EP4294525A1 - Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof - Google Patents

Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

Info

Publication number
EP4294525A1
EP4294525A1 EP21710375.3A EP21710375A EP4294525A1 EP 4294525 A1 EP4294525 A1 EP 4294525A1 EP 21710375 A EP21710375 A EP 21710375A EP 4294525 A1 EP4294525 A1 EP 4294525A1
Authority
EP
European Patent Office
Prior art keywords
dihydroxypropoxy
fluoro
difluoro
iodo
benzamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21710375.3A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kristin Patterson
Jiping Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SpringWorks Therapeutics Inc
Original Assignee
SpringWorks Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SpringWorks Therapeutics Inc filed Critical SpringWorks Therapeutics Inc
Publication of EP4294525A1 publication Critical patent/EP4294525A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to dispersible formulations of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide for use in administration to patients in need thereof, and methods of producing such dispersible formulations.
  • the present disclosure further relates to dispersible formulations comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; methods of producing dispersible formulations comprising N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and methods and uses of treating a tumor, a cancer, or a Rasopathy disorder by administering N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide to a subject in need thereof.
  • Neurofibromatosis Type 1 (“NF1”) is characterized by diverse, progressive cutaneous, neurological, skeletal and neoplastic manifestations with no standard drug treatment options available.
  • Neurofibromas are benign peripheral nerve sheath tumors comprised of a mixture of Schwann cells, fibroblasts, perineurial cells, and mast cells and occur in 20 to 50% of NF1 patients (Tucker, et al. (2011) J. Histochem. Cytochem. 59(6):584-590).
  • PN plexiform neurofibroma
  • Plexiform neurofibromas rarely regress spontaneously, and in many patients their growth is relentless.
  • Plexiform neurofibromas represent a major cause of morbidity and disfigurement in individuals with NF1, and when symptomatic, are associated with increased mortality (Rasmussen, et al. (2001) Am. J. Hum. Genet. 68(5): 1110-1118; Prada, et al. (2012) J. Pediat. 160(3):461-467). As tumor growth progresses, such lesions produce dysfunction, pain, and cosmetic disfigurement and can compress the airway or spinal cord. Furthermore, PNs have the potential to undergo malignant transformation producing malignant peripheral nerve sheath tumors (MPNSTs).
  • MPNSTs malignant peripheral nerve sheath tumors
  • Nguyen et al. conducted a retrospective study of 71 patients with an evaluable PN for a median follow-up of 2.2 years (range 1.1 to 4.9 years).
  • tumors that grew more than 20% per year were significantly more frequent among children than among adults (p ⁇ 0.001).
  • findings from three independent retrospective reviews of PN volume clearly show that the growth rate of PNs in NFl patients is inversely correlated with age, indicating discrete age dependent tumor differences and an unmet need in the pediatric population.
  • Dysphagia any patient in need of treatment but who experiences difficulty swallowing (“dysphagia”) would benefit from a non-capsule or tablet formulation which can be orally administered.
  • Dysphagia can be caused by a variety of circumstances affecting one or more components of the swallowing process.
  • These can include but are not limited to: physical damage to the tongue, pharynx, larynx, esophagus, or trachea caused by trauma, infection, proliferative disease; treatment for a such a condition; congenital anatomical defects such as cleft palate; underdevelopment at young age; weakening at old age; dementia, memory loss, or cognitive decline; or any condition which otherwise weakens or damages the muscles or nerves used in the swallowing process, such as Parkinson’s disease, stroke, or nervous system disease.
  • N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (“mirdametinib", or "PD-0325901") is a small molecule drug which has been designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1”) and mitogen- activated protein kinase kinase 2 (“MEK2").
  • MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase (“MAPK”) signaling pathway.
  • Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEKl and MEK2.
  • mirdametinib leads to significantly inhibited phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby leading to impaired growth of tumor cells both in vitro and in vivo.
  • evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.
  • Form IV is incorporated by reference.
  • the '856 patent indicates that the material produced by this method was greater than 90% Form IV (The '856 patent, Example 1).
  • the '856 patent also states that the differential scanning calorimetry ("DSC") of the material produced shows an onset of melting at 110°C, as well as a small peak with an onset at 117°C, consistent with the material being a mixture of two forms.
  • Compositions containing more than one polymorphic form are generally undesirable because of the potential of interconversion of one polymorphic form to another. Polymorphic interconversion can lead to differences in the effective dose or physical properties affecting processability of a drug, caused by differences in solubility or bioavailability.
  • FIG. 1 A is a X-ray powder diffraction pattern ("XRPD") corresponding to essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide.
  • XRPD X-ray powder diffraction pattern
  • FIG. IB is a thermogravimetric analysis thermogram ("TGA”) and a differential scanning calorimetry thermogram (“DSC”) corresponding to essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- pheny 1 amino)-b enzami de .
  • TGA thermogravimetric analysis thermogram
  • DSC differential scanning calorimetry thermogram
  • FIG. 3A is an XRPD corresponding to essentially pure Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after storage for 68 months after production at 25°C and ⁇ 65% relative humidity.
  • FIG. 3B is an XRPD corresponding to essentially pure Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after storage for 140 months after production at 25°C and ⁇ 65% relative humidity.
  • compositions for treating disorders whereby aberrant MEK1 or MEK2 activity is implicated e.g., a tumor, a cancer, or a Rasopathy disorder, such as neurofibromatosis type 1, in a subject in need thereof.
  • the methods and compositions described herein are useful in treating patients who struggle to swallow whole capsules or tablets, e.g., pediatric patients or subjects suffering from dysphagia, such as patients with esophageal cancer, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, achalasia, or esophageal narrowing.
  • compositions comprise Form I, Form II, or Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the present disclosure is directed to a pharmaceutical composition comprising an amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide of Formula (I)
  • composition wherein the pharmaceutical composition is dispersible in a potable liquid (e.g., water) or orodispersible in a subject’s saliva.
  • a potable liquid e.g., water
  • orodispersible in a subject saliva.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide in the pharmaceutical compositions described herein is crystalline.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is selected from the group consisting of: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, and 14.6 ⁇ 0.2 degrees two theta; (b) a crystalline form of N-((R)-
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, and 14.6 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, 14.6 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 1 A.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC profile which does not include an endotherm with an onset at about 117°C.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by one or both of: (a) a TGA profile substantially as shown in FIG. IB; and/or (b) a DSC profile substantially as shown in FIG. IB.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.
  • 2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IV.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is essentially pure Form IV.
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 year at standard warehouse conditions (15°C- 25°C and ⁇ 65% relative humidity).
  • the essentially pure Form IV of N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the essentially pure Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for >140 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for >14 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the XRPD pattern is generated using a P ANALYTICAL ® X'Pert
  • Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03° 2Q with a X'CELERATOR ® Real Time Multi-Strip detector configured (a) on the incidental beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit or a BRUKER ® D8 ® ADVANCETM system using Cu Ka (40 kV/40 mA) radiation and a step size of 0.03° 20 with a LYNXEYETM detector, configured (a) on the incidental beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Soller slit, beam knife, and (b) on
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 19.0 ⁇ 0.2, and 23.7 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 14.6 ⁇ 0.2, 17.3 ⁇ 0.2, 18.0 ⁇ 0.2, 18.2 ⁇ 0.2, 19.0 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 21.0 ⁇ 0.2, 21.9 ⁇ 0.2, 22.4 ⁇ 0.2, 23.7 ⁇ 0.2, 24.0 ⁇ 0.2, 24.9 ⁇ 0.2, 26.3 ⁇ 0.2, 27.6 ⁇ 0.2, 28.0 ⁇ 0.2, 30.1 ⁇ 0.2, 32.1 ⁇ 0.2, 32.3 ⁇ 0.2,
  • 2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC profile with an endotherm with onset at about 117 °C.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 ⁇ 0.2 and 19.6 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 ⁇ 0.2, 10.7 ⁇ 0.2, 16.5 ⁇ 0.2, 19.6 ⁇ 0.2, 22.0 ⁇ 0.2, 22.5 ⁇ 0.2, 23.6 ⁇ 0.2, 24.1 ⁇ 0.2, 25.0 ⁇
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC profile with an endotherm with onset at about 87 °C.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form II.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is dispersible. In some aspects, the pharmaceutical composition is orodispersible.
  • the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets (also called beads).
  • the pharmaceutical composition is a powder. In some aspects, the pharmaceutical composition is a dispersible powder. In some aspects, a capsule or sachet comprises the dispersible powder.
  • the pharmaceutical composition is in the form of granules.
  • the granules are dispersible granules.
  • a capsule or sachet comprises the dispersible granules.
  • the pharmaceutical composition is in the form of minitablets.
  • the minitablets are dispersible minitablets.
  • a capsule or sachet comprises the dispersible minitablets.
  • the pharmaceutical composition is in the form of pellets.
  • the pellets are dispersible pellets.
  • a capsule or sachet comprises the dispersible pellets.
  • the pharmaceutical composition is a tablet.
  • the tablet is a dispersible tablet.
  • the tablet is an orodispersible tablet.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.2 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 75 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 3 wt/wt% to about 8 wt/wt% of one or more disintegrants
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegr
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 3 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide.
  • At least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose.
  • At least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium.
  • At least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
  • at least one of the flavoring agents is grape flavoring.
  • At least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects, at least one of the sweeteners is sucralose.
  • At least one of the lubricants is selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glycerol dibehenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate.
  • the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment a pharmaceutical composition (e.g., a dispersible tablet, a dispersible powder, dispersible granules, dispersible mintablets, or dispersible pellets) described herein.
  • a pharmaceutical composition e.g., a dispersible tablet, a dispersible powder, dispersible granules, dispersible mintablets, or dispersible pellets
  • the present disclosure provides use of a pharmaceutical composition (e.g., a dispersible tablet, a dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) described herein for the manufacture of a medicament for treating a tumor, a cancer, or a Rasopathy disorder.
  • a pharmaceutical composition e.g., a dispersible tablet, a dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets
  • the tumor is a neurofibroma.
  • the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, or malignant peripheral nerve sheath tumor.
  • the tumor is plexiform neurofibroma.
  • the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitf s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non- small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one dispersible tablet, more than one dose of dispersible powder, more than one dose of dispersible granules, more than one dose of dispersible minitablets, more than one dose of dispersible pellets, or a combination thereof.
  • a dose of 3 mg of the N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two dispersible tablets - one containing 2 mg and the other containing 1 mg or as three dispersible tablets each containing 1 mg.
  • a dose of 1.5 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide can be administered as two dispersible dosage forms - one dispersible tablet containing 1 mg and a separate unit of dispersible powder containing 0.5 mg or as three units of dispersible powder each containing 0.5 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is administered in a total daily dose that does not exceed 2 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is administered in a total daily dose that does not exceed 1 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • theN-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
  • the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
  • the subject is a pediatric subject.
  • the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.25 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 5 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 1 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 10 mg.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 4 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 2 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
  • the present disclosure provides a method of manufacturing a pharmaceutical composition, the method comprising forming a pharmaceutical composition described herein.
  • mirdametinib and “PD-0325901” refer to the single enantiomer N-
  • subject refers to an animal, including, but not limited to, a primate
  • subject e.g., human
  • cow, sheep, goat horse, dog, cat, rabbit, rat, or mouse.
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the term "pediatric” refers to a human subject under the age of 21 years at the time of treatment.
  • the term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty- second birthday)).
  • neonates from birth through the first 28 days of life
  • infants 29 days of age to less than two years of age
  • children two years of age to less than 12 years of age
  • adolescents (12 years of age through 21 years of age (up to, but not including, the twenty- second birthday)).
  • Berhman R E Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996
  • Rudolph A M et al. Rudolph's Pediatrics, 21st Ed.
  • the term “dispersible” as used herein refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets) which disintegrates and/or dissolves when combined with water or another potable liquid (e.g., a non-water beverage), or a subject’s own saliva when placed in the subject’s mouth, with or without the addition of agitation or temperature modification.
  • the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another potable liquid.
  • Such disintegration or dissolution need not be complete.
  • a dispersible tablet may dissolve almost entirely, but some undissolved particulate matter may remain.
  • orodispersible refers to a composition which is capable of dissolving or disintegrating in a subject’s mouth (/. ., dissolving or disintegrating in a subject’s saliva) if administered orally, without a requirement of first dissolving or disintegrating in a separate container.
  • the terms “treat,” “treated,” and “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • those in need of treatment include those already diagnosed with or suspected of having the disorder.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • therapeutically effective amount is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a subject is successfully "treated” for a tumor, according to the methods described herein if the patient shows one or more of the following: a reduction in the size of the tumor; relief of one or more symptoms associated with the specific tumor; a reduction in the volume of the tumor; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g ., CR, PFS, PR).
  • a subject is successfully "treated” for cancer, e.g., lung cancer or ovarian cancer, according to the methods described herein if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g, CR, PFS, PR).
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Excipients can include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient or a combination of multiple pharmaceutically acceptable excipients, and can be manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet (e.g., dispersible tablet), powder (e.g., dispersible powder) capsule, granules, minitablets, pellets, caplet, gelcap, or syrup).
  • the terms “about” or “approximately” means within a range of an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some aspects, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In some aspects, the term “about” or “approximately” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25,
  • the term "administration" refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject can be by any appropriate route, such as one described herein.
  • crystalline refers to a solid state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid state, which results in different crystal symmetries and/or unit cell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
  • Crystalline forms are commonly characterized by X-ray powder diffraction
  • XRPD XRPD
  • An XRPD pattern of reflections is commonly considered a fingerprint of a particular crystalline form.
  • the relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or the settings. In some instances, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type of instrument or the settings, the sensitivity of the instrument, measuring conditions, and/or purity of the crystalline form.
  • any particular peak in an XRPD may appear in a symmetric shape or in an asymmetric shape, e.g., having a shoulder.
  • instrument variation and other factors can affect the 2-theta values. A skilled artisan understanding these variations is capable of discriminating or ascertaining the defining features or characteristics of a particular crystal form using XRPD, as well as using other known physicochemical techniques.
  • anhydrate as applied to a compound refers to a crystalline form wherein the compound contains no structural water within the crystal lattice.
  • the term “essentially pure” with respect to Form IV means that the composition comprising Form IV contains no detectable amount of another polymorphic form (e.g., Form I or Form II), as determined by observing no detectable differences in an XRPD and/or DSC pattern between a single Form IV crystal and the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • another polymorphic form e.g., Form I or Form II
  • “essentially pure” Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis.
  • the term “aberration” as applied to a gene refers to a mutation, chromosomal loss or fusion, epigenetic chemical modification, or other event which alters the sequence, level of expression, or processed mRNA sequence associated with a gene relative to the sequence, level of expression, or processed mRNA sequence associated with the wild-type gene.
  • Dispersible formulations e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets
  • N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide which are safely administrable to a patient who has difficulty swallowing (e.g., a pediatric patient or a patient suffering from dysphagia) are described herein.
  • These properties include, but are not limited to: (1) packing properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions comprising the compound.
  • N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as Form I, Form II, or Form IV (e.g., essentially pure Form IV) of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide in addition to pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising an amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide of Formula (I)
  • composition wherein the pharmaceutical composition is dispersible in a potable liquid (e.g., water) or orodispersible in a subject’s saliva.
  • a potable liquid e.g., water
  • orodispersible in a subject saliva.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is crystalline.
  • the crystalline form of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is selected from the group consisting of: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, and 14.6 ⁇ 0.2 degrees two theta; (b) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide characterized by an XRPD pattern having peaks at 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 19.0 ⁇ 0.2, and 2
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, and 14.6 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, 14.6 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by an XRPD pattern substantially as shown in FIG. 1 A.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by one or both of: (a) a TGA profile substantially as shown in FIG. IB; and/or (b) a DSC profile substantially as shown in FIG. IB.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by a DSC profile which does not include an endotherm with an onset at about 117°C.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is anhydrous.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is Form IV.
  • the crystalline form of of N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is essentially pure Form IV.
  • the crystalline Form IV composition included in the pharmaceutical compositions described herein is stable, as demonstrated by a substantially unchanged XRPD pattern and/or DSC profile over time.
  • the crystalline Form IV composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 140 months, 12 years, 13 years, 14 years, or 15 years at standard warehouse conditions (15°C- 25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 year at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 5 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for >140 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for >14 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the XRPD pattern for Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is generated using a PANALYTICAL ® X'Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03° 2Q with a X'CELERATOR ® Real Time Multi-Strip detector, configured (a) on the incidental beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Sober slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Sober slit or a BRUKER ®
  • the DSC pattern is generated using a TA Instruments Q 100 or
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by an XRPD pattern having peaks at 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 19.0 ⁇ 0.2, and 23.7 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by an XRPD pattern having one or more peaks at 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 14.6 ⁇ 0.2, 17.3 ⁇ 0.2, 18.0 ⁇ 0.2, 18.2 ⁇ 0.2, 19.0 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 21.0 ⁇ 0.2, 21.9 ⁇ 0.2, 22.4 ⁇ 0.2, 23.7 ⁇ 0.2, 24.0 ⁇ 0.2, 24.9 ⁇ 0.2, 26.3 ⁇ 0.2, 27.6 ⁇ 0.2, 28.0 ⁇ 0.2, 30.1 ⁇ 0.2, 32.1 ⁇ 0.2, 32.3 ⁇ 0.2, 32.9 ⁇ 0.2, 35.8 ⁇ 0.2, and 37.7 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by a DSC profile with an endotherm with onset at about 117 °C.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is Form I.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by an XRPD pattern having peaks at 5.5 ⁇ 0.2 and/or 19.6 ⁇ 0.2 degrees two theta.
  • the crystalline form of N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 ⁇ 0.2, 10.7 ⁇ 0.2, 16.5 ⁇ 0.2, 19.6 ⁇ 0.2, 22.0 ⁇ 0.2, 22.5 ⁇ 0.2, 23.6 ⁇ 0.2, 24.1 ⁇ 0.2, 25.0 ⁇ 0.2, 26.2 ⁇ 0.2, 27.6 ⁇ 0.2,
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is characterized by a DSC profile with an endotherm with onset at about 87 °C.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the pharmaceutical compositions described herein is Form II.
  • the present disclosure provides a pharmaceutical composition
  • the pharmaceutical composition (e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets
  • the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is orodispersible.
  • the potable liquid is water, milk or a juice (e.g., orange juice or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is a juice.
  • the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets.
  • the pharmaceutical composition is a powder.
  • the powder is a dispersible powder.
  • a capsule or sachet comprises the dispersible powder.
  • the pharmaceutical composition is in the form of granules.
  • the granules are dispersible granules.
  • a capsule or sachet comprises the dispersible granules.
  • the pharmaceutical composition is in the form of minitablets.
  • the minitablets are dispersible minitablets.
  • a capsule or sachet comprises the dispersible minitablets.
  • the pharmaceutical composition is in the form of pellets.
  • the pellets are dispersible pellets.
  • a capsule or sachet comprises the dispersible pellets.
  • the pharmaceutical composition is a tablet.
  • the tablet is a dispersible tablet.
  • the dispersible tablet is an orodispersible tablet.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide wherein each component of the pharmaceutical composition is as follows: (a) about 0.2 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 75 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 3 wt/wt% to about 8 wt/wt% of one or more disintegrants;
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegr
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.5 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 4 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 6 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 7 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 8 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 9 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 11 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 12 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 13 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 14 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 15 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 16 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 17 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 18 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 19 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 20 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 wt/wt% to about 7 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 wt/wt% to about 5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.75 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.8 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises one or more diluents. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 50 wt/wt% to about 98 wt/wt% of one or more diluents.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible disgranules, dispersible minitablets, or dispersible pellets comprises about 75 wt/wt% to about 98 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 85 wt/wt% to about 95 wt/wt% of one or more diluents.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%, about 58 wt/wt%, about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%, about 63 wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67 wt/wt%, about 68 wt/wt%, about 69 wt/wt%,
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 90 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 91 wt/wt% of one or more diluents.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 92 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 93 wt/wt% of one or more diluents.
  • At least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
  • at least one of the diluents is microcrystalline cellulose.
  • the pharmaceutical composition comprises about 50 wt/wt% to about 98 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 75 wt/wt% to about 98 wt/wt% microcrystalline cellulose.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 85 wt/wt % to about 95 wt/wt % microcrystalline cellulose.
  • the pharmaceutical composition comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%, about 58 wt/wt%, about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%, about 63 wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67 wt/wt%, about 68 wt/wt%, about 69 wt/wt%, about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt %, about 73
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 90 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 91 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 92 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 93 wt/wt% microcrystalline cellulose.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 1.0 wt/wt% to about 10 wt/wt% of one or more disintegrants. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants.
  • the pharmaceutical composition comprises about 1.0 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2.0 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/w
  • At least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
  • at least one of the disintegrants is croscarmellose sodium.
  • the disintegrant is croscarmellose sodium.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 1.0 wt/wt % to about 10 wt/wt % croscarmellose sodium.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 3.5 wt/wt % to about 6 wt/wt % croscarmellose sodium.
  • the pharmaceutical composition comprises about about 1.0 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2.0 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 5 wt/wt % croscarmellose sodium.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 w
  • At least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
  • at least one of the flavoring agents is grape flavoring.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 5.0 wt/wt% grape flavoring.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 2.5 wt/wt% grape flavoring.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 w
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 5 wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 2 wt/wt% of one or more sweeteners.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 w
  • At least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
  • at least one of the sweeteners is sucralose.
  • the sweetener is sucralose.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 5 wt/wt% sucralose.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 2 wt/wt% sucralose.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 w
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 5 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 wt/wt% to about 5 wt/wt% of one or more lubricants.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
  • the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about
  • At least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
  • at least one of the lubricants is magnesium stearate.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt% to about 5 wt/wt% magnesium stearate.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 wt/wt% to about 2 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.5 wt/wt% to about 2 wt/wt% magnesium stearate.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt % magnesium stearate. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 1 wt/wt % magnesium stearate.
  • the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.
  • the tumor is a neurofibroma.
  • the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • the tumor is plexiform neurofibroma.
  • the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitf s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one tablet, more than one dose of dispersible powder, more than one dose of dispersible granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
  • a dose of 3 mg of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two dispersible tablets - one containing 2 mg and the other containing 1 mg or as three dispersible tablets each containing 1 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg to about 20 mg per dose of the pharmaceutical compositions described herein.
  • the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is provided in an amount of about 0.5 mg per dose. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is provided in an amount of about 1 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is provided in an amount of about 2 mg per dose. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 3 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 4 mg per dose. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 5 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 10 mg per dose. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 20 mg per dose.
  • the pharmaceutical composition comprising N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered one time, two times, three times, or four times per day.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times per day.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.
  • the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
  • the N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose does not exceed 2 mg. In some aspects, the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • theN-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
  • the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • the subject has been diagnosed with an autism spectrum disorder.
  • the subject has been diagnosed with a craniofacial disorder.
  • the subject has been diagnosed with myasthenia gravis.
  • the subject has been diagnosed with tardive dyskinesia.
  • the subject is a pediatric subject. In some aspects, the subject is less than 18 years old, less than 17 years old, less than 16 years old, less than 15 years old, less than 14 years old, less than 13 years old, less than 12 years old, less than 11 years old, less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, or less than 1 year old.
  • the subject is 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, or 17 years old. In some aspects, the subject is less than 13 years old. In some aspects, the subject is less than 12 years old. In some aspects, the subject is less than 11 years old. In some aspects, the subject is less than 10 years old. In some aspects, the subject is less than 9 years old. In some aspects, the subject is less than 8 years old. In some aspects, the subject is less than 7 years old. In some aspects, the subject is less than 6 years old.
  • the subject is less than 5 years old. In some aspects, the subject is less than 4 years old. In some aspects, the subject is less than 3 years old. In some aspects, the subject is less than 2 years old. In some aspects, the subject is less than 1 year old. In some aspects, the subject is about 2 to about 18 years old. In some aspects, the subject is about 3 to about 17 years old. In some aspects, the subject is about 4 to about 16 years old. In some aspects, the subject is about 5 to about 15 years old. In some aspects, the subject is about 6 to about 14 years old. In some aspects, the subject is about 7 to about 13 years old. In some aspects, the subject is about 8 to about 12 years old.
  • the subject is a geriatric subject. In some aspects, the subject is more than 30 years old, more than 35 years old, more than 40 years old, more than 45 years old, more than 50 years old, more than 55 years old, more than 60 years old, more than 65 years old, more than 70 years old, more than 75 years old, more than 80 years old, more than 85 years old, more than 90 years old, more than 95 years old, or more than 100 year old. In some aspects, the subject is more than 50 years old. In some aspects, the subject is more than 60 years old. In some aspects, the subject is more than 70 years old. In some aspects, the subject is more than 80 years old. In some aspects, the subject is more than 90 years old. In some aspects, the subject is more than 100 years old.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide can be divided so the patient receives different doses at each administration.
  • the patient can receive 0.5 mg (e.g., as one 0.5 mg dispersible tablet) in the morning and 1.5 mg (e.g., as one 0.5 mg dispersible tablet and one 1 mg dispersible tablet) in the evening.
  • 0.5 mg e.g., as one 0.5 mg dispersible tablet
  • 1.5 mg e.g., as one 0.5 mg dispersible tablet and one 1 mg dispersible tablet
  • the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.
  • the total daily dose of the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.25 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 5 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered once daily at a dose of about 10 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered via a pharmaceutical composition described herein, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is provided at a total daily dose that does not exceed 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg,
  • the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
  • the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
  • the N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
  • the present disclosure provides use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a tumor, a cancer, or a Rasopathy disorder.
  • Step 3 Preparation of PD-0325901
  • PD-0325901 is separated from process impurities and degradants by reversed- phase liquid chromatography with UV detection at 275 nm. Identification of PD- 0325901 is performed by obtaining either an infrared or proton NMR spectrum, in addition to the HPLC retention time. For purity evaluation, process impurities and degradants are identified by their characteristic relative retention times and quantitated by area normalization.
  • Chromatographic Conditions Agilent Zorbax SB C18, 5 pm, 4.6 x 250 mm (or equivalent); flow rate is 1.0 mL/min; column temperature is 30 °C; detector wavelength is 275 nm; diluent is 50/50 acetonitrile/water; mobile phase A is 0.1% trifluoroacetic acid (TFA) in water; mobile phase B is methanol; and the gradient conditions below.
  • the assay is determined against a reference standard and reported on an anhydrous, solvent free basis. Quantification of specified and unspecified impurities is reported by area percent. Total impurities is the sum of all impurities present above the reporting threshold of 0.05%.
  • the route is a convergent four step synthesis with six chemical steps overall, using the proposed starting materials fV)-(+)-2,2-di methyl -1 ,3-dioxolane-4-methanol (SGA), 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-idodoaniline (FIA), and N- hydroxyphthalimide (NHP).
  • SGA 2,3,4-trifluorobenzoic acid
  • FIA 2-fluoro-4-idodoaniline
  • NHS N- hydroxyphthalimide
  • Step 1 (Preparation ofPD-0337792 (IPGA )): A clean, dry 100-gallon reactor was charged with toluene (139.3 kg, 8 volumes) and (S)-(+)-2,2-Dimethyl-l,3-dioxolane-4- methanol (SGA; 20.0 kg, 1.0 equivalents). Triethylamine (18.8 kg, 1.22 equivalents) was charged to the reactor. The reactor contents were agitated and cooled to -10 ⁇ 10 °C. Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was added to a clean 50- L round bottom flask under nitrogen then cooled to a temperature of ⁇ -10 °C.
  • the cooled trifluoromethanesulfonic anhydride was slowly transferred to the 100-gallon reactor while maintaining the internal temperature at -10 ⁇ 10 °C.
  • the reaction mixture was agitated at -10 ⁇ 10 °C for 30 minutes. Reaction monitoring by TLC indicated the conversion to be complete.
  • anhydrous toluene 99.8 kg, 5.75 volumes
  • N-hydroxyphthalimide 26.4 kg, 1.07 equivalents
  • the contents were warmed to 20 ⁇ 5 °C then agitated at this temperature for at least 5 hours, until the triflate intermediate was not detectable by TLC.
  • the reaction mixture was split into two equal portions. Each toluene solution was quenched with USP purified water (66 kg, 6.7 volumes). The toluene solution was then washed twice with USP purified water (66 kg, 6.7 volumes).
  • the toluene solutions were recombined in a 100-gallon reactor.
  • the organic solution was treated with 28% ammonium hydroxide solution (41.5 kg, 7.8 equivalents).
  • the contents were heated to 35 ⁇ 5 °C then agitated for not less than (“NLT”) 12 hours.
  • NLT not less than
  • the toluene solution was dried via azeotropic distillation of toluene.
  • the toluene solution was then concentrated to minimum stir volume.
  • the concentrated solution was filtered to remove by-product solids.
  • the cake was washed with toluene and the filtrates were combined.
  • Assay of the toluene solution indicated 8.6 kg (36.7% yield) ofPD-0337792 (IPGA) was present.
  • Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon reactor was purged with nitrogen then charged with lithium amide (LiNH2, 8.8 kg, 3.4 equivalents) followed by tetrahydrofuran (THF, 56.8 kg, 3.2 volumes). The mixture was cooled to 10 ⁇ 10 °C then additional THF (15.1 kg, 0.85 volumes) was charged to the reactor, followed by a solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equivalent) in THF (26.4 kg, 1.15 volumes). The reaction mixture was heated to NMT (“not more than”) 50 °C.
  • TFBA 2,3,4-trifluorobenzoic acid
  • Step 3 (Preparation of crude PD-0325901): A clean, dry 100-gallon reactor was purged with nitrogen then charged with PD-0315209 (18.0 kg, 1 equivalent) and THF (113.0 kg, 7 volumes). The mixture was cooled to 5 ⁇ 5 °C. N,N-diisopropylethylamine (15.1 kg, 2.55 equivalents) was charged maintaining the temperature NMT 25 °C. The mixture was cooled to 5 ⁇ 5 °C then stirred for 10 minutes.
  • PD-0337792 solution in toluene (121.7 kg total, 1.3 equivalents) was charged to the reactor at 5 ⁇ 5 °C, followed by 50% T3P in ethyl acetate (42.0 kg, 1.45 equivalents). The reaction mixture stirred at 10 ⁇ 5 °C for NLT 3 hours. An additional charge of N,N-diisopropylethylamine (1.9 kg, 0.3 equivalents) and 50% T3P in ethyl acetate (4.1 kg, 0.15 equivalents) were made to advance the coupling to completion. The reaction was reverse quenched into a 5% sodium hydroxide solution (50 kg), followed by washing with 5% brine (55.4 kg). The organic solution was concentrated then solvent swapped with toluene. Acetonitrile (43.0 kg, 2.4 volumes) was added to the reactor followed by 2M hydrochloric acid (117.6 kg, 5.1 equivalents). The mixture stirred at 25 ⁇ 5 °C until reaction completion after 16 hours.
  • Step 4 Preparation of Essentially Pure Form IV Mirdametinib: A clean, dry
  • FIG. 1 A An XRPD pattern for essentially pure Form IV used herein is shown in FIG. 1 A.
  • FIG. IB TGA and DSC analysis of essentially pure Form IV used herein are shown in FIG. IB.
  • Example 4 0.5 mg and 1.0 mg Dispersible Tablet Formulations
  • Example 5 A Manufacturing Process for Mirdametinib Dispersible Tablets
  • a non-limiting example of an exemplary process for producing mirdametinib dispersible tablets is described herein.
  • Microcrystalline cellulose (approximately 30% w/w of microcrystalline cellulose in final composition) is blended in a vessel.
  • Mirdametinib, croscarmellose, and microcrystalline cellulose (approximately 50% w/w of microcrystalline cellulose in final composition) are added to the vessel and blended.
  • the remaining microcrystalline cellulose is added to the vessel and blended.
  • Intragranular magnesium stearate is added for lubrication, and the blend is roller compacted into dry granules. Grape flavor and sucralose are blended into the granules, and extragranular magnesium stearate is added for lubrication.
  • the blend is compressed, and checked for in-process control based on appearance, weight, thickness, hardness, friability, and disintegration.
  • the tablets are dedusted and checked for metal impurities, then bulk packaged.
  • ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is selected from the group consisting of: a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, and 14.6 ⁇ 0.2 degrees two theta; a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at one or more of 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 19.0 ⁇ 0.2, and 23.7 ⁇ 0.2 degrees two thet
  • E4 The pharmaceutical composition of E2 or E3, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, and 14.6 ⁇ 0.2 degrees two theta.
  • E5. The pharmaceutical composition of any one of E2-E4, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenyla inoj-benzamide is characterized by an XRPD pattern having peaks at 4.6 ⁇ 0.2, 7.3 ⁇ 0.2, 14.6 ⁇ 0.2, and 25.0 ⁇ 0.2 degrees two theta. [0185] E6.
  • composition of any one of E2-E5, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 1A.
  • E7 The pharmaceutical composition of any one of E2-E6, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by one or both of: a) a TGA profile substantially as shown in FIG. IB; and/or b) a DSC profile substantially as shown in FIG. IB.
  • E8 The pharmaceutical composition of any one of E2-E7, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by a DSC profile which does not include an endotherm with an onset at about 117°C.
  • E9 The pharmaceutical composition of any one of E2-E8, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.
  • E10 The pharmaceutical composition of any one of E2-E9, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E12 The pharmaceutical composition of any one of E2-E11, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 year at standard warehouse conditions (15°C- 25 °C and ⁇ 65% relative humidity).
  • E13 The pharmaceutical composition of any one of E2-E12, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E14 The pharmaceutical composition of any one of E2-E13, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for >140 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E15 The pharmaceutical composition of any one of E2-E14, wherein the DSC pattern is generated using a TA Instruments Q 100 or Q2000 differential scanning calorimeter at a rate of temperature increase of about 15°C/min.
  • E16 The pharmaceutical composition of any one of E2-E15, wherein the crystalline form is anhydrous.
  • E17 The pharmaceutical composition of any one of E2-E16, wherein the crystalline form is Form IV.
  • E18 The pharmaceutical composition of E2 or E3, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is characterized by an XRPD pattern having peaks at one or more of 10.6 ⁇
  • E19 The pharmaceutical composition of E2, E3, or E18, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is characterized by an XRPD pattern having peaks at one or more of 10.6 ⁇
  • E20 The pharmaceutical composition of E2, E3, E18, or E19, wherein the crystalline form is characterized by a DSC profile with an endotherm with onset at about 117 °C.
  • E21 The pharmaceutical composition of any one of E2, E3, and E18-E20, wherein the crystalline form is Form I.
  • E22 The pharmaceutical composition of E2 or E3, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is characterized by an XRPD pattern having peaks at 5.5 ⁇ 0.2 and/or 19.6 ⁇ 0.2 degrees two theta.
  • E23 The pharmaceutical composition of E2, E3, or E22, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is characterized by an XRPD pattern having peaks at one or more of 5.5 ⁇ 0.2, 10.7 ⁇ 0.2, 16.5 ⁇ 0.2, 19.6 ⁇ 0.2, 22.0 ⁇ 0.2, 22.5 ⁇ 0.2, 23.6 ⁇ 0.2, 24.1 ⁇ 0.2, 25.0 ⁇
  • E24 The pharmaceutical composition of E2, E3, E22, or E23, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by a DSC profile with an endotherm with onset at about 87 °C.
  • E25 The pharmaceutical composition of any one of E2, E3, and E22-E24, wherein the crystalline form is Form II.
  • E26 The pharmaceutical composition of any one of E1-E25, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • E27 The pharmaceutical composition of any one of E1-E26, wherein the pharmaceutical composition is for oral administration.
  • E28 The pharmaceutical composition of any one of E1-E27, wherein the pharmaceutical composition is orodispersible.
  • E29 The pharmaceutical composition of any one of E1-E28, wherein the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets.
  • E30 The pharmaceutical composition of E29, wherein the pharmaceutical composition is a powder.
  • E31 The pharmaceutical composition of E30, wherein the powder is a dispersible powder.
  • E32 The pharmaceutical composition of E30 or E31, wherein a capsule or sachet comprises the powder or dispersible powder.
  • E33 The pharmaceutical composition of E29, wherein the pharmaceutical composition is in the form of granules.
  • E34 The pharmaceutical composition of E33, wherein the granules are dispersible granules.
  • E35 The pharmaceutical composition of E33 or E34, wherein a capsule or sachet comprises the granules or dispersible granules.
  • E36 The pharmaceutical composition of E29, wherein the pharmaceutical composition is in the form of minitablets.
  • E37 The pharmaceutical composition of E36, wherein the minitablets are dispersible minitablets.
  • E38 The pharmaceutical composition of E36 or E37, wherein a capsule or sachet comprises the minitablets or dispersible minitablets.
  • E39 The pharmaceutical composition of E29, wherein the pharmaceutical composition is in the form of pellets.
  • E40 The pharmaceutical composition of E39, wherein the pellets are dispersible pellets.
  • E41 The pharmaceutical composition of E39 or E40, wherein a capsule or sachet comprises the minitablets or dispersible minitablets.
  • E42 The pharmaceutical composition of E29, wherein the pharmaceutical composition is a tablet.
  • E43 The pharmaceutical composition of E42, wherein the pharmaceutical composition is a dispersible tablet.
  • E44 The pharmaceutical composition of any one of E1-E43, comprising: about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide; and wherein each component of the pharmaceutical composition is as follows: a. about 0.1 wt/wt% to about 7 wt/wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b.
  • wt/wt% about 50 wt/wt% to about 98 wt/wt% of one or more diluents; c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. about 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
  • E45 The pharmaceutical composition of any one of E1-E43, comprising: about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide; and wherein each component of the pharmaceutical composition is as follows: a. about 0.5 wt/wt% to about 1.2 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-
  • 3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide b. about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c. about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; d. 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; e. 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and f. about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
  • E46 The pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-
  • E47 The pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • E48 The pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • E49 The pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • E50 The pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • E51 The pharmaceutical composition of any one of E44-E50, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, and dibasic calcium phosphate.
  • E52 The pharmaceutical composition of E51, wherein at least one of the diluents is microcrystalline cellulose.
  • E53 The pharmaceutical composition of any one of E44-E52, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
  • E54 The pharmaceutical composition of E53, wherein at least one of the disintegrants is croscarmellose sodium.
  • E55 The pharmaceutical composition of any one of E44-E54, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
  • E56 The pharmaceutical composition of E55, wherein at least one of the flavoring agents is grape flavoring.
  • E57 The pharmaceutical composition of any one of E44-E56, wherein at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
  • E58 The pharmaceutical composition of E57, wherein at least one of the sweeteners is sucralose.
  • E59 The pharmaceutical composition of any one of E44-E58, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, and talc.
  • the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, and talc.
  • E60 The pharmaceutical composition of E59, wherein at least one of the lubricants is magnesium stearate.
  • E61 The pharmaceutical composition of any one of E1-E60, wherein the potable liquid is water milk or a juice.
  • E62 The pharmaceutical composition of any one of E1-E60, wherein the pharmaceutical composition is dispersible in a subject’s saliva.
  • E63 A method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment the pharmaceutical composition of any one of E1-E62.
  • E64 The method of E63, wherein the tumor is a neurofibroma.
  • E65 The method of E64, wherein the tumor is a neurofibroma associated with
  • E66 The method of any one of E63-E65, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • E67 The method of E66, wherein the tumor is plexiform neurofibroma.
  • E68 The method of E67, wherein the subject has been diagnosed with a
  • Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • E69 The method of E63, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer,
  • E70 The method of E69, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • E71 The method of E69, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitfs lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • E72 The method of E69, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • E73 The method of any one of E63-E72, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • E74 The method of any one of E63-E73, wherein an individual dose of the N-
  • ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one tablet, more than one dose of dispersible powder, more than one dose of dispersible granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
  • E75 The method of any one of E63-E74, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E76 The method of any one of E63-E74, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E77 The method of any one of E63-E74, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E78 The method of any one of E63-E74, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E79 The method of any one of E63-E74, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
  • E80 The method of any one of E78-E79, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • E81 The method of any one of E63-E80, wherein the subject experiences dysphagia.
  • E82 The method of E81, wherein the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
  • E83 The method of any one of E63-E80, wherein the subject is a pediatric subject.
  • N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily.
  • E85 The method of E84, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • E86 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.25 mg each.
  • E87 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
  • E88 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
  • E89 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • E90 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
  • E91 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 5 mg each.
  • E92 The method of E85, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • E93 The method of any one of E63-E83, wherein the total daily dose of the N-
  • E95 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg.
  • E96 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg.
  • E97 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
  • E98 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • E99 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
  • E100 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 10 mg.
  • E101 The method of E94, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • E102 The method of any one of E63-E101, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
  • E104 The method of any one of claims E63-E101, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
  • E105 The method of any one of E63-E101, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • E106 The method of any one of E63-E101, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 4 mg.
  • E107 The method of any one of E63-E101, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 2 mg.
  • E108 The method of any one of E63-E101, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
  • E109 Else of the pharmaceutical composition of any one of E1-E62 for the manufacture of a medicament for treating a tumor, a cancer, or a Rasopathy disorder.
  • E110 The use of El 09, wherein the tumor is a neurofibroma.
  • E109-E111 wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • E109 wherein the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • E109 wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • skin cancer malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma
  • El 16. The use of El 15, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • El 17 The use of El 15, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitfs lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitfs lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • El 18 The use of El 15, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • E109-E118 wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • E120 The use of any one of E109-E119, wherein an individual dose of the N-
  • ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one tablet, more than one dose of dispersible powder, more than one dose of dispersible granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
  • E121 The use of any one of E109-E119, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E122 The use of any one of E109-E119, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E123 The use of any one of E109-E119, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E124 The use of any one of E109-E119, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E125 The use of any one of E109-E119, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
  • E126 The use of any one of E124-E125, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • E127 The use of any one of E109-E126, wherein the subject experiences dysphagia.
  • E128 The use of E127, wherein the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
  • E129 The use of any one of E109-E128, wherein the subject is a pediatric subject.
  • E130 The use of any one of E109-E129, wherein the total daily dose of N-((R)-
  • E131 The use of El 30, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • E132 The use of El 31, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.25 mg each.
  • E133 The use of El 31, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
  • E134 The use of E131, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
  • E135. The use of El 31, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • E136 The use of E131, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
  • E137 The use of E131, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 5 mg each.
  • E138 The use of El 31, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • E139 The use of any one of E109-E129, wherein the total daily dose of the N-
  • E140 The use of E139, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg .
  • E141 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg.
  • E142 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg.
  • E143 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
  • E144 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • E145 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
  • E146 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 10 mg.
  • E147 The use of E140, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • E148 The use of any one of E109-E147, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
  • E149 The use of any one of E109-E148, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • E150 The use of any one of E109-E148, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
  • E151 The use of any one of E109-E148, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • E152 The use of any one of E109-E148, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 4 mg.
EP21710375.3A 2021-02-17 2021-02-17 Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof Pending EP4294525A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2021/018373 WO2022177555A1 (en) 2021-02-17 2021-02-17 Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

Publications (1)

Publication Number Publication Date
EP4294525A1 true EP4294525A1 (en) 2023-12-27

Family

ID=74859524

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21710375.3A Pending EP4294525A1 (en) 2021-02-17 2021-02-17 Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

Country Status (10)

Country Link
EP (1) EP4294525A1 (ko)
JP (1) JP2024507213A (ko)
KR (1) KR20230157314A (ko)
CN (1) CN117279630A (ko)
AR (1) AR124908A1 (ko)
AU (1) AU2021428601A1 (ko)
CA (1) CA3207271A1 (ko)
IL (1) IL305079A (ko)
TW (1) TW202245745A (ko)
WO (1) WO2022177555A1 (ko)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1219753C (zh) 2000-07-19 2005-09-21 沃尼尔·朗伯公司 4－碘苯氨基苯氧肟酸的氧合酯
CA2542210A1 (en) 2003-10-21 2005-05-06 Warner-Lambert Company Llc Polymorphic form of n-[(r)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide

Also Published As

Publication number Publication date
WO2022177555A1 (en) 2022-08-25
AU2021428601A1 (en) 2023-09-28
TW202245745A (zh) 2022-12-01
CN117279630A (zh) 2023-12-22
JP2024507213A (ja) 2024-02-16
KR20230157314A (ko) 2023-11-16
AR124908A1 (es) 2023-05-17
CA3207271A1 (en) 2022-08-25
IL305079A (en) 2023-10-01

Similar Documents

Publication Publication Date Title
US20230330047A1 (en) Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benazmide and uses thereof
US11066358B1 (en) Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
US11884610B2 (en) Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
CA3177000A1 (en) Novel compounds
US20110269838A1 (en) Novel processes and pure polymorphs
AU2021428601A1 (en) Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
AU2021428932A1 (en) Compositions of essentially pure form iv of n-((r)-2,3- dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodophenylamino)- benzamide and uses thereof
CN110267661B (zh) 包括trh类似物和丙基辛酸的组合的组合物和丙基辛酸的药学上可接受的盐
TW202302526A (zh) Ｍｅｋ抑制劑ｎ－（（ｒ）－２，３－二羥基丙氧基）－３，４－二氟－２－（２－氟－４－碘－苯基胺基）－苯甲醯胺之結晶固體及其用途
KR20190090729A (ko) 토파시티닙의 신규 염, 이의 제조방법 및 이를 포함하는 약학 조성물
CA2744448A1 (en) Polymorphs
EP3170829A1 (en) Novel salt of tenofovir disoproxil
US20220227759A1 (en) Amorphous pi3k inhibitor and pharmaceutical composition comprising same
EP2266948A1 (en) Salts of tramadol and diflunisal and their crystal form in the treatment of pain

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20230913

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR