% glidant. In certain embodiments, provided compositions comprise about 0.1%, about 0.2%>, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% glidant.
[00108] In some embodiments, a glidant is colloidal silica. In some embodiments, provided compositions comprise from about 0.1 % to about 2.5%, or about 0.1 % to about 2.0%), or about 0.1 % to about 1.5%, or about 0.5% to about 1.5% colloidal silica, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.5% to about 1.5% colloidal silica. In some embodiments, provided compositions comprise 1.0% colloidal silica. vii. Lubricants
[00109] Pharmaceutical compositions of the present invention may further comprise one or more lubricants. Lubricants are agents added in small quantities to formulations to improve certain processing characteristics. For example, lubricants prevent the formulation mixture from sticking to the compression machinery and enhance product flow by reducing interparticulate friction. Such compounds include, by way of example and without limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, boric acid, mineral oil, stearic acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, glyceryl behenate, magnesium lauryl sulfate, sodium lauryl sulfate, hydrogenated vegetable oil, glyceryl distearate, sodium stearyl fumarate, sodium oleate, fatty acids (e.g., palmitic and stearic acids) and other materials known to one of ordinary skill in the art.
[00110] In some embodiments, provided compositions comprise from about 0.1% to about 3%) lubricant, based on the total weight of the composition. In some embodiments, provided compositions comprise from about 0.1% to about 2.5%, or about 0.1% to about 2.0%>, or about 0.1%) to about 1.5%, or about 0.5% to about 1.5%, or about 0.8% to about 1.2% lubricant. In certain embodiments, provided compositions comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% lubricant.
[00111] In certain embodiments, a lubricant is magnesium stearate. In some embodiments, provided compositions comprise from about 0.1% to about 2.5% magnesium stearate. In some embodiments, provided compositions comprise from about 0.1% to about 2.0% magnesium stearate. In some embodiments, provided compositions comprise from about 0.5%) to about 1.5% magnesium stearate. In certain embodiments, provided compositions comprise about 1% magnesium stearate.
C. Exemplary Formulations
[00112] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 60% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 50%> solubilizer;
(c) about 0.1%) to about 10%> surfactant/wetting agent;
(d) about 0.1%) to about 20%> dispersing agent;
(e) about 10% to about 90% filler;
(f) about 1%) to about 30%> disintegrant;
(g) about 0.1%) to about 3% glidant; and
(h) about 0.1%) to about 3% lubricant;
wherein the amount of each component is based upon the total weight of the composition. In some embodiments, a provided composition is any of those described below and herein, wherein the composition comprises compound 2. In certain embodiments, a provided composition is any of those described below and herein, wherein the composition comprises Form A of compound 2.
[00113] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 60% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 50% betadex sulfobutylether sodium;
(c) about 0.1%) to about 10% sodium lauryl sulfate;
(d) about 0.1%) to about 20% sodium bicarbonate;
(e) about 10% to about 90% microcrystalline cellulose;
(f) about 1%) to about 30% crospovidone;
(g) about 0.1%) to about 3% colloidal silicon dioxide; and
(h) about 0.1%) to about 3% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition. [00114] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 30%> solubilizer;
(c) about 0.1%) to about 5% surfactant/wetting agent;
(d) about 0.1%) to about 10%> dispersing agent;
(e) about 15% to about 85% filler;
(f) about l%o to about 15% disintegrant;
(g) about 0.1%) to about 2% glidant; and
(h) about 0.1%) to about 2% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00115] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 30% betadex sulfobutylether sodium;
(c) about 0.1%) to about 5% sodium lauryl sulfate;
(d) about 0.1%) to about 10% sodium bicarbonate;
(e) about 15% to about 85% microcrystalline cellulose;
(f) about 1%) to about 15% crospovidone;
(g) about 0.1%) to about 2% colloidal silicon dioxide; and
(h) about 0.1% to about 2% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00116] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 25% solubilizer;
(c) about 0.1%) to about 3% surfactant/wetting agent;
(d) about 0.1%) to about 5% dispersing agent;
(e) about 15% to about 85% filler;
(f) about 2%o to about 8% disintegrant;
(g) about 0.5%) to about 1.5% glidant; and (h) about 0.5% to about 1.5% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00117] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 25% betadex sulfobutylether sodium;
(c) about 0.1%) to about 3% sodium lauryl sulfate;
(d) about 0.1%) to about 5% sodium bicarbonate;
(e) about 15% to about 85% microcrystalline cellulose;
(f) about 2%) to about 8% crospovidone;
(g) about 0.5%) to about 1.5% colloidal silicon dioxide; and
(h) about 0.5%) to about 1.5% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00118] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 25% solubilizer;
(c) about 0.1%) to about 3% surfactant/wetting agent;
(d) about 0.1%) to about 3% dispersing agent;
(e) about 15% to about 85% filler;
(f) about 5%) disintegrant;
(g) about 0.8%) to about 1.2% glidant; and
(h) about 0.8%) to about 1.2% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00119] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 25% betadex sulfobutylether sodium;
(c) about 0.1%) to about 3% sodium lauryl sulfate;
(d) about 0.1%) to about 3% sodium bicarbonate;
(e) about 15% to about 85% microcrystalline cellulose; (f) about 5% crospovidone;
(g) about 0.8% to about 1.2% colloidal silicon dioxide; and
(h) about 0.8%) to about 1.2% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00120] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 20% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 10%> solubilizer;
(c) about 0.1%) to about 10%> surfactant/wetting agent;
(d) about 0.1%) to about 5% dispersing agent;
(e) about 50% to about 90% filler;
(f) about 1%) to about 20%> disintegrant;
(g) about 0.1%) to about 3% glidant; and
(h) about 0.1%) to about 3% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00121] In some embodiments, a provided composition comprises the following components:
(a) about 1% to about 20% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 10% betadex sulfobutylether sodium;
(c) about 0.1%) to about 10% sodium lauryl sulfate;
(d) about 0.1%) to about 5% sodium bicarbonate;
(e) about 50% to about 90% microcrystalline cellulose;
(f) about 1%) to about 20% crospovidone;
(g) about 0.1%) to about 3% colloidal silicon dioxide; and
(h) about 0.1%) to about 3% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00122] In some embodiments, a provided composition comprises the following components:
(a) about 4% to about 12% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 5% solubilizer;
(c) about 0.1%) to about 5% surfactant/wetting agent; (d) about 0.1% to about 2% dispersing agent;
(e) about 70% to about 90% filler;
(f) about 1%) to about 10%> disintegrant;
(g) about 0.1%) to about 2% glidant; and
(h) about 0.1%) to about 2% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00123] In some embodiments, a provided composition comprises the following components:
(a) about 4% to about 12% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 1%) to about 5% betadex sulfobutylether sodium;
(c) about 0.1%) to about 5% sodium lauryl sulfate;
(d) about 0.1%) to about 2% sodium bicarbonate;
(e) about 70% to about 90% microcrystalline cellulose;
(f) about 1%) to about 10% crospovidone;
(g) about 0.1%) to about 2% colloidal silicon dioxide; and
(h) about 0.1% to about 2% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00124] In some embodiments, a provided composition comprises the following components:
(a) about 5% to about 10% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 2%o to about 4% solubilizer;
(c) about 0.1%) to about 1% surfactant/wetting agent;
(d) about 0.1%) to about 1% dispersing agent;
(e) about 75% to about 85% filler;
(f) about 2%o to about 8% disintegrant;
(g) about 0.5%) to about 1.5% glidant; and
(h) about 0.5%) to about 1.5% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00125] In some embodiments, a provided composition comprises the following components:
(a) about 5% to about 10% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2); (b) about 2% to about 4% betadex sulfobutylether sodium;
(c) about 0.1% to about 1% sodium lauryl sulfate;
(d) about 0.1% to about 1% sodium bicarbonate;
(e) about 75% to about 85% microcrystalline cellulose;
(f) about 2%> to about 8% crospovidone;
(g) about 0.5%) to about 1.5% colloidal silicon dioxide; and
(h) about 0.5%) to about 1.5% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00126] In some embodiments, a provided composition comprises the following components:
(a) about 7% to about 8% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 3.3%) solubilizer;
(c) about 0.1%) to about 0.5% surfactant/wetting agent;
(d) about 0.2%) to about 0.6% dispersing agent;
(e) about 78% to about 82% filler;
(f) about 4%) to about 6% disintegrant;
(g) about 0.8%) to about 1.2% glidant; and
(h) about 0.8%) to about 1.2% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00127] In some embodiments, a provided composition comprises the following components:
(a) about 7% to about 8% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 3.3%) betadex sulfobutylether sodium;
(c) about 0.1%) to about 0.5% sodium lauryl sulfate;
(d) about 0.2%) to about 0.6% sodium bicarbonate;
(e) about 78% to about 82% microcrystalline cellulose;
(f) about 4%) to about 6% crospovidone;
(g) about 0.8%) to about 1.2% colloidal silicon dioxide; and
(h) about 0.8%) to about 1.2% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00128] In some embodiments, a provided composition comprises the following components: (a) about 7.59% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 3.33% betadex sulfobutylether sodium;
(c) about 0.33%) sodium lauryl sulfate;
(d) about 0.42%) sodium bicarbonate;
(e) about 81.33% microcrystalline cellulose;
(f) about 5% crospovidone;
(g) about 1% colloidal silicon dioxide; and
(h) about 1%) magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00129] In some embodiments, a provided composition comprises the following components:
(a) about 20%> to about 60%> compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 10% to about 30% solubilizer;
(c) about 0.1%) to about 10%> surfactant/wetting agent;
(d) about 0.1%) to about 15% dispersing agent;
(e) about 10% to about 50% filler;
(f) about 1%) to about 20%> disintegrant;
(g) about 0.1%) to about 3% glidant; and
(h) about 0.1%) to about 3% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00130] In some embodiments, a provided composition comprises the following components:
(a) about 20% to about 60% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 10%) to about 30% betadex sulfobutylether sodium;
(c) about 0.1% to about 10% sodium lauryl sulfate;
(d) about 0.1% to about 15% sodium bicarbonate;
(e) about 10% to about 50% microcrystalline cellulose;
(f) about 1%) to about 20% crospovidone;
(g) about 0.1%) to about 3% colloidal silicon dioxide; and
(h) about 0.1%) to about 3% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition. [00131] In some embodiments, a provided composition comprises the following components:
(a) about 30% to about 50%> compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 15%) to about 25% solubilizer;
(c) about 0.5% to about 5% surfactant/wetting agent;
(d) about 0.5%) to about 10%> dispersing agent;
(e) about 10% to about 30% filler;
(f) about 1%) to about 10%> disintegrant;
(g) about 0.1%) to about 2% glidant; and
(h) about 0.1%) to about 2%o lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00132] In some embodiments, a provided composition comprises the following components:
(a) about 30% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 15%) to about 25% betadex sulfobutylether sodium;
(c) about 0.5% to about 5% sodium lauryl sulfate;
(d) about 0.5%) to about 10% sodium bicarbonate;
(e) about 10% to about 30% microcrystalline cellulose;
(f) about 1%) to about 10% crospovidone;
(g) about 0.1%) to about 2% colloidal silicon dioxide; and
(h) about 0.1%) to about 2% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00133] In some embodiments, a provided composition comprises the following components:
(a) about 40% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 17%) to about 23% solubilizer;
(c) about 1%) to about 4% surfactant/wetting agent;
(d) about 1 % to about 4% dispersing agent;
(e) about 15% to about 25% filler;
(f) about 2%o to about 8% disintegrant;
(g) about 0.5%) to about 1.5% glidant; and (h) about 0.5% to about 1.5% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00134] In some embodiments, a provided composition comprises the following components:
(a) about 40% to about 50% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 17%) to about 23% betadex sulfobutylether sodium;
(c) about 1%) to about 4% sodium lauryl sulfate;
(d) about 1 % to about 4% sodium bicarbonate;
(e) about 15% to about 25% microcrystalline cellulose;
(f) about 2%> to about 8% crospovidone;
(g) about 0.5%) to about 1.5% colloidal silicon dioxide; and
(h) about 0.5%) to about 1.5% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00135] In some embodiments, a provided composition comprises the following components:
(a) about 44% to about 46% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 19%) to about 21% solubilizer;
(c) about 1.5% to about 2.5% surfactant/wetting agent;
(d) about 2%) to about 3% dispersing agent;
(e) about 20% to about 25% filler;
(f) about 4%) to about 6% disintegrant;
(g) about 0.8%) to about 1.2% glidant; and
(h) about 0.8%) to about 1.2% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
[00136] In some embodiments, a provided composition comprises the following components:
(a) about 44% to about 46% compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 19%) to about 21% betadex sulfobutylether sodium;
(c) about 1.5% to about 2.5% sodium lauryl sulfate;
(d) about 2%) to about 3% sodium bicarbonate;
(e) about 20% to about 25% microcrystalline cellulose; (f) about 4% to about 6% crospovidone;
(g) about 0.8% to about 1.2% colloidal silicon dioxide; and
(h) about 0.8%) to about 1.2% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
[00137] In some embodiments, a provided composition comprises the following components:
(a) about 45.53%) compound 1, or a pharmaceutically acceptable salt thereof (e.g., compound 2);
(b) about 20%) betadex sulfobutylether sodium;
(c) about 2%o sodium lauryl sulfate;
(d) about 2.5%o sodium bicarbonate;
(e) about 22.98%> microcrystalline cellulose;
(f) about 5.0 crospovidone;
(g) about 1%) colloidal silicon dioxide; and
(h) about 1%) magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
HI. Production
[00138] In certain embodiments, provided formulations are prepared by dry blending compound 2 and excipients. Exemplary such methods are described below and in the Examples section.
[00139] In some embodiments, a provided formulation is prepared by a process comprising:
(a) blending a surfactant/wetting agent, a dispersing agent, a solubilizer, and a disintegrant to form a first blended powder;
(b) adding compound 2 to the first blended powder and blending to form a second blended powder;
(c) screening the second blended powder;
(d) adding a portion of filler to the screened second blended powder and blending to form a third blended powder;
(e) screening the third blended powder;
(f) adding a glident and the remaining filler to the screened third blended powder and blending to form a fourth blended powder; and (g) adding a lubricant to the fourth blended powder and blending to form a fifth blended powder.
[00140] In certain embodiments, provided formulations are prepared by dry blending compound 2 and excipients. In some embodiments, a provided formulation is prepared by a process comprising:
(a) blending sodium lauryl sulfate, sodium bicarbonate, betadex sulfobutyl ether sodium, and crospovidone to form a first blended powder;
(b) adding compound 2 to the first blended powder and blending to form a second blended powder;
(c) screening the second blended powder;
(d) adding a portion of microcrystalline cellulose to the screened second blended powder and blending to form a third blended powder;
(e) screening the third blended powder;
(f) adding colloidal silicon dioxide and the remaining microcrystalline cellulose to the screened third blended powder and blending to form a fourth blended powder; and
(g) adding magnesium stearate to the fourth blended powder and blending to form a fifth blended powder.
[00141] In some embodiments, capsules are filled with the final blended powder.
[00142] In some embodiments, the above procedure is used to prepare a capsule containing compound 2 in an amount of about 1 wt% to about 20 wt%, or from about 2 wt% to about 18 wt%, or from about 4 wt% to about 12 wt%, or from about 5 wt% to about 10 wt%, or from about 6 wt% to about 9 wt%, or from about 7 wt% to about 8 wt%. In certain embodiments, the above procedure is used to prepare a capsule containing compound 2 in an amount of about 7.59 wt%.
[00143] In some embodiments, a provided formulation is prepared by a process comprising:
(a) blending a surfactant/wetting agent and a dispersing agent to form a first blended powder;
(b) screening the first blended powder;
(c) adding a disintegrant to the first blended powder and blending to form a second blended powder;
(d) screening the second blended powder;
(e) adding a solubilizer to the screened second blended powder and blending to form a third blended powder; (f) screening the third blended powder;
(g) adding a glidant and a filler to the screened third blended powder and blending to form a fourth blended powder;
(h) screening the fourth blended powder;
(i) adding compound 2 to the fourth blended powder and blending to form a fifth blended powder;
(j) screening the fifth blended powder;
(k) blending the screened fifth blended powder; and
(1) adding a lubricant to the screened fifth blended powder to form a sixth blended powder.
[00144] In some embodiments, a provided formulation is prepared by a process comprising:
(a) blending sodium lauryl sulfate and sodium bicarbonate to form a first blended powder;
(b) screening the first blended powder;
(c) adding crospovidone to the first blended powder and blending to form a second blended powder;
(d) screening the second blended powder;
(e) adding betadex sulfobutyl ether sodium to the screened second blended powder and blending to form a third blended powder;
(f) screening the third blended powder;
(g) adding colloidal silicon dioxide and microcrystalline cellulose to the screened third blended powder and blending to form a fourth blended powder;
(h) screening the fourth blended powder;
(i) adding compound 2 to the fourth blended powder and blending to form a fifth blended powder;
(j) screening the fifth blended powder;
(k) blending the screened fifth blended powder; and
(1) adding magnesium stearate to the screened fifth blended powder to form a sixth blended powder.
[00145] In some embodiments, a provided formulation is prepared by a process comprising:
(a) blending sodium lauryl sulfate, sodium bicarbonate, and betadex sulfobutyl ether sodium to form a first blended powder; (b) adding compound 2, crospovidone, microcrystalline cellulose, and colloidal silicon dioxide to the first blended powder and blending to form a second blended powder;
(c) screening the second blended powder;
(d) blending for a second time the screened second blended powder;
(f) adding magnesium stearate to the screened second blended powder to form a third powder; and
(g) blending the third powder.
[00146] In some embodiments, a provided formulation is prepared by a process comprising:
(a) blending sodium lauryl sulfate, sodium bicarbonate, and crospovidone to form a first blended powder;
(b) adding compound 2, betadex sulfobutyl ether sodium, microcrystalline cellulose, and colloidal silicon dioxide to the first blended powder and blending to form a second blended powder;
(c) screening the second blended powder;
(d) blending for a second time the screened second blended powder;
(e) screening for a second time the second blended powder;
(f) adding magnesium stearate to the screened second blended powder to form a third powder; and
(g) blending the third powder.
[00147] In some embodiments, capsules are filled with the final blended powder.
[00148] In some embodiments, the above procedure is used to prepare a capsule containing compound 2 in an amount of about 20 wt% to about 60 wt%, or from about 25 wt% to about 55 wt%, or from about 30 wt% to about 50 wt%, or from about 35 wt% to about 50 wt%, or from about 40 wt% to about 50 wt%, or from about 41 wt% to about 49 wt%, or from about 42 wt% to 48 wt%, or from about 43 wt% to 47 wt%, or from about 44 wt% to about 46 wt%, or from about 45 wt% to about 46 wt%. In certain embodiments, the above procedure is used to prepare a capsule containing compound 2 in an amount of about 45.53 wt%.
IV. Unit Dosage Form
[00149] Provided formulations may be prepared as a unit dosage form. Indeed, a tablet or capsule is typically a unit dosage form. A person of ordinary skill will appreciate that the unit dosage forms described herein refer to an amount of compound 1, i.e. the free base form of the active pharmaceutical ingredient, which may be provided as the free base or as a pharmaceutically acceptable salt thereof. A person skilled in the art will further appreciate that, when a pharmaceutical composition comprises a salt form of compound 1, for example the phosphate salt form referred to herein as compound 2, the amount of the salt form present in the composition is an amount that is equivalent to a unit dose of free base compound 1. For example, a pharmaceutical composition comprising compound 2 would contain 6.07 mg of compound 2 necessary to deliver an equivalent 5 mg unit dose of the free base compound 1. In some embodiments, a unit dosage form contains 5 mg compound 1. In some embodiments, a unit dosage form contains 30 mg compound 1. In some embodiments, a unit dosage form contains 150 mg compound 1.
V. Administration
[00150] Provided formulations may be administered to a patient one or more times daily, as required to provide an effective amount of compound 1. For example, one or more unit dosage forms of a provided formulation may be administered to a patient in a single day. In some embodiments, a unit dose of compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day (QD). In some embodiments, a unit dose of compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day (BID). In some embodiments, two or more different unit doses are administered to provide a therapeutically effective amount of compound 1. For example, a 180 mg dose of compound 1 can be administered as one 150 mg unit dose and one 30 mg unit dose. It will be appreciated that such unit doses can be administered at the same time or at different times during a day.
[00151] In some embodiments, the present invention provides a method for treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more unit doses of a provided formulation. In some embodiments, the present invention provides a method of treating an ERKl and/or ERK2- mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides about 5, 30, or 150 mg of compound 1. In certain such embodiments, the amount of compound 1 is provided in the form of compound 2, e.g., Form A of compound 2. In some embodiments, the present invention provides a method of treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides any amount of compound 1 described above and herein.
[00152] In some embodiments, the present invention provides a method for treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more unit doses of a provided formulation. In some embodiments, the present invention provides a method of treating an ERKl and/or ERK2- mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides about 5 mg to about 1000 mg of compound 1. In certain embodiments, a formulation of the present invention provides about 1 mg, 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg of compound 1.
[00153] In some embodiments, the present invention provides a method of treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules of the present invention wherein said capsule provides about 5 mg, 30 mg, or 150 mg of compound 1. In certain embodiments, a capsule formulation of the present invention provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of compound 1.
[00154] In some embodiments, the present invention provides a method of treating an ERKl and/or ERK2 -mediated disorder in a patient in need thereof, comprising the step of administering to said patient one or more capsules comprising compound 1 in the form of compound 2, Form A. VI. Uses, Formulation and Administration
Pharmaceutically Acceptable Compositions
[00155] In some embodiments, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions of this invention is such that it is effective to measurably inhibit one or both of ERKl and ERK2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
[00156] The term "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.
[00157] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
[00158] A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
[00159] As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of one or both of ERKl and ERK2, or a mutant thereof.
[00160] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[00161] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
[00162] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
Uses of Compounds and Pharmaceutically Acceptable Compositions
[00163] As described generally above, compound 1, and pharmaceutically acceptable salts thereof described herein, is an inhibitor of one or both of ERKl and ERK2. One of ordinary skill in the art will recognize that ERK is one of the key components in the RAS-RAF-MEK- ERK MAPK pathway and that ERKl and ERK2 are downstream nodes within the MAPK pathway. Without wishing to be bound by theory, because of the downstream location of ERKl and ERKl in the MAPK pathway, an ERK inhibitor can treat disease or disorders in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERKl and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek). Furthermore, because ERK is a downstream target, ERK inhibitors are believed to be able to overcome, in some instances, drug resistance induced by inhibitors of targets upstream of ERK within the MAPK pathway. For example, small molecule inhibitors of RAF or MEK utilized in the treatment of K-RAS and B-RAF mutant tumors have resulted in such drug resistance. Similarly, drug resistance has been associated with other tumors driven by hyperactivation of the MAPK pathway (such as NF1 mutant tumors). Kinase selectivity was achieved through silencing the selective Cys in a combination of the interactions between the covalent inhibitors of the invention and unique amino acids in the ATP binding pocket. Targeting the selective Cys provides for prolonged pharmacodynamics in silencing ERK activity, as well as potential lower doses in cancer treatment, compared to reversible inhibitors.
[00164] The activity of compound 1, and pharmaceutically acceptable salts thereof, as an inhibitor of one or both of an ERKl and ERK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of downstream phosphorylation, changes in gene expression, subsequent functional markers and consequences, and/or kinase activity of one or both of activated ER 1 and ERK2 kinase, or a mutant thereof. Alternate in vitro assays quantitate the ability of the test compound to bind to one or both of ER 1 and ERK2. Test compound binding may be measured by radiolabeling the test compound prior to binding, isolating one or both of the compound / ERK1 complex and the compound / ERK2 complex, and determining the amount of radiolabel bound. Alternatively, test compound binding may be determined by running a competition experiment where test compounds are incubated with one or both of ERK1 and ERK2 kinase bound to known radioligands. Test compound binding may be determined by competition with an ERK covalent probe that is amenable to further functionalization with a detection probe, such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of one or both of ERKl and ERK2, or a mutant thereof, are also set forth below and/or in the Examples of the '230 publication.
[00165] The term "measurably inhibit", as used herein means a measurable change in one or both of ERKl and ERK2 protein kinase activity between a sample comprising a provided composition, and one or both of an ERKl and ERK2 protein kinase and an equivalent sample comprising one or both of ERKl and ERK2 protein kinase in the absence of a provided composition. Such measurements of protein kinase activity are known to one of ordinary skill in the art and include those methods set forth herein below and/or in the Examples of the '230 publication.
[00166] As described above, in some embodiments, compound 1, and pharmaceutically acceptable salts thereof, is an inhibitor of one or both of ERKl and ERK2 protein kinases, and ERKl and ERK2 are downstream targets within the MAPK pathway. Without wishing to be bound by any particular theory, such compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role. Such disease, condition, or disorder may be referred to herein as associated with the MAPK pathway or alternatively as associated with one or both of ERKl and ERK2. Such diseases, conditions, or disorders may also be referred to herein as an "ERKl- or ERK2 -mediated disease, condition, or disorder."
[00167] In some embodiments, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK), including one or both of ERKl and ERK2 protein kinases, is implicated in said disease, condition, or disorder, wherein said method comprises administering to a patient in need thereof a compound of the present invention.
[00168] In some embodiments, the present invention relates to a method of inhibiting one or both of ER 1 and ERK2 protein kinase activity in a patient comprising the step of administering to said patient a composition comprising a compound of the present invention.
[00169] In other embodiments, the present invention provides a method for treating a disease, condition, or disorder mediated by one or both of ERK1 and ERK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound of the present invention.
[00170] In certain embodiments, the present invention provides a method for overcoming drug resistance to Raf or MEK inhibitors, comprising the step of administering to a patient an inhibitor compound of one or both of ER l and ERK2, such as a compound of the present invention. In certain embodiments, the mechanism of drug resistance is through mutation of a target protein or reactivation of the MAPK pathway.
[00171] As used herein, the term "resistance" may refer to changes in a wild-type nucleic acid sequence coding a target protein, and/or to the amino acid sequence of the target protein and/or to the amino acid sequence of another protein, which changes, decreases or abolishes the inhibitory effect of the inhibitor on the target protein. The term "resistance" may also refer to overexpression or silencing of a protein differing from a target protein that can reactivate the MAPK pathway or other survival pathways.
[00172] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.
[00173] In some embodiments, the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2 comprising administering to a patient in need thereof a composition comprising a compound of the present invention. [00174] General diseases, conditions, or disorders treated by a compound of the present invention include cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, liver disease, a cardiac disorder, schizophrenia, or a bone-related disorder.
[00175] In some embodiments, the present invention relates to a method of treating or lessening the severity of a disease, condition, or disorder selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone- related diseases, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention.
[00176] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention. In some embodiments, the cancer is recurring. In certain embodiments, the cancer is refractory. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is locally advanced.
[00177] In certain embodiments, the cancer is a RAF inhibitor-resistant cancer. In some such embodiments, the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
[00178] In certain embodiments, the cancer is a MEK inhibitor-resistant cancer.
[00179] In certain embodiments, the cancer is a MAPK pathway-mediated cancer.
[00180] In some embodiments, the cancer is a BRAF -mutated cancer. In certain embodiments, the BRAF-mutated cancer is a BRAFV600-mutated cancer, such as BRAF
BRAFV600K BRAFV600R and BRAFV600D
[00181] In some embodiments, the cancer is a RAS-mutated cancer. In certain embodiments, the RAS-mutated involves codons 12, 13, or 61. In certain embodiments, the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS , KRASG13C/D, or KRAsQeiL/H/R Jn certain embodiments, the RAS-mutated cancer is an
NRAS-mutated cancer, including, but not limited to, NRASQ61R, NRASQ61K, NRASQ61L, or NRAS^61H. In certain embodiments, the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRASG12V, HRASQ61R, and HRASG12S.
[00182] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular carcinoma (HCC)) and biliary passage carcinoma), kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colorectal carcinoma, large intestine, rectum, brain and central nervous system, endometrial, multiple myeloma (MM), prostate, AML, and leukemia. In some such embodiments, the cancer is relapsed. In some embodiments, the cancer is refractory. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is metastatic.
[00183] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia. In some embodiments, a sarcoma is a soft tissue sarcoma. In some embodiments, a lymphoma is non-hodgkins lymphoma. In some embodiments, a lymphoma is large cell immunoblastic lymphoma. In some embodiments, the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; esophogeal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung, papillary lung adenocarcinoma, small-cell lung cancer, squamous carcinoma of the lung, non-small cell lung cancer; melanoma and nonmelanoma skin cancer; lymphoid disorders; myeloproliferative disorders, such as, for example, polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), hypereosinophilic syndrome, systematic mast cell disease, atypical CML, AML, or juvenile myelomonocytic leukemia; plasmacytoma; multiple myeloma; neuroblastoma; ovarian cancer; papillary carcinoma; pancreatic cancer; cancer of the peritoneum; prostate cancer, including benign prostatic hyperplasia; rectal cancer; salivary gland carcinoma; sarcoma; seminoma; squamous cell cancer; small cell carcinoma; cancer of the small intestine; stomach cancer; testicular cancer; thyroid cancer; undifferentiated carcinoma; and vulval cancer. In some such embodiments, the cancer is relapsed. In some embodiments, the cancer is refractory. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is metastatic.
[00184] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non- small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia. In some embodiments, a leukemia is an acute leukemia. In certain embodiments, a leukemia is acute myeloid leukemia. In certain embodiments, a leukemia is acute lymphoblastic leukemia.
[00185] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic.
[00186] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is melanoma. In certain embodiments, the melanoma is uveal melanoma. In some embodiments, the melanoma is a melanoma of the skin. In certain embodiments, the melanoma is locally advanced. In some embodiments, the melanoma is metastatic. In some embodiments, the melanoma is recurring. In some embodiments, the melanoma is BRAFv60°- mutated melanoma. In certain embodiments, the melanoma is a RAS-mutated melanoma. In some embodiments, the melanoma is NRAS-mutated melanoma. In certain embodiments, the melanoma is wild type for KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAF inhibitor-resistant (e.g., Vemurfenib-resistant, dabrafenib-resistant, etc.) melanoma. In certain embodiments, the cancer is a VemR (i.e., Vemurfenib-resistant) BRAF-mutated melanoma. In some embodiments, the melanoma is relapsed. In some embodiments, the melanoma is refractory.
[00187] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is colorectal cancer. In certain embodiments, the colorectal cancer is locally advanced. In certain embodiments, the colorectal cancer is metastatic. In certain embodiments, the colorectal cancer is a BRAF-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a BRAFv600-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a RAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a KRAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a NRAS-mutated colorectal cancer. In some embodiments, the colorectal cancer is relapsed. In some embodiments, the colorectal cancer is refractory.
[00188] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is pancreatic cancer. In certain embodiments, the pancreatic cancer is locally advanced. In certain embodiments, the pancreatic cancer is metastatic. In certain embodiments, the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC). In certain embodiments, the pancreatic cancer is a RAS-mutated pancreatic cancer. In certain embodiments, the pancreatic cancer is a KRAS-mutated pancreatic cancer. In certain embodiments, the pancreatic cancer is KRAS-mutated pancreatic cancer, including, but not limited to, KRASG12C/D/V, KRASG13C/D,or KRASQ61L/H/R. In some embodiments, the pancreatic cancer is relapsed. In some embodiments, the pancreatic cancer is refractory.
[00189] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a papillary thyroid cancer. In certain embodiments, the papillary thyroid cancer is locally advanced. In some embodiments, the papillary thyroid cancer is metastatic. In some embodiments, the papillary thyroid cancer is recurring. In some embodiments, the papillary thyroid cancer is BRAF-mutated papillary thyroid cancer. In some embodiments, the papillary thyroid cancer is BRAFv600-mutated papillary thyroid cancer. In some embodiments, the papillary thyroid cancer is relapsed. In some embodiments, the papillary thyroid cancer is refractory. In some embodiments, the papillary thyroid cancer includes undifferentiated or dedifferentiated histology.
[00190] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the lung cancer is locally advanced. In certain embodiments, the lung cancer is metastatic. In certain embodiments, the lung cancer is a RAS-mutated lung cancer. In certain embodiments, the lung cancer is KRAS-mutated lung cancer. In certain embodiments, the lung cancer is a KRAS-mutated lung cancer, including, but not limited to, KRASG12C/D/V, KRASG13C/D,or KRASQ61L/H/R. In some embodiments, the lung cancer is relapsed. In some embodiments, the lung cancer is refractory.
[00191] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a leukemia. In some embodiments, a leukemia is a chronic leukemia. In certain embodiments, a leukemia is chronic myeloid leukemia. In some embodiments, a leukemia is an acute leukemia. In certain embodiments, a leukemia is acute myeloid leukemia (AML). In certain embodiments, a leukemia is acute monocytic leukemia (AMoL, or AML-M5). In certain embodiments, a leukemia is acute lymphoblastic leukemia (ALL). In certain embodiments, a leukemia is acute T cell leukemia. In certain embodiments, a leukemia is myelomonoblastic leukemia. In certain embodiments, a leukemia is human B cell precursor leukemia. In certain embodiments, a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia is refractory.
[00192] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a CNS cancer, for instance CNS tumors. In certain embodiments, a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM). In some embodiments, the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
[00193] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is multiple myeloma (MM). In certain embodiments, the multiple myeloma is locally advanced. In certain embodiments, the multiple myeloma is metastatic. In certain embodiments, the multiple myeloma is a RAS-mutated multiple myeloma. In certain embodiments, the multiple myeloma is KRAS-mutated multiple myeloma. In certain embodiments, the multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS , KRAS^ u , or KRASy In some embodiments, the multiple myeloma is relapsed. In some embodiments, the multiple myeloma is refractory.
[00194] In some embodiments, the present invention relates to a method of treating a cancer, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is hepatocellular carcinoma (HCC). In certain embodiments, the HCC is locally advanced. In certain embodiments, the HCC is metastatic. In certain embodiments, the HCC is a RAS- mutated HCC. In certain embodiments, the HCC is KRAS-mutated HCC. In certain embodiments, the HCC is a KRAS-mutated HCC, including, but not limited to, KRASG12C/D/V, KRASG13C/D, or KRASQ61L/H/R. In some embodiments, the hepatocellular carcinoma is relapsed. In some embodiments, the hepatocellular carcinoma is refractory.
[00195] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
[00196] All features of each of the aspects of the invention apply to all other aspects mutatis mutandis.
[00197] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
[00198] The following examples describe the development and manufacture of representative formulations of the present invention.
Example A
Preparation of Compound 1
Figure imgf000051_0001
compound 1
[00199] The title compound was prepared according to the steps and intermediates described below and in the '230 publication, the entirety of which is incorporated herein by reference.
Step 1: N-(2-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)5- methylphenyl)acrylamide (Intermediate 1)
Figure imgf000051_0002
[00200] To a stirred solution of N-(2-amino-5-methylphenyl)acrylamide (22.2 mmol) in dimethyl acetamide (25 mL) was added potassium carbonate (46.0 mmol) at rt, and the mixture was stirred for 15 minutes. To this reaction mixture, 2,4-dichloro-5- trifluoromethylpyrimidine (22.2 mmol) was added, and the stirring continued at 60 °C for 1 h. Upon completion, the reaction mixture was diluted with water (2x50 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate and concentrated to get the crude product. This crude was purified by silica gel column chromatography and subsequently purified by prep-HPLC to get desired intermediate 1.
Step 2: Acid-catalyzed coupling method
[00201] To a solution of Intermediate 1 (2.923 mmol) in 0.04 M PTSA solution in 1,4- dioxane (20 mL) was added 2-methoxy-5-methylpyridin-4-amine (3.5076 mmol), and the mixture was stirred at 95 °C for 16 h. Upon completion, the reaction mixture was directly absorbed on silica gel and purified by column chromatography. The resulting product was stirred in a mixture of DCM: EtOAc: diethyl ether (10 mL: 10 mL:30 mL) for 10 min, then filtered and dried under vacuum to obtain the desired compound.
[00202] MS m/z 459.2 (ES+, M+H). 1HNMR (DMSO-< 5) δ 2.10 (s, 3H), 2.32 (s, 3H), 3.75 (s, 3H), 5.78 (dd, 1H, J = 2.0, 10.0 Hz), 6.28 (dd, 1H, J = 2.0, 16.8 Hz), 6.45 (dd, 1H, J = 10.6, 16.8 Hz), 7.09 (br t, 3 H, J = 8.0 Hz), 7.50 (d, 1H, J = 8.4 Hz), 7.79 (s, 1H), 8.36 (s, 2H), 8.72 (s, 1H), 10.25 (s, 1H).
Alternative Step 2: Pd-catalyzed coupling method:
[00203] Alternatively, Step 2 can be carried out by adding Intermediate 1 to a suitable coupling partner in the presence of Na2C03, a degassed solvent (e.g., tert-amyl alcohol), a suitable palladium catalyst (e.g., tris-dibenzylamino dipalladium) and a suitable phosphine ligand (e.g., Dave Phos) under conditions suitable to effect coupling.
[00204] The present invention provides, inter alia, oral dosage forms (e.g., capsules) of compound 2. It has been unexpectedly found that the inclusion of certain ingredients in oral dosage forms of compound 2 significantly improve capsule performance by, for instance, improving, solubility of compound 2, minimizing gelling tendency of compound 2 in wet environments, and/or improving dispersion of compound 2.
[00205] For instance, in some embodiments, solubility and dispersion are improved by adding an amount of each of Captisol USP, sodium lauryl sulfate, and sodium bicarbonate in a capsule. Exemplary such formulations are described further below and herein.
Example B
Preparation of Form A of Compound 2
Figure imgf000052_0001
[00206] Form A of compound 2 was prepared as follows.
[00207] Procedure A: Compound 1 was dissolved in 15x tetrahydrofuran. One molar equivalent of 2 molar phosphoric acid in acetonitrile was charged. The batch was slurried at 20 °C for 1 to 2 hours. The solvent was removed under reduced pressure. The resulting solids were slurried in acetone for about 16 hours at 20 °C, filtered and dried.
[00208] Procedure B: Compound 1 was dissolved in THF. Equal molar equivalent of 1.08 M phosphoric acid in acetonitrile was charged. The sample was shaken at ambient temperature at 200 RPM for 1 hour. The solvent was removed under nitrogen purge. The resulting solids were slurried in acetone with a stirring bar at ambient temperature overnight, then filtered and dried in vacuum oven at 30 °C overnight.
[00209] Procedure C: Compound 1 was dissolved in THF (20x vol) at 20 °C. Seeds of compound 2 Form A (5% wt) were charged. A I M solution of phosphoric acid (1 mol eq.) in ethanol was charged. The batch was left under vigorous agitation for two hours. Solvent exchange to isopropyl acetate was carried out with a constant volume distillation under reduced pressure, with temperature not exceeding 40 °C. The batch was cooled to 20 °C. The solvent was removed under nitrogen purge. The batch was filtered, washed two times with isopropyl acetate and dried in a vacuum oven at ~40 °C overnight, under vacuum with nitrogen bleed.
[00210] Procedure D: Compound 1 was dissolved in 9x vol THF/ H20 (95:5 vol). A solution of H3PO4 (1.2 mol eq.) in ethanol was charged to a second flask, seeds of compound 2 form A (5%) were charged and vigorous agitation was started. The solution of compound 1 was charged to the H3PO4 solution (reverse addition) over one hour. The slurry was aged for one hour. Solvent exchange to ethanol was started (constant volume vacuum distillation with continuous addition of ethanol, final THF NMT 0.5%). The batch was cooled to 20 °C, filtered and dried in a vacuum oven at ~40 °C overnight, under vacuum with nitrogen bleed.
[00211] Procedure E: Compound 1 was dissolved in lOx vol THF/H20 (95:5 vol). Isopropyl alcohol (5x vol) was charged. Constant volume distillation, with continuous addition of isopropyl alcohol was started at atmospheric pressure. Solvent exchange was carried out until THF content was below 5%. Compound 1 recrystallized during the solvent exchange. The batch was cooled to 30 °C. A 1M solution of H3PO4 in IPA was charged over 2 hours. Seeds of compound 2 Form A (1%) were then charged. The batch was stirred vigorously overnight. The batch was filtered and dried in a vacuum oven at ~40 °C overnight, under vacuum with nitrogen bleed.
[00212] Procedure F: Compound 1 was dissolved in 9x vol THF/H20 (95:5 vol). After polish filtration, distillation to reduce volume from 9x to 5x was performed, followed by addition of 8x ethyl acetate to bring the total volume to 13x. Solvent exchange to ethyl acetate, with constant volume distillation was carried out (final THF NMT 2%). The temperature was then reduced to 30 °C. Seeds of compound 2 (1% wt) were charged. A solution of H3PO4 (1.2 eq.) in ethanol (5x) was then dosed in over 2 hours. The temperature was reduced to 20 °C, the batch was aged for 12 hours under vigorous stirring, then filtered, washed two times with ethyl acetate and dried in a vacuum oven at ~40 °C overnight, under vacuum with nitrogen bleed.
[00213] Procedure G: Compound 1 was charged to a reactor, then ethanol (4x vol) and ethyl acetate (6x), were charged. The batch was agitated at 30 °C. A solution of H3PO4 (1.2 mol eq.) in ethanol (2x vol) was charged over 2 hours. Seeds of compound 2 Form A (1%) were charged. The batch was filtered, washed two times with ethyl acetate, dried overnight at -40 °C, under vacuum with nitrogen bleed.
[00214] Characterization of the resulting material demonstrated a crystalline, anhydrous Form A of compound 2. Up to 3.8% water uptake was observed for this Form at 95% relative humidity.
[00215] Table 1, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 2.
Table 1 - XRPD Peak Positions for Form A of Compound 2
Figure imgf000054_0001
In this and all subsequent tables,
the position 2d? is within ± 0.2. [00216] Figure 1 depicts an XRPD pattern of Form A of compound 2.
[00217] Elemental analysis - Calculated: C 47.49; H 4.35; N 15.10; P 5.57; Found: C
47.09; H 4.33; N 14.90; P 5.57.
[00218] Karl Fisher titration: 0.22%
Example 1. PK and Food Effects in Dogs
[00219] A first formulation comprising compound 1 (freebase) in a vehicle of 5% SBE betacyclodextrin (e.g., Captisol®) and 0.2% polysorbate 80 (Tween 80) was developed. This formulation provided sufficient exposure of compound 1 in dogs. After salt selection, it was found that the compound 2 (phosphate salt) had much better solubility in Captisol solution and sodium lauryl sulfate (SLS) solution. (See Figures 5 and 6)
[00220] Table 5 shows the pharmacokinetic results of (1) compound 2 in two different vehicles when administered to dogs at fasted state (see columns 3 and 4); (2) compound 2 formulated with different concentrations of SBE betacyclodextrin (see columns 5 and 6); and (3) food effects when compound 2 is administered in an SBE betacyclodextrin formulation to either fasted or fed dogs (columns 4 and 5).
[00221] The data from columns 3 and 4 suggest that compound 2 formulated in 20% SBE betacyclodextrin/0.2%) Tween 80/0.05 M citric acid showed increased exposure compared with compound 2 formulated in 0.5% MC/0.2% Tween 80/0.05 M citric acid. Varying the concentration of SBE betacyclodextrin from 20% to 10% afforded only slight differences in exposure (see columns 5 and 6). As can be seen from a comparison of the data in columns 4 and 5, compound 2 demonstrated a positive food effect.
Table 5
Figure imgf000056_0001
*one dog was excluded from final PK calculation for 20% SBE betacyclodextrin formulation groups because extremely high exposure was observed under fasted and fed conditions.
Example 2. Formulations for Dissolution Study
[00222] Three formulations were evaluated for dissolution. The first formulation was a capsule containing only compound 2. The second formulation contained SBE betacyclodextrin (Captisol®) (see Table 6, below). The third formulation contained citric acid (see Table 6, below). Both the SBE betacyclodextrin formulation and citric acid formulation were prepared using a wet granulation process.
Table 6
Figure imgf000057_0001
Capsule Preparation:
[00223] A liquid phase was prepared for each formulation by weighing out SLS and PVP (SBE betacyclodextrin formulation) or citric acid and PVP (citric acid formulation) into a 6 mL vial and adding to each an amount of 0.5 mL water. For the citric acid solution preparation, it was found that predissolving the PVP in water prior to addition of citric acid expedited solvation of PVP. Next, a solid phase was prepared for each formulation by weighing out and mixing compound 2 and all remaining excipients except for magnesium stearate. Each dry blend was then sieved three times through a 35 mesh (500 μΜ) and transferred to its own mortar.
[00224] A liquid phase was added to each mortar, with constant stirring. Once the liquid and solid phases were well mixed, the resulting mixtures were sieved through a 14 mesh (1410 μΜ) and dried at 60 °C for one hour. The dried mixtures were then sieved through a 20 mesh (841 μΜ). Magnesium stearate was then added to each formulation and mixed lightly. 400 mgs of each formulation were then weighed into separate capsules.
[00225] Dissolution results and visual observation indicated that the formulation with citric acid had relatively poor dissolution, similar to that of the capsule containing only compound 2.
Example 3. Formulations for Dog PK Study [00226] As the citric acid formulation had poor dissolution, citric acid was replaced with sodium chloride in the formulations for dog PK comparison study. Three formulations were prepared according to the method described above. The first formulation contained only compound 2 in a capsule. The second formulation contained SBE betacyclodextrin (e.g., Captisol®) (see Table 7, below). The third formulation contained sodium chloride (see Table 7, below).
Number of capsules: 20 for each formulation.
Table 7
Figure imgf000058_0001
[00227] Results from the formulation PK comparison study illustrated that formulations containing SBE beta cyclodextrin (Captisol®) gave comparable exposure to the formulation containing only compound 2, though a trend towards improved exposure was noted in presence of SBE beta cyclodextrin. Formulations containing NaCl resulted in lower exposure than was observed with the formulation containing only compound 2. Results are depicted graphically in Figure 7. Dosing group 1 tests a suspension of compound 2 in 5% SBE betacyclodextrin and 0.2% polysorbate; dosing group 2 tests a suspension of compound 2 in 5% SBE betacyclodextrm and 0.2% polysorbate; dosing group 3 tests a capsule of compound 2 only; dosing group 4 tests a capsule of compound 2 and 20% SBE betacyclodextrm as described in Table 7; and dosing group 5 tests a capsule of compound 2 and 10%> NaCl as described in Table 7. The results shown in Figure 7 are also displayed in Tables 8 and 9.
Table 8
Figure imgf000059_0001
Table 9
Figure imgf000059_0002
Example 4. Formulations for Stability Study
[00228] Six capsule formulations were prepared for the stability study using the procedure described above. The goals of this study were to evaluate the stability of the SBE betacyclodextrin formulation and to compare the stability of such formulations when prepared using a wet granulation process versus a dry blend process. Table 10 outlines the components of SBE betacyclodextrin formulation using wet and dry granulation processes. Table 10
Figure imgf000060_0001
[00229] Results from the excipient compatibility study indicated that compound 2 is unstable in an acidic environment at 75% RH. Therefore, a dry blend process was chosen to prepare the acidified formulation by adding citric acid to the formulations with and without SBE betacyclodextrin (e.g., Captisol®) in Table 11.
Table 11
Figure imgf000060_0002
[00230] Based on positive food effect information, a lipid (Phospholipon 90H) was added to the formulation, and the formulation was again prepared using a wet granulation process and a dry process for comparative purposes as shown in Table 12.
Table 12
Figure imgf000061_0001
[00231] The above results from the dissolution, PK, and stability studies led to the following conclusions: lactose appeared to cause discoloration; citric acid formulations exhibited relatively poor dissolution and relatively poor stability; the addition of Phospholipon to a provided formulation, at least at the amount tested above, did not appear to cause significant improvement in exposure; and, wet granulation preparation processes appear to cause higher levels of degradation than dry blend preparation processes.
[00232] Accordingly, a lactose-free SBE betacyclodextrin formulation prepared using a dry blend process was indicated as beneficial.
Example 5. Formulations Addressing Drug Dispersion
[00233] Three formulations were prepared to assess the effect, if any, on the amount of sodium bicarbonate (see Table 13). 150 mg dry blend capsules of compound 2 formulated with SBE betacyclodextrin showed relatively poor dissolution at pH 1.0. The content of the capsules did not disperse during dissolution due to the tendency of compound 2 to gel in a wet environment. It was surprisingly discovered that sodium bicarbonate greatly assisted in the dispersing of capsule content and provided an immediate release effect for capsules containing 150 mg of compound 2. The effect of different amounts of sodium bicarbonate on capsules containing 150 mg compound 2 and formulated with SBE betacyclodextrin is shown in Figure 8.
Table 13
Figure imgf000062_0001
[00234] The resulting final formulation is shown in Table 14, below, for 5 mg, 30 mg, and 150 mg capsules.
Table 14
Figure imgf000063_0001
[00235] Preparation of 5 mg capsule:
Sodium lauryl sulfate, sodium bicarbonate, betadex sulfobutyl ether sodium and crospovidone were combined together and mixed. To this mixture was added compound 2. This mixture was further mixed and then screened. Approximately a half portion of microcrystalline cellulose was then added to the mixture, which was again mixed and screened. The remaining microcrystalline cellulose and colloidal silicon dioxide were then added to the mixture, which was again mixed and screened. The resulting mixture was blended in a blender for about 400 revolutions. Sieved magnesium stearate was then added to the blend and the blend was again blended, this time for about 60 revolutions. 80 mg of the final blend was added into each size 4 gelatin capsule.
[00236] Preparation of 30 mg and 150 mg capsules:
Sodium lauryl sulfate and sodium bicarbonate were combined together and mixed, and the mixture was screened. To this was added crospovidone, and the mixture was again mixed and screened. To this was added betadex sulfobutyl ether sodium, and the mixture was again mixed and screened. To this was added microcrystalline cellulose and colloidal silicon dioxide, and the mixture was again mixed and screened. To this was added compound 2, and the mixture was again mixed and screened. The resulting mixture was blended in a blender for about 400 revolutions. Sieved magnesium stearate was then added to the blend and blended for about 60 revolutions. For the 30 mg API capsules, 80 mg of the final blend were added to each size 4 gelatin capsule. For the 150 mg API capsules, 400 mg of the final blend were added to each size 0 gelatin capsule.
[00237] Preparation of 5 mg capsule (scale up):
Sodium lauryl sulfate, sodium bicarbonate and betadex sulfobutyl ether sodium were combined together and mixed. Blended into this mixture was compound 2, Crospovidone, microcrystalline cellulose, and colloidal silicon dioxide. The resulting mixture was blended in a blender for about 250 revolutions and then screened. The screened mixture was again blended in a blender for about 400 revolutions. Magnesium stearate was added to the blend and blended for about 60 revolutions. 80 mg of the final blend were added into each size 4 gelatin capsule.
[00238] Preparation of 30 mg capsule (scale up):
Sodium lauryl sulfate, sodium bicarbonate and Crospovidone were combined together and mixed. Blended into this mixture was compound 2, betadex sulfobutyl ether sodium, microcrystalline cellulose, and colloidal silicon dioxide. The resulting mixture was blended in a blender for about 250 revolutions and then screened. The screened mixture was again blended in a blender for about 400 revolutions. Magnesium stearate was added to the blend and blended for about 60 revolutions. 80 mg of the final blend were added into each size 4 gelatin capsule.
[00239] Preparation of 150 mg capsule (scale up):
Sodium lauryl sulfate, sodium bicarbonate and Crospovidone were combined together and mixed. Blended into this mixture was compound 2, betadex sulfobutyl ether sodium, microcrystalline cellulose, and colloidal silicon dioxide. The resulting mixture was blended in a blender for about 250 revolutions and then screened. The screened mixture was again blended in a blender for about 400 revolutions. Magnesium stearate was added to the blend and blended for about 60 revolutions. 400 mg of final blend were added into each size 0 gelatin capsule.

Claims

CLAIMS We claim:
1. A pharmaceutically acceptable formulation for oral administration comprising compound 1 :
Figure imgf000065_0001
1 or a pharmaceutically acceptable salt thereof.
2. The formulation according to claim 1, wherein compound 1 is in the form of compound 2:
Figure imgf000065_0002
Compound 2
and at least one additional agent selected from the group consisting of: solubilizers, surfactants/wetting agents, dispersing agents, fillers, disintegrants, glidants, lubricants, and combinations thereof.
3. The formulation according to claim 2, wherein the formulation comprises at least one additional agent selected from a solubilizer, a surfactant/wetting agent, and a dispersing agent.
4. The formulation according to claim 3, wherein the formulation comprises at least two additional agents selected from a solubilizer, a surfactant/wetting agent, and a dispersing agent.
5. The formulation according to claim 4, wherein the formulation comprises a solubilizer, a surfactant/wetting agent, and a dispersing agent.
6. The formulation according to claim 2, wherein the formulation comprises about 1% to about 60% compound 2, by weight.
7. The formulation according to claim 6, wherein the formulation comprises about 1% to about 20% compound 2, by weight.
8. The formulation according to claim 6, wherein the formulation comprises about 30%) to about 50%o compound 2, by weight.
9. The formulation according to claim 8, wherein the formulation comprises from about 1% to about 50% solubilizer, based upon total weight of the formulation.
10. The formulation according to claim 9, wherein the solubilizer is cyclodextrin.
1 1. The formulation according to claim 10, wherein the solubilizer is betadex sulfobutyl ether sodium.
12. The formulation according to claim 2, wherein the surfactant/wetting agent is sodium lauryl sulfate.
13. The formulation according to claim 2, wherein the dispersing agent is sodium bicarbonate.
14. The formulation according to claim 2, wherein the formulation comprises from about 10% to about 90% filler, based upon total weight of the formulation.
15. The formulation according to claim 14, wherein the filler is microcrystalline cellulose.
16. The formulation according to claim 2, wherein the formulation comprises from about 1% to about 15% disintegrant, based upon total weight of the formulation.
17. The formulation according to claim 16, wherein the disintegrant is crospovidone.
18. The formulation according to claim 2, wherein the formulation further comprises from about 0.1% to about 3% glidant.
19. The formulation according to claim 18, wherein the glidant is colloidal silicon dioxide.
20. The formulation according to claim 2, wherein the formulation comprises from about 1% to about 3% lubricant, based upon total weight of the formulation.
21. The formulation according to claim 20, wherein the lubricant is magnesium stearate.
22. The formulation according to claim 2, wherein the provided composition comprises the following components:
(a) about 1% to about 60%> compound 2;
(b) about 1%) to about 50%> solubilizer;
(c) about 0.1%) to about 10%> surfactant/wetting agent;
(d) about 0.1%) to about 20%> dispersing agent;
(e) about 10% to about 90% filler;
(f) about l%o to about 30%> disintegrant;
(g) about 0.1%) to about 3% glidant; and
(h) about 0.1%o to about 3% lubricant;
wherein the amount of each component is based upon the total weight of the composition.
23. The formulation according to claim 2, wherein provided composition comprises the following components:
(a) about 1% to about 60% compound 2;
(b) about l%o to about 50% betadex sulfobutylether sodium;
(c) about 0.1%) to about 10% sodium lauryl sulfate; (d) about 0.1% to about 20% sodium bicarbonate;
(e) about 10%> to about 90%> microcrystalline cellulose;
(f) about 1%) to about 30%> crospovidone;
(g) about 0.1%) to about 3% colloidal silicon dioxide; and
(h) about 0.1%) to about 3% magnesium stearate;
wherein the amount of each component is based upon the total weight of the composition.
24. The formulation according to claim 2, wherein the polymorphic form of compound 2 is Form A.
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