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

Abstract

Provided is a dispersible pharmaceutical composition comprising N - ((R) -2, 3-dihydroxypropoxy) - 3, 4-difluoro-2 - (2-fluoro-4-iodo-phenylamino) - benzamide, and optionally a pharmaceutically acceptable carrier.SOLUTION: Provided is a pharmaceutical composition comprising N - ((R) -2, 3-dihydroxypropoxy) - 3, 4-difluoro-2 - (2-fluoro-4-iodo-phenylamino) - benzamide, wherein the pharmaceutical composition is dispersible in a drinkable liquid or orodispersible in the saliva of a subject. The compositions can be used to treat a tumor, cancer, or a Rasopathy disorder by administration to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a dispersible formulation of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide for use in administering to a patient in need thereof, and to a method for making such a dispersible formulation. The present disclosure further relates to a dispersible formulation comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; a method for making a dispersible formulation comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and a method and use for treating tumors, cancers, or rasopathy disorders by administering N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof. [Background technology]

[0002] Neurofibromatosis type 1 (NF1) is characterized by diverse and progressive cutaneous, neurological, skeletal, and neoplastic symptoms, with no standard drug treatment options. Neurofibromas are benign peripheral nerve sheath tumors composed of a mixture of Schwann cells, fibroblasts, perineurial cells, and mast cells, occurring in 20–50% of NF1 patients (Tucker, et al. (2011) J. Histochem. Cytochem. 59(6):584–590). When neurofibromas extend longitudinally along nerves and involve multiple fascicles, they are classified as plexiform neurofibromas (PN). Plexiform neurofibromas rarely regress spontaneously, and in many patients, their growth continues relentlessly. Plexiform neurofibromas are 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 can cause dysfunction, pain, and cosmetic damage and may compress the airway or spinal cord. Furthermore, PNs can undergo malignant transformation, giving rise to malignant peripheral nerve sheath tumors (MPNSTs).

[0003] Previous longitudinal and retrospective studies have demonstrated age-dependent differences in plexiform neurofibromas, showing a high inverse correlation between PN growth and patient age (Dombi, et al. (2007) Neurology. 68(9):643-647; Nguyen, et al. (2012) Orphanet J. Rare Dis. 7(75); Tucker, et al. (2008) Am. J. Med. Genet. 46:81-85). In a retrospective review, Tucker et al. analyzed serial MRI scans of 34 patients (median age 10 years, range 1-47 years) with measurable PN over a median follow-up of 6 years (range 1-15 years). In this study, the difference between initial and final bidimensional estimated tumor size was observed to be significantly greater in younger patients compared with older patients (3.2 cm vs. 0.2 cm, respectively, p = 0.031). Furthermore, the tumor growth rate in patients younger than 10 years of age (0.7 cm / year) was significantly higher than in patients older than 10 years of age (0.03 cm / year, p = 0.014). Similarly, in an observational study of 49 patients aged 3 to 25 years (median age 8.3 years), Dombi et al. observed that PN volume increased more rapidly than body weight over time (p = 0.026). Furthermore, patients younger than the median age of 8.3 years tended to have a greater increase in annual PN volume compared with older children (annual volume change of 21.1% vs. 8.4%, respectively, p = 0.001). This trend also holds when PN growth rates are expressed relative to the rate of increase in body size.

[0004] Based on the findings of Tucker and Dombi, Nguyen et al. conducted a retrospective study of 71 patients with evaluable PN with a median follow-up of 2.2 years (range, 1.1–4.9 years). Individual tumor growth rates were inversely correlated with age at initial examination (Spearman's rho = −0.33, p<0.001), but not with tumor volume on initial MRI. Furthermore, tumors growing at ≥20% per year were significantly more common in children than in adults (p<0.001). In summary, the findings of three independent retrospective reviews of PN volume clearly demonstrate that the rate of PN growth in NF1 patients is inversely correlated with age, indicating discrete, age-dependent tumor differences and unmet needs in the pediatric population.

[0005] These observations suggest that the youngest patients may derive the greatest clinical benefit from treatment. However, the youngest potential patients in urgent need of treatment may struggle to receive treatment due to their inability to swallow capsules or tablets whole. Therefore, age-appropriate pediatric formulations that allow for accurate dosing and enhanced adherence are needed to optimize efficacy and safety in this population.

[0006] Additionally, patients who require treatment but experience difficulty swallowing ("dysphagia") would benefit from a non-capsule or tablet formulation that can be administered orally. Dysphagia can be caused by a variety of conditions that affect one or more components of the swallowing process. These include, but are not limited to, physical damage to the tongue, pharynx, larynx, esophagus, or trachea due to trauma, infection, or proliferative disease; treatment of such conditions; congenital anatomical defects such as cleft palate; growth retardation at a young age; wasting in older age; dementia, memory loss, or cognitive decline; or any condition that otherwise weakens or damages the muscles or nerves used in the swallowing process, such as Parkinson's disease, stroke, or neurological disease.

[0007] N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide ("mirdametinib" or "PD-0325901") is a small molecule drug 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. The MAPK pathway is important for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and proliferation. Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2. By virtue of its mechanism of action, mirdametinib significantly inhibits the phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby resulting in tumor cell growth impairment both in vitro and in vivo. Furthermore, 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.

[0008] Crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide have been previously described. WO 2002 / 006213 describes crystalline Forms I and II, which are incorporated by reference. Form I is characterized by an XRPD containing one or more peaks at 10.6, 13.7, 19.0, and 23.7 degrees 2θ; Form II is characterized by an XRPD containing peaks at 5.5 and / or 19.6 degrees 2θ. Form I was characterized by XRPD peaks at 5.5 and / or 19.6 degrees 2θ as measured by DSC. Form I is characterized by a melting point of about 117°C to 118°C, while Form II is characterized by a melting point of 89°C to 90°C.

[0009] U.S. Patent No. 7,060,856 ("the '856 patent") describes a method for producing Form IV and is incorporated by reference. The '856 patent indicates that the material produced by this method was greater than 90% Form IV ('856 patent, Example 1). The '856 patent also states that differential scanning calorimetry ("DSC") of the material produced exhibits an onset of melting at 110°C, as well as a small peak with an onset at 117°C, consistent with a mixture of two forms. Compositions containing multiple polymorphs are generally undesirable due to the potential for interconversion of one polymorph to another. Polymorphic interconversion can cause differences in physical properties that affect the effective dose or processability of the drug due to differences in solubility or bioavailability. Summary of the Invention

[0010] There is a need for dispersible formulations of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide that can be safely administered to patients who have difficulty swallowing capsules or tablets completely (e.g., pediatric patients or patients suffering from dysphagia) for use in treating tumors, cancer, or rasopathy disorders. In view of the apparent mixture of forms in previously disclosed Form IV, there is a need for dispersible formulations comprising essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to limit polymorphic interconversion between forms, which can affect solubility and bioavailability. [Brief explanation of the drawings]

[0011] [Figure 1A] FIG. 1 is the 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. [Figure 1B]1 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-phenylamino)-benzamide. [Figure 2] 1 is an XRPD corresponding to the first prepared batch of essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and an XRPD of a known reference standard of Form IV. [Figure 3A] Figure 1 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 at 25°C and ≤65% relative humidity for 68 months after manufacture. [Figure 3B] Figure 1 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 at 25°C and ≤65% relative humidity for 140 months after manufacture. DETAILED DESCRIPTION OF THE INVENTION

[0012] The disclosure features compositions useful for treating a disorder involving aberrant MEK1 or MEK2 activity, e.g., a tumor, cancer, or a Rasopathy disorder, such as neurofibromatosis type 1, in a subject in need thereof. In some embodiments, the methods and compositions described herein are useful for treating patients who have difficulty swallowing capsules or tablets whole, e.g., pediatric patients. The compositions are useful for treating subjects suffering from dysphagia, such as those with esophageal cancer, Parkinson's disease, amyotrophic lateral sclerosis, stroke, achalasia, or esophageal stricture. In some embodiments, the 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.

[0013] Pharmaceutical Compositions In some aspects, the present disclosure provides an amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of formula (I): [ka] wherein the pharmaceutical composition is dispersible in a potable liquid (e.g., water) or orodispersible in the saliva of a subject.

[0014] In some embodiments, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in the pharmaceutical compositions described herein is crystalline. In some embodiments, 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 with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ; (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 with peaks at 10.6±0.2, 13.7±0.2, 14.6±0.2 degrees 2θ; (c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern with peaks at 0.2, 19.0±0.2, and 23.7±0.2 degrees two-theta; and (d) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.5±0.2 and 19.6±0.2 degrees two-theta.

[0015] In some embodiments, 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 with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees two-theta. In some embodiments, 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 with peaks at 4.6±0.2, 7.3±0.2, 14.6±0.2, and 25.0±0.2 degrees two-theta.

[0016] In some embodiments, 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.

[0017] In some embodiments, 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 without an endothermic onset at about 117°C.

[0018] In some embodiments, 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. 1B; and / or (b) a DSC profile substantially as shown in FIG. 1B.

[0019] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide does not contain a detectable amount of Form I or Form II by XRPD and / or DSC.

[0020] In some embodiments, the crystalline form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is anhydrous.

[0021] In some embodiments, the crystalline form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IV. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is essentially pure Form IV.

[0022] In some embodiments, essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and / or DSC profile that is substantially unchanged after 3 months of storage at standard warehouse conditions (15° C.-25° C. and 65% or less relative humidity). In some embodiments, essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and / or DSC profile that is substantially unchanged after 6 months of storage at standard warehouse conditions (15° C.-25° C. and 65% or less relative humidity). In some embodiments, essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD and / or DSC profile that remains substantially unchanged after storage for one year at standard warehouse conditions (15° C.-25° C., 65% or less relative humidity). In some embodiments, essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 68 months at standard warehouse conditions (15° C.-25° C., 65% or less relative humidity). In some embodiments, essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 140 months or more at standard warehouse conditions (15° C.-25° C., 65% or less relative humidity). In some embodiments, essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 14 years or more at standard warehouse conditions (15° C.-25° C., 65% or less relative humidity).

[0023] In some embodiments, XRPD patterns were recorded using a PANALYTICAL® X'Pert™ detector using Ni-filtered CuKα (45 kV / 40 mA) radiation and a step size of 0.03° 2θ with an X'CELERATOR® Real Time Multi-Strip detector configured as follows: (a) on the incident beam side: variable divergence slit (10 mm exposure length), 0.04 rad Soller slit, fixed anti-scatter slit (0.50°), and 10 mm beam mask; and (b) on the diffracted beam side: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit. DSC patterns are generated using a BRUKER® D8® ADVANCE™ system using CuKα (40 kV / 40 mA) radiation and a step size of 0.03°2θ, equipped with a LYNXEYE™ detector configured as follows: (a) on the incident beam side: a Göbel mirror, a mirror exit slit (0.2 mm), a 2.5° Soller slit, and a beam knife; and (b) on the diffracted beam side: an anti-scatter slit (8 mm) and a 2.5° Soller slit, with the sample mounted flat on a zero-background Si wafer. In some embodiments, DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature ramp rate of about 15°C / min.

[0024] In some embodiments, 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 2θ. In some embodiments, 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 , characterized by an XRPD pattern with peaks at 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 2θ.

[0025] In some embodiments, the crystalline form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC profile with an endothermic onset at about 117°C.

[0026] In some embodiments, the crystalline form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form I.

[0027] In some embodiments, 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 with peaks at 5.5±0.2 and 19.6±0.2 degrees 2θ. In some embodiments, 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 with 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, 29.1±0.2, 30.5±0.2, 31.7±0.2, 33.3±0.2, and 39.0±0.2 degrees 2θ.

[0028] In some embodiments, 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 endothermic onset at about 87°C.

[0029] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form II.

[0030] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0031] In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is dispersible. In some embodiments, the pharmaceutical composition is orally dispersible.

[0032] In some embodiments, the pharmaceutical composition is a tablet, powder, granule, minitablet, or pellet (also called a bead).

[0033] In some embodiments, the pharmaceutical composition is a powder. In some embodiments, the pharmaceutical composition is a dispersible powder. In some embodiments, a capsule or sachet comprises the dispersible powder.

[0034] In some embodiments, the pharmaceutical composition is in the form of granules. In some embodiments, the granules are dispersible granules. In some embodiments, a capsule or sachet comprises the dispersible granules.

[0035] In some embodiments, the pharmaceutical composition is in the form of minitablets. In some embodiments, the minitablets are dispersible minitablets. In some embodiments, a capsule or sachet comprises the dispersible minitablets.

[0036] In some embodiments, the pharmaceutical composition is in the form of a pellet. In some embodiments, the pellet is a dispersible pellet. In some embodiments, a capsule or sachet comprises a dispersible pellet.

[0037] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is a dispersible tablet. In some embodiments, the tablet is an orodispersible tablet.

[0038] In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, 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% w / w to about 7% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) from about 50% w / w to about 98% w / w of one or more diluents, (c) from about 1% w / w to about 10% w / w of one or more disintegrants, (d) from 0% w / w to about 5% w / w of one or more flavoring agents, (e) from 0% w / w to about 5% w / w of one or more sweeteners, and (f) from 0% w / w to about 5% w / w of one or more lubricants.

[0039] In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains from about 0.1 mg to about 20 mg of N-((R) (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) from about 0.2% w / w to about 1.5% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, (b) from about 75% w / w to about 98% w / w of one or more diluents, (c) from about 3% w / w to about 8% w / w of one or more disintegrants, (d) from 0% w / w to about 5% w / w of one or more flavoring agents, (e) from 0% w / w to about 5% w / w of one or more sweeteners, and (f) from 0% w / w to about 5% w / w of one or more lubricants.

[0040] In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, 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% w / w to about 1.2% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85% w / w to about 95% w / w of one or more diluents, (c) about 3.5% w / w to about 6% w / w of one or more disintegrants, (d) 0% w / w to about 2.5% w / w of one or more flavoring agents, (e) 0% w / w to about 2% w / w of one or more sweeteners, and (f) about 0.5% w / w to about 2% w / w of one or more lubricants.

[0041] In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, contains about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0042] In some embodiments, 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 embodiments, at least one of the diluents is microcrystalline cellulose.

[0043] In some embodiments, 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 embodiments, at least one of the disintegrants is croscarmellose sodium.

[0044] In some embodiments, at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors, including, but not limited to, grape flavor, bubble gum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor. In some embodiments, at least one of the flavoring agents is grape flavor.

[0045] In some embodiments, at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame, hi some embodiments, at least one of the sweeteners is sucralose.

[0046] In some embodiments, 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, hi some embodiments, at least one of the lubricants is magnesium stearate.

[0047] Treatment methods In some aspects, the present disclosure provides methods of treating a tumor, cancer, or a rasopathy disorder, comprising administering a pharmaceutical composition described herein (e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) to a subject in need of such treatment.

[0048] In some aspects, the present disclosure provides for the use of a pharmaceutical composition (e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) described herein for the manufacture of a medicament for treating a tumor, cancer, or a rasopathy disorder.

[0049] In some embodiments, the tumor is a neurofibroma. In some embodiments, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some embodiments, 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. In some embodiments, the tumor is a plexiform neurofibroma.

[0050] In some embodiments, 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.

[0051] In some aspects, the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, 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 carcinoma, biliary tract cancer, and peritoneal serous carcinoma. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In some embodiments, the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia. In some aspects, 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.

[0052] In some embodiments, the subject has a mutation or other abnormality in one or more genes that causes a gain or loss of function characteristic of a particular cancer, and the mutation or other abnormality in the one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0053] In some embodiments, individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as two or more dispersible tablets, two or more doses of dispersible powder, two or more doses of dispersible granules, two or more doses of dispersible minitablets, two or more doses of dispersible pellets, or combinations thereof. For example, a 3 mg dose of 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 one containing 1 mg—or as three dispersible tablets, each containing 1 mg. As another example, a 1.5 mg dose of 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.

[0054] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 6 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 1 mg.

[0055] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days during which the total daily dose is administered; and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 consecutive days during which the total daily dose is administered; followed by (b) 7 consecutive days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. 4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each of which comprises (i) 5 days during which the total daily dose is administered, and (ii) 2 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each comprising (i) 5 consecutive days during which the total daily dose is administered, and (ii) 2 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0056] In some embodiments, the 28-day administration cycle is repeated for up to a total of 24 consecutive 28-day administration cycles.

[0057] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle consisting of 28 days in which the total daily dose is administered.

[0058] In some embodiments, the subject experiences dysphagia caused by one or more of the following: a nervous system disease, muscle weakness, a developmental disorder, a stroke, trauma, an anatomical defect, cancer, cancer treatment, an allergic reaction, dementia, memory loss, or cognitive decline.

[0059] In some embodiments, the subject is a pediatric subject.

[0060] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.25 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 0.5 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 1 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 2 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 4 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 5 mg each, administered twice daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 10 mg each, administered twice daily.

[0061] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily. In some embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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 embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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 embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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 embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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.

[0062] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 6 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 4 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

[0063] Method for producing pharmaceutical compositions In some aspects, the present disclosure provides a method of making a pharmaceutical composition comprising forming a pharmaceutical composition described herein.

[0064] definition To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0065] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0066] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more" and "at least one," may be used interchangeably herein. In certain aspects, the terms "a" or "an" mean "single." In other aspects, the terms "a" or "an" include "two or more" or "multiple."

[0067] Furthermore, "and / or" as used herein should be interpreted as a specific disclosure of each of the two specified features or components, whether or not the other is present. Thus, the term "and / or" used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0068] The terms "mirdametinib" and "PD-0325901" refer to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0069] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as, for example, a human subject.

[0070] The term "child" refers to a human subject under the age of 21 at the time of treatment. The term "child" can be further divided into various subpopulations, including neonates (birth to 28 days after birth), infants (29 days to under 2 years of age), children (2 to under 12 years of age), and adolescents (12 to 21 years of age (up to but excluding their 22nd birthday)). See, e.g., Berhman RE, Kliegman R, Arvin AM, Nelson See W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. Younger pediatric patients, especially neonates, infants, and toddlers, may have difficulty swallowing whole capsules or tablets.

[0071] The term "dispersible" as used herein refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets) that disintegrates and / or dissolves when combined with water or another drinking liquid (e.g., a non-aqueous beverage), or the subject's own saliva when placed in the subject's mouth, with or without stirring or temperature change. In some embodiments, a dispersible composition disintegrates or dissolves within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute after being combined with water or another drinking liquid. Such disintegration or dissolution need not be complete. For example, a dispersible tablet may dissolve almost completely, although some undissolved particulate matter may remain.

[0072] The term "orodispersible" refers to a composition that, when orally administered, can dissolve or disintegrate in a subject's mouth (i.e., dissolve or disintegrate in the subject's saliva) without first having to be dissolved or disintegrated in a separate container.

[0073] As used herein, the terms "treat," "treated," and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Thus, those in need of treatment include those already diagnosed with a disorder or suspected of having a disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; a decrease in the extent of the condition, disorder, or disease; a stabilized (i.e., non-worsening) state of the condition, disorder, or disease; a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or remission (partial or complete) of the condition, disorder, or disease state; an improvement in at least one measurable physical parameter not necessarily discernible by the patient; or an enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not receiving treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to that amount of a compound that is sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or clinician.

[0074] In certain embodiments, if a patient shows one or more of the following: reduction in tumor size; reduction in one or more symptoms associated with a particular tumor; reduction in tumor volume; improvement in quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS) increase, complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in progressive disease (PD), increase in time to progression (TTP), or any combination thereof, according to the methods described herein, the subject is "treated" successfully for tumor.In some embodiments, the nationally or internationally accepted standard of treatment outcome for a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these specific endpoints (for example, CR, PFS, PR).

[0075] In certain embodiments, a subject is diagnosed with a disease that has progressed beyond the initial stage of progression, and the subject is considered to have progressed to the methods described herein if the patient exhibits one or more of the following: a reduction in the number or complete absence of cancer cells; a reduction in one or more symptoms associated with the particular cancer; a decrease in morbidity and mortality; an improvement in quality of life; an increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), a complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increase in time to progression (TTP), or any combination thereof. According to the above, the cancer, for example, lung cancer or ovarian cancer, is successfully "treated." In some embodiments, nationally or internationally accepted standards for treatment outcome in a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0076] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference). Excipients can include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and hydration water.Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0077] The term "pharmaceutical composition," as used herein, refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient or a combination of pharmaceutically acceptable excipients, and may be manufactured or sold as part of a therapeutic regimen for the treatment of a disease in a mammal, subject to the approval of a government regulatory agency. The pharmaceutical composition may be formulated, for example, for oral administration in a unit dosage form, such as a tablet (e.g., dispersible tablet), powder (e.g., dispersible powder), capsule, granule, minitablet, pellet, caplet, gelcap, or syrup.

[0078] The term "about" or "approximately" means within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, depending on how the value is measured or determined. In some embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" means an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0079] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any suitable route, such as those described herein.

[0080] The term "crystalline" as used herein refers to a solid form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound, or their salts, hydrates, or solvates, result from different molecular packing in the solid state, which results in different crystal symmetries and / or unit cell parameters. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995) (incorporated herein by reference).

[0081] Crystalline forms are commonly characterized by powder X-ray diffraction (XRPD). The XRPD pattern of reflections (peaks, typically expressed in degrees 2θ) is generally considered a fingerprint of a particular crystalline form. The relative intensities of XRPD peaks can vary widely, depending, inter alia, on the sample preparation technique, crystal size distribution, filters, sample mounting procedure, and the particular instrument used. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type or settings of the instrument. In some instances, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type or settings of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystalline form. In some instances, any particular peak in an XRPD pattern may appear as a symmetrical or asymmetrical shape, e.g., a shouldered shape. Furthermore, instrumental variations and other factors can affect 2θ values. Those skilled in the art who understand these variations can use XRPD, as well as other known physicochemical techniques, to identify or confirm the features or characteristics that define a particular crystalline form.

[0082] The term "anhydrous" as applied to a compound refers to a crystalline form in which the compound does not contain structural water within the crystal lattice.

[0083] As used herein, the term "essentially pure" with respect to Form IV means that a composition comprising Form IV does not contain a detectable amount of another polymorphic form (e.g., Form I or Form II), as determined by observing a detectable difference in the XRPD and / or DSC patterns between a single crystal of Form IV and a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. However, an "essentially pure" Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can contain impurities, such as, but not limited to, synthetic reactants or by-products produced during chemical synthesis.

[0084] As used herein, the term "abnormality" as applied to a gene refers to a mutation, chromosomal loss or fusion, epigenetic chemical modification, or other event that alters the sequence, expression level, or processed mRNA sequence relative to the wild-type gene.

[0085] Wherever embodiments are described herein using the language "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0086] The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will become apparent from the description and claims.

[0087] Detailed Description of the Invention Described herein are dispersible formulations (e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets) of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide that can be safely administered to patients who have difficulty swallowing (e.g., pediatric patients or patients suffering from dysphagia).

[0088] As with all pharmaceutical compounds and compositions, the chemical and physical properties of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are important in its commercial development. 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, particularly against 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, compressibility, handleability, flow, and blending; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions containing the compound. In some embodiments, 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 of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (e.g., essentially pure Form IV) in addition to a pharmaceutically acceptable carrier or excipient.

[0089] Pharmaceutical Compositions In some embodiments, the present disclosure provides a method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a compound comprising administering to a patient a therapeutically effective amount of a compound comprising administering to a patient a therapeutically effective amount of a compound comprising administering to a patient a therapeutically effective amount of a compound comprising administering to a patient a therapeutically effective amount of a compound comprising administering to a patient a therapeutically effective amount of a compound comprising administering to a patient a therapeutically effective amount of a compound [ka] wherein the pharmaceutical composition is dispersible in a potable liquid (e.g., water) or orodispersible in the saliva of a subject.

[0090] In some embodiments, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide contained in the pharmaceutical compositions described herein is crystalline. In some embodiments, 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 with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ; (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 with peaks at 10.6±0.2, 13.7±0.2, and 14.6±0.2 degrees 2θ; (c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern with peaks at 0.2, 19.0±0.2, and 23.7±0.2 degrees two-theta; and (d) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.5±0.2 and 19.6±0.2 degrees two-theta.

[0091] In some embodiments, 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 with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ. In some embodiments, 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 with peaks at 4.6±0.2, 7.3±0.2, 14.6±0.2, and 25.0±0.2 degrees 2θ.

[0092] In some embodiments, 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. 1A.

[0093] In some embodiments, 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. 1B; and / or (b) a DSC profile substantially as shown in FIG. 1B.

[0094] In some embodiments, 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 that does not have an endothermic onset at about 117°C.

[0095] In some embodiments, 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 a detectable amount of Form I or Form II by XRPD and / or DSC.

[0096] In some embodiments, 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.

[0097] In some embodiments, 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. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is essentially pure Form IV.

[0098] In some embodiments, the crystalline Form IV compositions included in the pharmaceutical compositions described herein are stable, as evidenced by an XRPD pattern and / or DSC profile that remains substantially unchanged over time. In some embodiments, the crystalline Form IV compositions exhibit an XRPD pattern and / or DSC profile that remains 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. to 25° C., 65% relative humidity or less). In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after 3 months of storage at standard warehouse conditions (15°C to 25°C and 65% or less relative humidity). In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after 6 months of storage at standard warehouse conditions (15°C to 25°C and 65% or less relative humidity). In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after one year of storage at standard warehouse conditions (15° C.-25° C. and 65% or less relative humidity). In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after five years of storage at standard warehouse conditions (15° C.-25° C. and 65% or less relative humidity).In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after storage for 68 months at standard warehouse conditions (15° C.-25° C. and 65% or less relative humidity). In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after storage for 140 months or more at standard warehouse conditions (15° C.-25° C. and 65% or less relative humidity). In some embodiments, crystalline Form IV compositions of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibit substantially unchanged XRPD patterns and / or DSC profiles after storage for 14 years or more at standard warehouse conditions (15° C. to 25° C. and 65% or less relative humidity).

[0099] In some embodiments, the XRPD pattern of Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide contained in the pharmaceutical compositions described herein is (a) at the incident beam as follows: variable divergence slit (10 mm exposure length), 0.04 rad solar (b) a PANALYTICAL® X'Pert™ detector using Ni-filtered CuKα (45 kV / 40 mA) radiation and a step size of 0.03° 2θ, equipped with an X'CELERATOR® Real Time Multi-Strip detector configured as follows on the diffracted beam side: a variable anti-scatter slit (10 mm observed length) and a 0.04 rad Soller slit. The samples were generated using a Pro diffractometer or using a BRUKER® D8® ADVANCE™ system using CuKα (40 kV / 40 mA) radiation and a step size of 0.03° 2θ, equipped with a LYNXEYE™ detector configured as follows: (a) on the incident beam side: Göbel mirror, mirror exit slit (0.2 mm), 2.5° Soller slit, beam knife; and (b) on the diffracted beam side: anti-scatter slit (8 mm) and 2.5° Soller slit, with the sample flat-mounted on a zero-background Si wafer.

[0100] In some embodiments, DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature ramp rate of about 15° C. / min.

[0101] In some embodiments, 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 with peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2θ. In some embodiments, 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 with 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, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, Characterize the XRPD pattern with one or more peaks at 1.0±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, 37.7±0.2 degrees 2θ.

[0102] In some embodiments, 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 endothermic onset at about 117°C.

[0103] In some embodiments, 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.

[0104] In some embodiments, 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 with peaks at 5.5±0.2 and / or 19.6±0.2 degrees 2θ. In some embodiments, 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 with peaks at 5.5±0.2 and / or 19.6±0.2 degrees 2θ. In some embodiments, 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 with 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 , characterized by an XRPD pattern with peaks at 27.6±0.2, 29.1±0.2, 30.5±0.2, 31.7±0.2, 33.3±0.2, and 39.0±0.2 degrees 2θ.

[0105] In some embodiments, 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 endothermic onset at about 87°C.

[0106] In some embodiments, 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.

[0107] In some embodiments, the present disclosure provides a 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. In some embodiments, the pharmaceutical composition (e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) further comprises one or more pharmaceutically acceptable carriers.

[0108] In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is orodispersible.

[0109] In some embodiments, the drinking liquid is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the drinking liquid is water. In some embodiments, the drinking liquid is juice.

[0110] In some embodiments, the pharmaceutical composition is a tablet, powder, granules, minitablets, or pellets.

[0111] In some embodiments, the pharmaceutical composition is a powder. In some embodiments, the powder is a dispersible powder. In some embodiments, a capsule or sachet comprises the dispersible powder.

[0112] In some embodiments, the pharmaceutical composition is in the form of granules. In some embodiments, the granules are dispersible granules. In some embodiments, a capsule or sachet comprises the dispersible granules.

[0113] In some embodiments, the pharmaceutical composition is in the form of minitablets. In some embodiments, the minitablets are dispersible minitablets. In some embodiments, a capsule or sachet comprises the dispersible minitablets.

[0114] In some embodiments, the pharmaceutical composition is in the form of a pellet. In some embodiments, the pellet is a dispersible pellet. In some embodiments, a capsule or sachet comprises a dispersible pellet.

[0115] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is a dispersible tablet. In some embodiments, the dispersible tablet is an orodispersible tablet.

[0116] In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains from about 0.1 mg to about 20 mg of N-((R) (c) from about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants; (d) from 0 wt / wt% to about 5 wt / wt% of one or more flavoring agents; (e) from 0 wt / wt% to about 5 wt / wt% of one or more sweeteners; and (f) from about 0 wt / wt% to about 5 wt / wt% of one or more lubricants.

[0117] In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, 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% w / w to about 1.5% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) from about 75% w / w to about 98% w / w of one or more diluents; (c) from about 3% w / w to about 8% w / w of one or more disintegrants; (d) from 0% w / w to about 5% w / w of one or more flavoring agents; (e) from 0% w / w to about 5% w / w of one or more sweeteners; and (f) from 0% w / w to about 5% w / w of one or more lubricants.

[0118] In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 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 of the components of the pharmaceutical composition is as follows: (a) from about 0.5% w / w to about 1.2% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) from about 85% w / w to about 95% w / w of one or more diluents; (c) from about 3.5% w / w to about 6% w / w of one or more disintegrants; (d) from 0% w / w to about 2.5% w / w of one or more flavoring agents; (e) from 0% w / w to about 2% w / w of one or more sweeteners; and (f) from about 0.5% w / w to about 2% w / w of one or more lubricants.

[0119] In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains 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. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. It contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 6 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 7 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 8 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 9 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 11 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 12 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 13 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 14 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 15 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains about 16 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet. The pharmaceutical composition, which is a dispersible pellet, contains about 17 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, contains about 18 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, contains about 19 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0120] In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1% w / w to about 7% w / w of N-((R)-)2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1% w / w to about 5% w / w of N-((R)-2,3)-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a dispersible amount of 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 wt / wt%, about 2 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 Amount / wt%, about 2.6 wt / wt%, about 2.7 wt / wt%, about 2.8 wt / wt%, about 2.9 wt / wt%, about 3 wt / wt%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt% , about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4. 6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, about 5 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt / wt%, about 5.5 wt / wt%, about 5.6 wt / wt about 5.7 wt / wt%, about 5.8 wt / wt%, about 5.9 wt / wt%, about 6 wt / wt%, about 6.1 wt / wt%, about 6.2 wt / wt%, about 6.3 wt / wt%, about 6.4 wt / wt%, about 6.5 wt / wt%, about 6.6 wt / wt%, about 6.7 wt / wt%, about 6.8 wt / wt%, about 6.9 wt / wt%, or about 7 wt / wt% N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 0.5% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 0.8% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-. Includes difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0121] In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain one or more diluents. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain from about 50% w / w to about 98% w / w of one or more diluents. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain from about 75% w / w to about 98% w / w of one or more diluents. In some embodiments, pharmaceutical compositions contain from about 85% w / w to about 95% w / w of one or more diluents. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet is about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, about 55% w / w, about 56% w / w, about 57% w / w, about 58% w / w, about 59% w / w, about 60% w / w, about 61% w / w, about 62% w / w, about 63% w / w, about 64% w / w, about 65% w / w, about 66% w / w, about 67% w / w, about 68% w / w, about 69% w / w, about 70% w / w, about 71% w / w, about 72% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w, about 91% w / w, about 92% w / w, about 93% w / w, about 94% w / w, about 95% w / w, about 96% w / w, about 97% w / w, about 98% w / w, about 99% w / w, about 100% w / w, about 101% w / w, about 102% w / w, 2%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98% w / w of one or more diluents. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 90% w / w of one or more diluents.In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain about 91% w / w of one or more diluents. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain about 92% w / w of one or more diluents. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain about 93% w / w of one or more diluents.

[0122] In some embodiments, 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. In some embodiments, at least one of the diluents is microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% to about 98% w / w microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 75% to about 98% w / w microcrystalline cellulose. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and comprises about 85% to about 95% w / w microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, about 55% w / w, about 56% w / w, about 57% w / w, about 58% w / w, about 59% w / w, about 60% w / w, about 61% w / w, about 62% w / w, about 63% w / w, about 64% w / w, about 65% w / w, about 66% w / w, about 67% w / w, about 68% w / w, about 69% w / w, about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w, about 91% w / w, about 92% w / w, about 93% w / w, about 94% w / w, about 95% w / w, about 96% w / w, about 97% w / w, about 98% w / w, about 99% w / w, about 100% w / w, about 101% w / w, about 102% w / w, about 103% w / w, about 104% w / w, about 105% w / w, about %, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98% by weight of microcrystalline cellulose. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 90% by weight of microcrystalline cellulose. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain about 91% w / w microcrystalline cellulose. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain about 92% w / w microcrystalline cellulose. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain about 93% w / w microcrystalline cellulose.

[0123] In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain from about 1.0% w / w to about 10% w / w of one or more disintegrants. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain from about 3.5% w / w to about 6% w / w of one or more disintegrants. In some embodiments, 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 / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, About 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4. 5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, about 5.0 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt Amount / wt%, about 5.5 wt / wt%, about 5.6 wt / wt%, about 5.7 wt / wt%, about 5.8 wt / wt%, about 5.9 wt / wt%, about 6.0 wt / wt%, about 6.1 wt / wt%, about 6.2 wt / wt%, about 6.3 wt / wt Amount%, about 6.4 wt / wt%, about 6.5 wt / wt%, about 6.6 wt / wt%, about 6.7 wt / wt%, about 6.8 wt / wt%, about 6.9 wt / wt%, about 7.0 wt / wt%, about 7.1 wt / wt%, about 7.2 wt / wt%, About 7.3 wt / wt%, about 7.4 wt / wt%, about 7.5 wt / wt%, about 7.6 wt / wt%, about 7.7 wt / wt%, about 7.8 wt / wt%, about 7.9 wt / wt%, about 8.0 wt / wt%, about 8.1 wt / wt%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, or about 10.0% w / w of one or more disintegrants. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 5% w / w of one or more disintegrants.

[0124] In some embodiments, 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 embodiments, at least one of the disintegrants is croscarmellose sodium. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains about 1.0% to about 10% w / w of croscarmellose sodium. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains about 3.5% to about 6% w / w of croscarmellose sodium. In some embodiments, 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 / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3. 5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt% , about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt wt%, approx. 4.9 wt / wt%, approx. 5 wt / wt%, approx. 5.1 wt / wt%, approx. 5.2 wt / wt%, approx. 5.3 wt / wt%, approx. 5.4 wt / wt%, approx. 5.5 wt. / wt%, approx. 5.6 wt / wt%, approx. 5.7 wt / wt%, approx. 5.8 wt / wt%, approx. 5.9 wt / wt%, approx. 6.0 wt / wt%, approx. 6.1 wt / wt%, approx. 6.2wt / wt%, about 6.3wt / wt%, about 6.4wt / wt%, about 6.5wt / wt%, about 6.6wt / wt%, about 6.7wt / wt%, about 6.8wt / wt%, about 6.9wt / wt%, about 7.0wt / wt%, about 7.1wt / wt%, about 7.2wt Amount / wt%, about 7.3 wt / wt%, about 7.4 wt / wt%, about 7.5 wt / wt%, about 7.6 wt / wt%, about 7.7 wt / wt%, about 7.8 wt / wt%, about 7.9 wt / wt%, about 8.0 wt / wt%, about 8.1 wt / wt%, about 8.2 wt / wt% In some embodiments, the pharmaceutical composition comprises about 8.3 wt / wt%, about 8.4 wt / wt%, about 8.5 wt / wt%, about 8.6 wt / wt%, about 8.7 wt / wt%, about 8.8 wt / wt%, about 8.9 wt / wt%, about 9.0 wt / wt%, about 9.1 wt / wt%, about 9.2 wt / wt%, about 9.3 wt / wt%, about 9.4 wt / wt%, about 9.5 wt / wt%, about 9.6 wt / wt%, about 9.7 wt / wt%, about 9.8 wt / wt%, about 9.9 wt / wt%, or about 10.0 wt / wt% croscarmellose sodium. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 5 wt / wt% croscarmellose sodium.

[0125] In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises 0% w / w to about 5% w / w of one or more flavoring agents. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises 0% w / w to about 2.5% w / w of one or more flavoring agents. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has 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%, 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 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 / wt%, about 3.3 wt / wt In some embodiments, the pharmaceutical composition comprises about 2% w / w of one or more flavoring agents.

[0126] In some embodiments, at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors, including, but not limited to, grape flavor, bubble gum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor. In some embodiments, at least one of the flavoring agents is grape flavor. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains 0% w / w to about 5.0% w / w of grape flavor. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains 0% w / w to about 2.5% w / w of grape flavor.In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet is 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%, 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 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 / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt%, approx. 2.4 wt / wt%, approx. 2.5 wt / wt%, approx. 2.6 wt / wt%, approx. 2.7 wt / wt%, approx. 2.8 wt / wt%, approx. 2.9 wt / wt%, approx. 3.0 wt / wt Amount%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt %, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5.0% w / w of grape flavor. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 2% w / w of grape flavor.

[0127] In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain 0% w / w to about 5% w / w of one or more sweeteners. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain 0% w / w to about 2% w / w of one or more sweeteners. In some embodiments, pharmaceutical compositions that are dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain 0%, about 0.1%, about 0.2%, about 0.3%, approx. 0.4 wt / wt%, approx. 0.5 wt / wt%, approx. 0.6 wt / wt%, approx. 0.7 wt / wt%, approx. 0.8 wt / wt%, approx. 0.9 wt / wt%, approx. 1 wt / wt%, approx. 1.1 wt / wt%, approx. 1.2 wt / wt%, approx. 1.3 wt / wt%, approx. 1.4 wt / wt%, approx. .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 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 %, about 2.9 wt / wt%, about 3.0 wt / wt%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, or about 5.0 wt / wt% of one or more sweeteners. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1% w / w of one or more sweeteners.

[0128] In some embodiments, 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 embodiments, at least one of the sweeteners is sucralose. In some embodiments, the sweetener is sucralose. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains 0% to about 5% wt / wt of sucralose. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and contains 0% to about 2% wt / wt of sucralose. In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet is 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 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 / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 w wt%, approx. 2.4 wt / wt%, approx. 2.5 wt / wt%, approx. 2.6 wt / wt%, approx. 2.7 wt / wt%, approx. 2.8 wt / wt%, approx. 2.9 wt / wt%, approx. 3.0 wt / wt Amount%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt %, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5% wt / wt of sucralose.In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1% w / w sucralose.

[0129] In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises 0% w / w to about 5% w / w of one or more lubricants. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.1 ... Pharmaceutical compositions that are dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets contain from about 0.5% w / w to about 2% w / w of one or more lubricants. In some embodiments, the pharmaceutical composition comprises 0%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6 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 / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, or about 5 wt / wt% of one or more lubricants. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1% w / w of one or more lubricants.

[0130] In some embodiments, 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. In some embodiments, at least one of the lubricants is magnesium stearate. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains 0% w / w to about 5% w / w magnesium stearate. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 0.1% w / w to about 2% w / w magnesium stearate. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet contains about 0.5% w / w to about 2% w / w magnesium stearate.In some embodiments, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet is 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%, 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 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%, Approx. 3.1 wt / wt%, approx. 3.2 wt / wt%, approx. 3.3 wt / wt%, approx. 3.4 wt / wt%, approx. 3.5 wt / wt%, approx. 3.6 wt / wt%, approx. 3.7 wt / wt%, approx. 3 In some embodiments, the pharmaceutical composition comprises about 0.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5% wt / wt% magnesium stearate. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and comprises 0% wt / wt% magnesium stearate. In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, and comprises 0% wt / wt% magnesium stearate. The pharmaceutical composition, which is a dispersible minitablet, or dispersible pellet, contains about 1% w / w magnesium stearate.

[0131] Methods of Treatment and Use In some aspects, the present disclosure provides methods of treating a tumor, cancer, or a Rasopathy disorder, comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.

[0132] In some embodiments, the tumor is a neurofibroma. In some embodiments, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some embodiments, 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. In some embodiments, the tumor is a plexiform neurofibroma.

[0133] In some embodiments, 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.

[0134] In some aspects, the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, 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 carcinoma, biliary tract cancer, and peritoneal serous carcinoma. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In some embodiments, the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia. In some embodiments, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, and small cell lung carcinoma.

[0135] In some embodiments, the subject has a mutation or other abnormality in one or more genes that causes a gain or loss of function characteristic of a particular cancer, and the mutation or other abnormality in the one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0136] In some embodiments, an individual dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as two or more tablets, two or more dispersible powders, two or more dispersible granules, two or more minitablets, two or more pellets, or a combination thereof. For example, a 3 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as two dispersible tablets (one containing 2 mg and the other containing 1 mg) or as three dispersible tablets (each containing 1 mg).

[0137] In some embodiments, 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. Difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in 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 per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 0.5 mg per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 1 mg per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 2 mg per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 3 mg per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 4 mg per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 5 mg per dose. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 10 mg per dose.In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a dose of about 20 mg per dose.

[0138] In some embodiments, the pharmaceutical composition comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once, twice, three times, or four times daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

[0139] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

[0140] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days during which the total daily dose is administered; and (b) 28 days during which the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 7 days when 2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 consecutive days during which the total daily dose is administered, followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each of which comprises (i) 5 days during which the total daily dose is administered, and (ii) 2 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered, and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) three 7 day periods, each of which comprises: (i) 5 consecutive days during which the total daily dose is administered, and (ii) 2 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered, followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0141] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising 28 days during which the total daily dose is administered.

[0142] In some embodiments, the 28-day administration cycle is repeated for a total of 24 consecutive 28-day administration cycles.

[0143] In some embodiments, the subject experiences dysphagia. In some embodiments, the subject experiences dysphagia caused by one or more of a neurological disease, muscle weakness, developmental disorder, stroke, trauma, anatomical defect, cancer, cancer treatment, an allergic reaction, dementia, memory loss, or cognitive decline. In some embodiments, the subject has been diagnosed with an autism spectrum disorder. In some embodiments, the subject has been diagnosed with a craniofacial disorder. In some embodiments, the subject has been diagnosed with myasthenia gravis. In some embodiments, the subject has been diagnosed with tardive dyskinesia.

[0144] In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is under 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year old. In some embodiments, the subject is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 years old. In some embodiments, the subject is under 13 years old. In some embodiments, the subject is under 12 years old. In some embodiments, the subject is under 11 years old. In some embodiments, the subject is under 10 years old. In some embodiments, the subject is under 9 years old. In some embodiments, the subject is under 8 years old. In some embodiments, the subject is under 7 years old. In some embodiments, the subject is under 6 years old. In some embodiments, the subject is under 5 years old. In some embodiments, the subject is under 4 years old. In some embodiments, the subject is less than 3 years old. In some embodiments, the subject is less than 2 years old. In some embodiments, the subject is less than 1 year old. In some embodiments, the subject is about 2 to about 18 years old. In some embodiments, the subject is about 3 to about 17 years old. In some embodiments, the subject is about 4 to about 16 years old. In some embodiments, the subject is about 5 to about 15 years old. In some embodiments, the subject is about 6 to about 14 years old. In some embodiments, the subject is about 7 to about 13 years old. In some embodiments, the subject is about 8 to about 12 years old.

[0145] In some embodiments, the subject is an elderly subject. In some embodiments, the subject is over 30 years old, over 35 years old, over 40 years old, over 45 years old, over 50 years old, over 55 years old, over 60 years old, over 65 years old, over 70 years old, over 75 years old, over 80 years old, over 85 years old, over 90 years old, over 95 years old, or over 100 years old. In some embodiments, the subject is over 50 years old. In some embodiments, the subject is over 60 years old. In some embodiments, the subject is over 70 years old. In some embodiments, the subject is over 80 years old. In some embodiments, the subject is over 90 years old. In some embodiments, the subject is over 100 years old.

[0146] In some embodiments, when N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered more than once daily, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be divided so that the patient receives a different dose each time. For example, if the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is 2 mg administered twice daily, the patient may 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.

[0147] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice 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. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 0.25 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 0.5 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 1 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 2 mg each. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 1 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 4 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 5 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of about 10 mg each.

[0148] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily. In some embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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 embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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 embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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 embodiments, the total daily dose of 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. In some embodiments, the total daily dose of 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.

[0149] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered via a pharmaceutical composition described herein, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 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, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 6 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 4 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 1 mg.

[0150] In some aspects, the present disclosure provides for the use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a tumor, cancer, or a Rasopathy disorder. [Example]

[0151] Example 1: Seed crystal production of Form IV Step 1: Preparation of "side chain", PD-0337792 14.4 kg of alcohol (99.4% chemical purity, 99.6% optical purity, enantiomeric excess) was converted to 97.5 kg of a 9.7% w / w solution of PD-0337792 (IPGA) in toluene (approximately 60% overall yield). Triflate activation was carried out in a 200 L reactor by maintaining the temperature below -20 °C during the addition of triflic anhydride. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxyphthalimide (NHP), and the reaction was allowed to proceed to completion at ambient temperature. Final base deprotection was carried out by adding aqueous ammonia (approximately 28% solution, 5 equivalents, 34 kg). After completion of the reaction, water was removed from the toluene by distillation, and the resulting solid by-product was filtered off to obtain the product solution.

[0152] Step 2: Preparation of PD-0315209 This process yielded 21.4 kg (99.4 wt / wt% assay) of 80% theoretical yield from the starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 equiv.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 equiv.) using lithium amide base (5 kg, 3.2 equiv.). The reaction was initiated by adding 5% of the total solution of TFBA and FIA to the lithium amide slurry at 50 °C. The reaction exhibited a minimum initiation period of approximately 10 min, observed by discoloration and a slight exotherm. The remaining TFBA / FIA solution in THF was added slowly via a pressure canister within 1 h, maintaining the reaction temperature within 45–55 °C. No significant pressure increase (due to ammonia gas evolution) was observed throughout the entire run.

[0153] Step 3: Preparation of PD-0325901 Modifications were made to the CDI charge to mitigate potential gas generation. Two equal portions of CDI were added to the solid FIPFA (via a shot loader) before and after solvent addition. The timing between the two solid CDI additions (4.6 kg each) should not exceed 30 minutes. The two intermediate filter cakes were then dissolved in ethanol. Excess ethanol was distilled and replaced with approximately 5% v / v ethanol with toluene prior to recrystallization of PD-0325901. Laboratory studies have demonstrated crystallization from toluene and acetonitrile. It has been suggested that recrystallization from ethanol in toluene fails to reduce the impurity essential for polymorphic transformation. The presence of a dimeric impurity (PF-00191189) at levels above 0.2% is known to result in the formation of undesired polymorphs. [ka]

[0154] Crude crystallization from the final reaction mixture reduced the dimeric impurity PF-00191189 to approximately 1.9%, and subsequent recrystallization further reduced it to approximately 0.4%. As a result, an undesired polymorph was produced. DSC patterns showed two distinct melting points: approximately 80°C (low-melting Form II) and approximately 117°C (Form I). Also, during processing, the solid crystallized at a much lower temperature than expected (approximately 10°C actual, expected approximately 40°C). The unsuccessful recrystallization is presumed to be due to a change in solvent composition resulting from incomplete drying of the crude material. Drying of the crude wet cake prior to dissolution in ethanol was stopped after approximately 36 hours when the crude product was approximately 28 kg (theoretical 26 kg).

[0155] Polymorphic transformation Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the final EtOH / water crystallization and the precipitate from the previous EtOH / toluene filtrate were carried forward for polymorph conversion. Both crops were dried separately on filters to constant weight, and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC, yielding an estimated 16.4 kg of PD-0325901. Recrystallization began after removing the EtOH by vacuum distillation and adjusting the solvent composition to approximately 5% EtOH in toluene at 65°C (i.e., EtOH was added dropwise at 65°C until complete solid dissolution).

[0156] A slow 4-hour cooling ramp to 5°C, followed by 12 hours of stirring, was used to ensure satisfactory results. The resulting slurry was filtered and again allowed to dry completely in the filter to constant weight (approximately 3 days). The purified solid exhibited 99.8% pure PD-0325901 with no detectable levels of the dimeric impurity PF-00191189.

[0157] The dried solid (15.4 kg) was redissolved from the filter in exactly 4 volumes of EtOH (62 L), transferred to a reactor, and precipitated by the slow (approximately 3 h) addition of water (308 L) at 30-35 °C, cooled to 20 °C, and stirred for 12 h. DSC analysis of a slurry sample taken at 2 h shows that the solid is entirely Form IV (the desired polymorph).

[0158] Using 21.4 kg of PD-0315209, 9.7 kg of CDI (1.05 equiv.), and 91 kg of a 9.7% toluene solution of PD-0337792 (1.1 equiv.), 12.74 kg of PD-0325901 was obtained (assay 99.4%, 100% Form IV, approximately 48% yield).

[0159] Example 2: Assay / Impurities and Identification 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 infrared or proton NMR spectra in addition to HPLC retention times. For purity assessment, process impurities and degradants are identified by their characteristic relative retention times and quantified by area normalization.

[0160] Chromatographic conditions: Agilent Zorbax SB C18, 5 μm, 4.6 × 250 mm (or equivalent), flow rate 1.0 mL / min, column temperature 30 °C, detector wavelength 275 nm, diluent 50 / 50 acetonitrile / water, mobile phase A 0.1% trifluoroacetic acid (TFA) in water, mobile phase B methanol, with the following gradient conditions: Assays are determined against reference standards and reported on an anhydrous, solvent-free basis. Quantitation of named and unnamed impurities is reported as area percent. Total impurities is the sum of all impurities present above the 0.05% reporting threshold. [Table 1]

[0161] Example 3: Improved process for the preparation of Form IV As described in Example 1, the synthetic method for producing mirdametinib as Form IV produced Form IV with the dimeric impurity PF-00191189, and further steps were required to convert the product to essentially pure Form IV, free of the undesired polymorphs of Forms I and II. Therefore, there was a need to develop a method for producing essentially pure Form IV without additional processing steps.

[0162] Mirdametinib Manufacturing Process This route is a convergent four-step synthesis with six chemical steps in total, using the proposed starting materials (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA), 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-iodoaniline (FIA), and N-hydroxyphthalimide (NHP). The final step (Step 4) provides essentially pure Form IV of mirdametinib. [ka]

[0163] Step 1 (Preparation of PD-0337792 (IPGA)): A clean, dry 100-gallon reactor was charged with toluene (139.3 kg, 8 volumes) and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA; 20.0 kg, 1.0 equiv.). Triethylamine (18.8 kg, 1.22 equiv.) was charged to the reactor. The reactor contents were stirred and cooled to −10±10°C. Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equiv.) was added to a clean 50-L round-bottom flask under nitrogen and then cooled to a temperature ≦−10°C. The cooled trifluoromethanesulfonic anhydride was slowly transferred to the 100-gallon reactor while maintaining an internal temperature of −10±10°C. The reaction mixture was stirred at -10±10°C for 30 minutes. Reaction monitoring by TLC indicated complete conversion. While maintaining the internal temperature at -10±10°C, anhydrous toluene (99.8 kg, 5.75 volumes) was charged to the reactor, followed by N-hydroxyphthalimide (26.4 kg, 1.07 equivalents). The contents were warmed to 20±5°C and then stirred at this temperature for at least 5 hours until the triflate intermediate was no longer detectable by TLC. The reaction mixture was divided 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).

[0164] The toluene solution was recombined in a 100-gallon reactor. The organic solution was treated with 28% ammonium hydroxide solution (41.5 kg, 7.8 equiv.). The contents were heated to 35±5°C and then stirred for not less than 12 hours ("NLT"). Upon reaction completion, the lower aqueous phase was removed. The toluene solution was dried via azeotropic distillation of toluene. The toluene solution was then concentrated to a minimum stirred 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 the presence of 8.6 kg (36.7% yield) of PD-0337792 (IPGA).

[0165] Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon reactor was purged with nitrogen and then charged with lithium amide (LiNH, 8.8 kg, 3.4 equiv.) followed by tetrahydrofuran (THF, 56.8 kg, 3.2 vol.). The mixture was cooled to 10±10°C, and then additional THF (15.1 kg, 0.85 vol.) was charged to the reactor, followed by a solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equiv.) in THF (26.4 kg, 1.15 vol.). The reaction mixture was heated to 50°C NMT ("no more than"). A solution of 2-fluoro-4-iodoaniline (FIA, 27.5 kg, 1.02 eq) in THF (17.8 kg, 1 vol) was added in portions to the reactor, maintaining the batch temperature at NMT 50°C and stirring for 1 hour between additions. After the addition was complete, the reaction mixture was stirred at 50±10°C for an additional 3 hours. Upon reaction completion, the mixture was cooled to NMT 10°C and then quenched with USP purified water (120.3 kg, 6 vol). The reaction mixture was distilled to approximately 30 gallons, after which methyl t-butyl ether (MTBE, 118.6 kg, 8 vol) was added. The MTBE solution was then quenched with 2 M hydrochloric acid solution (89.5 kg) to pH=7. The aqueous phase was then removed. The MTBE solution was filtered through Celite and then washed twice with 5% brine solution (104.1 kg, 5.2 volumes), followed by a 1 M hydrochloric acid solution (77.4 kg). The MTBE solution was solvent exchanged with toluene and then the volume was adjusted to approximately 50 gallons. The mixture was heated to 75±5°C for 1 hour, then cooled to 20±5°C and stirred for 1 hour. The product was filtered, washed with toluene (68.1 kg, approximately 4 volumes), and then dried under vacuum at 40°C to give 25.2 kg of PD-0315209 (56.4% yield).

[0166] Step 3 (Preparation of crude PD-0325901): A clean, dry 100-gallon reactor was purged with nitrogen and then charged with PD-0315209 (18.0 kg, 1 eq) and THF (113.0 kg, 7 vol). The mixture was cooled to 5±5°C. N,N-diisopropylethylamine (15.1 kg, 2.55 eq) was charged while maintaining a temperature of NMT 25°C. The mixture was cooled to 5±5°C and then stirred for 10 minutes. A solution of PD-0337792 in toluene (121.7 kg total, 1.3 eq) was charged to the reactor at 5±5°C, followed by 50% T3P in ethyl acetate (42.0 kg, 1.45 eq). The reaction mixture was stirred at 10±5°C for NLT 3 hours. To drive the coupling to completion, an additional charge of N,N-diisopropylethylamine (1.9 kg, 0.3 eq) and 50% T3P in ethyl acetate (4.1 kg, 0.15 eq) was made. The reaction was back-quenched into 5% sodium hydroxide solution (50 kg) and then washed with 5% brine (55.4 kg). The organic solution was concentrated and then solvent exchanged with toluene. Acetonitrile (43.0 kg, 2.4 vol) was added to the reactor, followed by 2 M hydrochloric acid (117.6 kg, 5.1 eq). The mixture was stirred at 25±5°C until the reaction was complete after 16 hours. The bottom aqueous phase was removed, and the reaction mixture was then washed with 5% brine (75.2 kg). The organic phase was concentrated and then solvent exchanged with toluene to the appropriate volume. The mixture was then heated to 75±5°C for 30 minutes and then slowly cooled to 20°C. The solid was filtered and then washed with toluene (31.1 kg, 1.7 vol).

[0167] The crude solid was returned to the 100-gallon reactor, followed by charging with 5% ethanol in toluene (170.0 kg). The mixture was heated to 75±5°C for 60 minutes to obtain a solution, then slowly cooled to 20°C. The solid was filtered and then washed twice with toluene (31 kg, 1.7 volumes). The wet cake was dried under vacuum at 45°C to give 8.2 kg of crude PD-0325901 (37.1% yield).

[0168] Step 4 (Preparation of Essentially Pure Form IV Mirdametinib): A clean, dry 100 gallon reactor was purged with nitrogen and then charged with USP purified water (164.1 kg, 20 volumes), followed by ethanol (200 proof, 20.8 kg, 3.25 volumes). The contents of the reactor were heated to 5±5°C. In a separate container, crude PD-0325901 (8.1 kg, 1 equivalent) was dissolved in ethanol (200 proof, 40.5 kg, 6.3 volumes). A portion of this solution (14.4 kg) was added to a 100-gallon reactor over 60 minutes. PD-0325901 Form IV seeds (82.6 g, 1 wt%) prepared in Example 1 were added to the reactor to facilitate precipitation. While the mixture was stirred at 35±5°C, the remainder of the crude PD-0325901 / ethanol solution (34.3 kg) was added to the reactor over 90 minutes. The contents of the reactor were continued to stir at 35±5°C for 5.5 hours and then slowly cooled to 20°C. The solid was then filtered, washed with USP purified water (16.5 kg, 2 volumes), and then dried under vacuum at 45°C for 16 hours. The dried solid was screened through a 10 mesh sieve to give 5.7 kg of PD-0325901 Form IV (70.4% yield).

[0169] The XRPD pattern for essentially pure Form IV used herein is shown in Figure 1A. The TGA and DSC analysis of essentially pure Form IV used herein is shown in Figure 1B.

[0170] Example 4: 0.5 mg and 1.0 mg Dispersible Tablet Formulations An example of a dispersible tablet formulation is shown in Table 1. [Table 2]

[0171] Example 5: Manufacturing process of Mirdametinib dispersible tablets Non-limiting examples of exemplary processes for manufacturing Mirdametinib dispersible tablets are described herein.

[0172] Microcrystalline cellulose (approximately 30% w / w of the microcrystalline cellulose in the final composition) is mixed in a vessel. Mirdametinib, croscarmellose, and microcrystalline cellulose (approximately 50% w / w of the microcrystalline cellulose in the final composition) are added to a vessel and mixed. The remaining microcrystalline cellulose is added to a vessel and mixed. Intragranular magnesium stearate is added for lubrication and the mixture is roller compacted into dry granules. Grape flavor and sucralose are mixed into the granules and extragranular magnesium stearate is added for lubrication. The mixture is compressed and characterized for appearance, weight, thickness, and In-process controls are checked based on hardness, friability, and disintegration. The tablets are de-dusted, inspected for metal impurities, and then bulk packaged.

[0173] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein serves as the definition of that term.

[0174] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is generally intended to cover any variations, uses, or adaptations in accordance with the principles of the present disclosure, including such departures from the present disclosure as are within known or customary practice in the art to which this invention pertains, as may be applied to the essential features described above and as fall within the scope of the appended claims.

[0175] In addition to the various embodiments described herein, the present disclosure includes the following embodiments, numbered E1 through E141. This list of embodiments is presented as an exemplary list, and the application is not limited to these embodiments.

[0176] E1. An amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of formula (I) [ka] 1. A pharmaceutical composition comprising:

[0177] E2. The pharmaceutical composition of E1, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is crystalline.

[0178] E3. The pharmaceutical composition of E2, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is: A crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ; 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 one or more peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2θ; and XRP with one or more peaks at 5.5±0.2 and 19.6±0.2 degrees 2θ Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by D pattern The pharmaceutical composition is selected from the group consisting of:

[0179] 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 2θ.

[0180] 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-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 2θ.

[0181] E6. The pharmaceutical 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.

[0182] E7. The crystalline form of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is: a) a TGA profile substantially as shown in Figure 1B; and / or b) A DSC profile substantially as shown in Figure 1B The pharmaceutical composition of any one of E2 to E6, characterized by one or both of the following:

[0183] 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 that does not have an endothermic onset at about 117°C.

[0184] 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 a detectable amount of Form I or Form II by XRPD and / or DSC.

[0185] E10. The pharmaceutical composition of any one of E2 to 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 that is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C to 25°C, relative humidity 65% ​​or less).

[0186] E11. The pharmaceutical composition of any one of E2 to E10, 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 that is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C to 25°C, relative humidity ≤65%).

[0187] E12. The pharmaceutical composition of any one of E2 to 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 that is substantially unchanged after storage for one year at standard warehouse conditions (15°C to 25°C, relative humidity ≤65%).

[0188] E13. The pharmaceutical composition of any one of E2 to 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 that is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C to 25°C, relative humidity ≤ 65%).

[0189] E14. The pharmaceutical composition of any one of E2 to 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 that is substantially unchanged after storage for 140 months or more at standard warehouse conditions (15°C to 25°C, relative humidity ≤ 65%).

[0190] E15. The pharmaceutical composition of any one of E2-E14, wherein said DSC pattern is generated using a TA Instruments Q100 or Q2000 Differential Scanning Calorimeter at a temperature ramp rate of about 15°C / min.

[0191] E16. The pharmaceutical composition of any one of E2-E15, wherein the crystalline form is anhydrous.

[0192] E17. The pharmaceutical composition of any one of E2-E16, wherein said crystalline form is Form IV.

[0193] 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 the following angles 2θ: 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2θ.

[0194] E19. The crystalline form of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was 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 2θ.

[0195] E20. The pharmaceutical composition of E2, E3, E18, or E19, wherein said crystalline form is characterized by a DSC profile with an endothermic onset at about 117°C.

[0196] E21. The pharmaceutical composition of any one of E2, E3, and E18-E20, wherein the crystalline form is Form I.

[0197] 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 2θ.

[0198] 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 the following: 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, 29.1±0.2, 30.5±0.2, 31.7±0.2, 33.3±0.2, and 39.0±0.2 degrees 2θ.

[0199] 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 endothermic onset at about 87°C.

[0200] E25. The pharmaceutical composition of any one of E2, E3, and E22-E24, wherein the crystalline form is Form II.

[0201] E26. The pharmaceutical composition of any one of E1-E25, wherein said pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0202] E27. The pharmaceutical composition of any one of E1-E26, wherein the pharmaceutical composition is for oral administration.

[0203] E28. The pharmaceutical composition of any one of E1-E27, wherein said pharmaceutical composition is orally dispersible.

[0204] E29. The pharmaceutical composition of any one of E1-E28, wherein the pharmaceutical composition is a tablet, powder, granules, minitablets, or pellets.

[0205] E30. The pharmaceutical composition of E29, wherein said pharmaceutical composition is a powder.

[0206] E31. The pharmaceutical composition of E30, wherein said powder is a dispersible powder.

[0207] E32. The pharmaceutical composition of E30 or E31, wherein a capsule or sachet contains said powder or dispersible powder.

[0208] E33. The pharmaceutical composition of E29, wherein said pharmaceutical composition is in the form of granules.

[0209] E34. The pharmaceutical composition of E33, wherein said granules are dispersible granules.

[0210] E35. A pharmaceutical composition according to E33 or E34, wherein a capsule or sachet contains said granules or dispersible granules.

[0211] E36. The pharmaceutical composition according to E29, wherein said pharmaceutical composition is in the form of minitablets.

[0212] E37. The pharmaceutical composition according to E36, wherein said minitablets are dispersible minitablets.

[0213] E38. A pharmaceutical composition according to E36 or E37, wherein a capsule or sachet contains said minitablets or dispersible minitablets.

[0214] E39. The pharmaceutical composition of E29, wherein said pharmaceutical composition is in the form of a pellet.

[0215] E40. The pharmaceutical composition of E39, wherein said pellets are dispersible pellets.

[0216] E41. A pharmaceutical composition according to E39 or E40, wherein a capsule or sachet contains said minitablets or dispersible minitablets.

[0217] E42. The pharmaceutical composition of E29, wherein said pharmaceutical composition is a tablet.

[0218] E43. The pharmaceutical composition according to E42, wherein said pharmaceutical composition is a dispersible tablet.

[0219] E44. The pharmaceutical composition 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; Each component of the pharmaceutical composition is as follows: a. about 0.1% w / w to about 7% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b. about 50% w / w to about 98% w / w of one or more diluents; c. about 1% w / w to about 10% w / w of one or more disintegrants; d. 0% w / w to about 5% w / w of one or more flavoring agents; e. 0% w / w to about 5% w / w of one or more sweeteners; and f. about 0% w / w to about 5% w / w of one or more lubricants The pharmaceutical composition according to any one of E1 to E43, wherein:

[0220] E45. The pharmaceutical composition 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; Each component of the pharmaceutical composition is as follows: a. about 0.5% w / w to about 1.2% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b. about 85% w / w to about 95% w / w of one or more diluents; c. about 3.5% w / w to about 6% w / w of one or more disintegrants; d. 0% w / w to about 2.5% w / w of one or more flavoring agents; e. 0% w / w to about 2% w / w of one or more sweeteners; and f. about 0.5% w / w to about 2% w / w of one or more lubricants The pharmaceutical composition according to any one of E1 to E43, wherein:

[0221] E46. The pharmaceutical composition according to E44 or E45 comprising about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0222] E47. The pharmaceutical composition according to E44 or E45, comprising about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0223] E48. The pharmaceutical composition according to E44 or E45, comprising about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0224] E49. The pharmaceutical composition according to E44 or E45 comprising about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0225] E50. The pharmaceutical composition according to E44 or E45 comprising about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0226] E51. The pharmaceutical composition of any one of E44 to 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.

[0227] E52. The pharmaceutical composition of E51, wherein at least one of said diluents is microcrystalline cellulose.

[0228] E53. The pharmaceutical composition of any one of E44 to 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.

[0229] E54. The pharmaceutical composition according to E53, wherein at least one of said disintegrants is croscarmellose sodium.

[0230] E55. The pharmaceutical composition of any one of E44-E54, wherein at least one of said flavoring agents is selected from the group consisting of natural or synthetic flavors, including but not limited to grape flavor, bubble gum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor.

[0231] E56. The pharmaceutical composition according to E55, wherein at least one of said flavoring agents is grape flavor.

[0232] E57. The pharmaceutical composition of any one of E44 to 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.

[0233] E58. The pharmaceutical composition according to E57, wherein at least one of said sweeteners is sucralose.

[0234] E59. At least one of the lubricants is magnesium stearate, stearate fumarate The pharmaceutical composition according to any one of E44 to E58, wherein the inactive ingredient is selected from the group consisting of sodium acrylate, glycerol dibehenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, and talc.

[0235] E60. The pharmaceutical composition according to E59, wherein at least one of said lubricants is magnesium stearate.

[0236] E61. The pharmaceutical composition of any one of E1-E60, wherein the drinkable liquid is water, milk, or juice.

[0237] E62. The pharmaceutical composition of any one of E1-E60, wherein said pharmaceutical composition is dispersible in the saliva of the subject.

[0238] E63. A method of treating a tumor, cancer, or a Rasopathy disorder, comprising administering to a subject in need of such treatment a pharmaceutical composition of any one of E1-E62.

[0239] E64. The method of E63, wherein said tumor is a neurofibroma.

[0240] E65. The method of E64, wherein said tumor is a neurofibroma associated with neurofibromatosis type 1.

[0241] 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.

[0242] E67. The method of E66, wherein said tumor is a plexiform neurofibroma.

[0243] 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.

[0244] E69. The method of E63, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial carcinoma, uterine tumor, 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 carcinoma, biliary tract cancer, and peritoneal serous carcinoma.

[0245] E70. The method of E69, wherein said leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

[0246] E71. The method of E69, wherein said lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.

[0247] E72. The method of E69, wherein said 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.

[0248] E73. The method of any one of E63 to E72, wherein the subject has a mutation or other abnormality in one or more genes that causes a gain or loss of function characteristic of a particular cancer, and the mutation or other abnormality in the one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0249] E74. The method of any one of E63-E73, wherein the individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as two or more tablets, two or more doses of dispersible powder, two or more doses of dispersible granules, two or more doses of minitablets, two or more doses of pellets, or a combination thereof.

[0250] E75. The method of any one of E63 to E74, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days during which the total daily dose is administered; and (b) 7 days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

[0251] E76. The method of any one of E63-E74, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 consecutive days during which the total daily dose is administered; followed by (b) 7 consecutive days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

[0252] E77. The method of any one of E63-E74, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each comprising (i) 5 days during which the total daily dose is administered, and (ii) 2 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0253] E78. The method of any one of E63-E74, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) three 7-day periods, each of which comprises: (i) 5 consecutive days during which the total daily dose is administered, and (ii) 2 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0254] E79. The method of any one of E63-E74, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle consisting of 28 days in which a total daily dose is administered.

[0255] E80. The method of any one of E78-E79, wherein said 28-day administration cycle is repeated for up to a total of 24 consecutive 28-day administration cycles.

[0256] E81. The method of any one of E63-E80, wherein said subject experiences dysphagia.

[0257] E82. The method of E81, wherein said subject experiences dysphagia caused by one or more of a disease of the nervous system, muscle weakness, developmental disorder, stroke, trauma, anatomical defect, cancer, cancer treatment, allergic reaction, dementia, memory loss, or cognitive decline.

[0258] E83. The method of any one of E63 to E80, wherein said subject is a pediatric subject.

[0259] E84. The method of any one of E63-E83, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

[0260] E85. The method of E84, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg each.

[0261] E86. The method of E85, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.25 mg each.

[0262] E87. The method of E85, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 0.5 mg each.

[0263] E88. The method of E85, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 1 mg each.

[0264] E89. The method of E85, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 2 mg each.

[0265] E90. The method of E85, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 4 mg each.

[0266] E91. The method of E85, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 5 mg each.

[0267] E92. The method of E85, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 10 mg each.

[0268] E93. The N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro The method of any one of E63 to E83, wherein said total daily dose of -2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day.

[0269] E94. The method of E93, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.1 mg to about 20 mg.

[0270] E95. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.5 mg.

[0271] E96. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 1 mg.

[0272] E97. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 2 mg.

[0273] E98. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 4 mg.

[0274] E99. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 8 mg.

[0275] E100. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 10 mg.

[0276] E101. The method of E94, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 20 mg.

[0277] E102. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg.

[0278] E103. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg.

[0279] E104. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg.

[0280] E105. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg.

[0281] E106. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg.

[0282] E107. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg.

[0283] E108. The method according to E63 to E101, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

[0284] E109. Use of a pharmaceutical composition according to any one of E1-E62 for the manufacture of a medicament for treating a tumor, cancer, or a Rasopathy disorder.

[0285] E110. The use of E109, wherein said tumor is a neurofibroma.

[0286] E111. The use of E110, wherein said tumor is a neurofibroma associated with neurofibromatosis type 1.

[0287] E112. The use of any one of 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.

[0288] E113. The use of E112, wherein said tumor is a plexiform neurofibroma.

[0289] E114. The use of 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.

[0290] E115. The use according to E109, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial carcinoma, uterine tumor, 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 carcinoma, biliary tract cancer, and peritoneal serous carcinoma.

[0291] E116. The use of E115, wherein said leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

[0292] E117. The use of E115, wherein said lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.

[0293] E118. The use of E115, wherein said 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.

[0294] E119. The subject has a mutation or other abnormality in one or more genes, and the mutation or The use of any one of E109 to E118, wherein the mutation or other abnormality in one or more genes causes a gain or loss of function characteristic of a particular cancer, and the mutation or other abnormality in one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0295] E120. The use of any one of E109 to E119, wherein the individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as two or more tablets, two or more doses of dispersible powder, two or more doses of dispersible granules, two or more doses of minitablets, two or more doses of pellets, or a combination thereof.

[0296] E121. The use of any one of E109 to E119, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days during which the total daily dose is administered; and (b) 7 days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

[0297] E122. The use of any one of E109 to E119, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 consecutive days during which the total daily dose is administered; followed by (b) 7 consecutive days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

[0298] E123. The use of any one of E109 to E119, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each comprising (i) 5 days during which the total daily dose is administered, and (ii) 2 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0299] E124. The use of any one of E109 to E119, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) three 7-day periods, each of which comprises: (i) 5 consecutive days during which the total daily dose is administered, and (ii) 2 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0300] E125. The use of any one of E109 to E119, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day administration cycle consisting of 28 days in which a total daily dose is administered.

[0301] E126. The use of any one of E124-E125, wherein said 28-day administration cycle is repeated up to a total of 24 consecutive 28-day administration cycles.

[0302] E127. The use of any one of E109 to E126, wherein said subject experiences dysphagia.

[0303] E128. The use of E127, wherein said subject experiences dysphagia caused by one or more of a disease of the nervous system, muscle weakness, developmental disorder, stroke, trauma, anatomical defect, cancer, cancer treatment, allergic reaction, dementia, memory loss, or cognitive decline.

[0304] E129. The use of any one of E109 to E128, wherein said subject is a pediatric subject.

[0305] E130. The method of any one of E109 to E129, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

[0306] E131. The use of E130, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.1 mg to about 10 mg each.

[0307] E132. The use of E131, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.25 mg each.

[0308] E133. The use of E131, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.5 mg each.

[0309] E134. The use of E131, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 1 mg each.

[0310] E135. The use of E131, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 2 mg each.

[0311] E136. The use of E131, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 4 mg each.

[0312] E137. The use of E131, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 5 mg each.

[0313] E138. The use according to E131, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 10 mg each.

[0314] E139. The use of any one of E109 to E129, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day.

[0315] E140. The use of E139, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.1 mg to about 20 mg.

[0316] E141. The use of E140, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.5 mg.

[0317] E142. The use according to E140, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 1 mg.

[0318] E143. The use according to E140, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 2 mg.

[0319] E144. The use according to E140, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 4 mg.

[0320] E145. The use according to E140, wherein said total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 8 mg.

[0321] E146. The use according to E140, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 10 mg.

[0322] E147. The use according to E140, wherein said total daily dose of said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 20 mg.

[0323] E148. The use of any one of E109 to E147, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg.

[0324] E149. The use of any one of E109 to E148, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg.

[0325] E150. The use of any one of E109 to E148, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg.

[0326] E151. The N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is more than 6 mg The use according to any one of E109 to E148, wherein the total daily dose is not more than 100 mg / kg.

[0327] E152. The use of any one of E109 to E148, wherein said N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg.

[0328] 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg.

[0329] 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

Claims

1. An amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of formula (I) 【Chemistry 1】 1. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is crystalline.

3. 3. The pharmaceutical composition of claim 2, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is: 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 with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ; 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 one or more peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees two-theta; and c) 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 one or more peaks at 5.5±0.2 and 19.6±0.2 degrees two-theta; The pharmaceutical composition is selected from the group consisting of:

4. 4. The pharmaceutical composition of claim 2 or claim 3, 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 with peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ.

5. 5. The pharmaceutical composition of any one of claims 2 to 4, 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 with peaks at 4.6±0.2, 7.3±0.2, 14.6±0.2, and 25.0±0.2 degrees 2θ.

6. The crystalline form of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is substantially as shown in FIG.

10. The pharmaceutical composition of any one of claims 2 to 5, characterized by the XRPD pattern shown in Figure 1A.

7. The crystalline form of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is as follows: a) a TGA profile substantially as shown in Figure IB; and / or b) A DSC profile substantially as shown in Figure 1B. The pharmaceutical composition according to any one of claims 2 to 6, characterized in that:

8. 8. The pharmaceutical composition of any one of claims 2 to 7, 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 that does not have an endothermic onset at about 117°C.

9. 9. The pharmaceutical composition of any one of claims 2 to 8, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide does not contain any detectable amount of Form I or Form II by XRPD and / or DSC.

10. 10. The pharmaceutical composition of any one of claims 2 to 9, 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 a DSC profile that is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C to 25°C, relative humidity up to 65%).

11. 11. The pharmaceutical composition of any one of claims 2 to 10, 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 a DSC profile that is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C to 25°C, relative humidity up to 65%).

12. 12. The pharmaceutical composition of any one of claims 2 to 11, 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 a DSC profile that remains substantially unchanged after storage for one year at standard warehouse conditions (15°C to 25°C, relative humidity up to 65%).

13. 13. The pharmaceutical composition of any one of claims 2 to 12, 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 a DSC profile that is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C to 25°C, relative humidity up to 65%).

14. 14. The pharmaceutical composition of any one of claims 2 to 13, 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 a DSC profile that remains substantially unchanged after storage for 140 months or more at standard warehouse conditions (15°C to 25°C, 65% or less relative humidity).

15. 15. The pharmaceutical composition of any one of claims 2 to 14, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 Differential Scanning Calorimeter at a temperature ramp rate of about 15°C / min.

16. The pharmaceutical composition of any one of claims 2 to 15, wherein the crystalline form is anhydrous.

17. 17. The pharmaceutical composition of any one of claims 2 to 16, wherein the crystalline form is Form IV.

18. 4. The pharmaceutical composition of claim 2 or claim 3, 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 the following angles: 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2θ.

19. The crystalline forms of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide were 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 20. The pharmaceutical composition of claim 2, claim 3, or claim 18, characterized by an XRPD pattern having peaks at one or more of the following angles: 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 2θ.

20. 20. The pharmaceutical composition of claim 2, claim 3, claim 18, or claim 19, wherein the crystalline form is characterized by a DSC profile with an endothermic onset at about 117°C.

21. The pharmaceutical composition of any one of claims 2, 3, and 18 to 20, wherein the crystalline form is Form I.

22. 4. The pharmaceutical composition of claim 2 or claim 3, 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 with peaks at 5.5±0.2 and / or 19.6±0.2 degrees 2θ.

23. 23. The pharmaceutical composition of claim 2, claim 3, or claim 22, 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 the following angles: 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, 29.1±0.2, 30.5±0.2, 31.7±0.2, 33.3±0.2, and 39.0±0.2 degrees 2θ.

24. 24. The pharmaceutical composition of claim 2, claim 3, claim 22, or claim 23, 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 endothermic onset at about 87°C.

25. The pharmaceutical composition of any one of claims 2, 3, and 22-24, wherein the crystalline form is Form II.

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the pharmaceutical composition is for oral administration.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the pharmaceutical composition is orally dispersible.

29. The pharmaceutical composition of any one of claims 1 to 28, wherein the pharmaceutical composition is a tablet, powder, granules, minitablets, or pellets.

30. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a powder.

31. 31. The pharmaceutical composition of claim 30, wherein the powder is a dispersible powder.

32. 32. The pharmaceutical composition of claim 30 or claim 31, wherein a capsule or sachet contains the powder or dispersible powder.

33. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of granules.

34. 34. The pharmaceutical composition of claim 33, wherein the granules are dispersible granules.

35. 35. A pharmaceutical composition according to claim 33 or claim 34, wherein a capsule or sachet contains the granules or dispersible granules.

36. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of minitablets.

37. 37. The pharmaceutical composition of claim 36, wherein the minitablets are dispersible minitablets.

38. 38. A pharmaceutical composition according to claim 36 or claim 37, wherein a capsule or sachet contains said minitablets or dispersible minitablets.

39. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of a pellet.

40. 40. The pharmaceutical composition of claim 39, wherein the pellets are dispersible pellets.

41. 41. A pharmaceutical composition according to claim 39 or claim 40, wherein a capsule or sachet contains said minitablets or dispersible minitablets.

42. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a tablet.

43. 43. The pharmaceutical composition of claim 42, wherein the pharmaceutical composition is a dispersible tablet.

44. The pharmaceutical composition comprises from about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxybenzoate). cyclopropyloxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, Each component of the pharmaceutical composition is as follows: a. about 0.1% w / w to about 7% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b. from about 50% w / w to about 98% w / w of one or more diluents; c. about 1% w / w to about 10% w / w of one or more disintegrants; d. 0% to about 5% w / w of one or more fragrance agents; e. 0% to about 5% w / w of one or more sweeteners; and f. from about 0% w / w to about 5% w / w of one or more lubricants The pharmaceutical composition according to any one of claims 1 to 43, wherein

45. the pharmaceutical composition comprising from about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; Each component of the pharmaceutical composition is as follows: a. about 0.5% to about 1.2% w / w of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b. about 85% w / w to about 95% w / w of one or more diluents; c. about 3.5% w / w to about 6% w / w of one or more disintegrants; d. 0% to about 2.5% w / w of one or more fragrance agents; e. 0% to about 2% w / w of one or more sweeteners; and f. about 0.5% w / w to about 2% w / w of one or more lubricants The pharmaceutical composition according to any one of claims 1 to 43, wherein

46. 46. ​​The pharmaceutical composition of claim 44 or claim 45, comprising about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

47. 46. ​​The pharmaceutical composition of claim 44 or claim 45, comprising about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

48. 46. ​​The pharmaceutical composition of claim 44 or claim 45, comprising about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

49. 46. ​​The pharmaceutical composition of claim 44 or claim 45, comprising about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

50. 46. ​​The pharmaceutical composition of claim 44 or claim 45, comprising about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

51. 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. The pharmaceutical composition according to any one of claims 44 to 50.

52. 52. The pharmaceutical composition of claim 51, wherein at least one of the diluents is microcrystalline cellulose.

53. 53. The pharmaceutical composition of any one of claims 44 to 52, 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.

54. 54. The pharmaceutical composition of claim 53, wherein at least one of the disintegrants is croscarmellose sodium.

55. 55. The pharmaceutical composition of any one of claims 44 to 54, 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 flavor, bubble gum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor.

56. 56. The pharmaceutical composition of claim 55, wherein at least one of the flavoring agents is grape flavor.

57. 57. The pharmaceutical composition of any one of claims 44 to 56, 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.

58. 58. The pharmaceutical composition of claim 57, wherein at least one of the sweeteners is sucralose.

59. 59. The pharmaceutical composition of any one of claims 44-58, 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.

60. 60. The pharmaceutical composition of claim 59, wherein at least one of the lubricants is magnesium stearate.

61. 61. The pharmaceutical composition of any one of claims 1 to 60, wherein the potable liquid is water, milk or juice.

62. 61. The pharmaceutical composition of any one of claims 1 to 60, wherein the pharmaceutical composition is dispersible in the saliva of a subject.

63. 63. A method of treating a tumor, cancer, or rasopathy disorder, comprising administering to a subject in need of such treatment a pharmaceutical composition of any one of claims 1 to 62.

64. 64. The method of claim 63, wherein the tumor is a neurofibroma.

65. 65. The method of claim 64, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1.

66. 66. The method of any one of claims 63 to 65, 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.

67. 67. The method of claim 66, wherein the tumor is a plexiform neurofibroma.

68. 68. The method of claim 67, 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.

69. 64. The method of claim 63, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, 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 carcinoma, biliary tract cancer, and peritoneal serous carcinoma.

70. 70. The method of claim 69, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

71. 70. The method of claim 69, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.

72. 70. The method of claim 69, 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.

73. 73. The method of any one of claims 63 to 72, wherein the subject has a mutation or other abnormality in one or more genes that causes a gain or loss of function characteristic of a particular cancer, and the mutation or other abnormality in the one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

74. 74. The method of any one of claims 63-73, wherein the individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as two or more tablets, two or more doses of dispersible powder, two or more doses of dispersible granules, two or more doses of minitablets, two or more doses of pellets, or combinations thereof.

75. 75. The method of any one of claims 63-74, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days during which the total daily dose is administered; and (b) 7 days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

76. 75. The method of any one of claims 63-74, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 consecutive days during which the total daily dose is administered; followed by (b) 7 consecutive days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

77. 75. The method of any one of claims 63-74, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) three 7 day periods each comprising (i) 5 days during which the total daily dose is administered, and (ii) 2 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

78. 75. The method of any one of claims 63-74, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) three 7 day periods each comprising: (i) 5 consecutive days during which the total daily dose is administered, and (ii) 2 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

79. 75. The method of any one of claims 63-74, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle consisting of 28 days during which a total daily dose is administered.

80. 80. The method of any one of claims 78-79, wherein the 28-day administration cycle is repeated for up to a total of 24 consecutive 28-day administration cycles.

81. 81. The method of any one of claims 63 to 80, wherein the subject experiences dysphagia.

82. 82. The method of claim 81, wherein the subject experiences dysphagia caused by one or more of a nervous system disease, muscle weakness, developmental disorder, stroke, trauma, anatomical defect, cancer, cancer treatment, allergic reaction, dementia, memory loss, or cognitive decline.

83. 81. The method of any one of claims 63 to 80, wherein the subject is a pediatric subject.

84. 84. The method of any one of claims 63-83, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

85. wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is 85. The method of claim 84, administered at a dose of about 0.1 mg to about 10 mg twice daily.

86. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.25 mg each.

87. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.5 mg each.

88. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 1 mg each.

89. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 2 mg each.

90. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 4 mg each.

91. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 5 mg each.

92. 86. The method of claim 85, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day in doses of about 10 mg each.

93. 84. The method of any one of claims 63-83, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day.

94. 94. The method of claim 93, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.1 mg to about 20 mg.

95. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.5 mg.

96. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 1 mg.

97. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 2 mg.

98. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 4 mg.

99. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 8 mg.

100. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 10 mg.

101. 95. The method of claim 94, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 20 mg.

102. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg.

103. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg.

104. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg.

105. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg.

106. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg.

107. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg.

108. 102. The method of any one of claims 63 to 101, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

109. 63. Use of the pharmaceutical composition of any one of claims 1 to 62 for the manufacture of a medicament for treating tumors, cancer, or rasopathy disorders.

110. 110. The use of claim 109, wherein the tumor is a neurofibroma.

111. The use of claim 110, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1. For.

112. 112. The use of any one of claims 109 to 111, 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.

113. 113. The use of claim 112, wherein the tumor is a plexiform neurofibroma.

114. 110. The use of claim 109, 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.

115. 110. The use of claim 109, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, 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 carcinoma, biliary tract cancer, and peritoneal serous carcinoma.

116. 116. The use of claim 115, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

117. 116. The use of claim 115, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.

118. 116. The use of claim 115, 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.

119. 119. The use of any one of claims 09 to 118, wherein the subject has a mutation or other abnormality in one or more genes that causes a gain or loss of function characteristic of a particular cancer, and the mutation or other abnormality in the one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

120. 120. The use of any one of claims 109 to 119, wherein the individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as two or more tablets, two or more doses of dispersible powders, two or more doses of dispersible granules, two or more doses of minitablets, two or more doses of pellets, or combinations thereof.

121. 120. The use of any one of claims 109 to 119, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days during which the total daily dose is administered; and (b) 7 days during which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

122. The N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-( 120. The use of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) 21 consecutive days during which the total daily dose is administered; followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

123. 120. The use of any one of claims 109 to 119, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) three 7 day periods each comprising (i) 5 days during which the total daily dose is administered, and (ii) 2 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

124. 120. The use of any one of claims 109 to 119, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle comprising: (a) three 7 day periods each comprising: (i) 5 consecutive days during which the total daily dose is administered, and (ii) 2 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days during which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

125. 120. The use of any one of claims 109 to 119, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28 day dosing cycle consisting of 28 days during which a total daily dose is administered.

126. 126. The use of any one of claims 124 to 125, wherein the 28-day administration cycle is repeated for up to a total of 24 consecutive 28-day administration cycles.

127. The use according to any one of claims 109 to 126, wherein the subject experiences dysphagia.

128. 128. The use of claim 127, wherein the subject experiences dysphagia caused by one or more of a nervous system disease, muscle weakness, developmental disorder, stroke, trauma, anatomical defect, cancer, cancer treatment, allergic reaction, dementia, memory loss, or cognitive decline.

129. 129. The use according to any one of claims 109 to 128, wherein the subject is a pediatric subject.

130. 130. The use of any one of claims 109 to 129, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day.

131. wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is 131. The use of claim 130, administered at a dose of about 0.1 mg to about 10 mg twice daily.

132. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.25 mg each.

133. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 0.5 mg each.

134. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 1 mg each.

135. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 2 mg each.

136. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 4 mg each.

137. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 5 mg each.

138. 132. The use of claim 131, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day at doses of about 10 mg each.

139. 130. The use of any one of claims 109 to 129, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day.

140. 140. The use of claim 139, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.1 mg to about 20 mg.

141. 141. The use of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 0.5 mg.

142. 141. The use of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 1 mg.

143. 141. The use of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 2 mg.

144. 141. The use of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 4 mg.

145. 141. The use of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 8 mg.

146. 141. The use of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 10 mg.

147. 141. The method of claim 140, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once a day at a dose of about 20 mg.

148. 148. The use of any one of claims 109 to 147, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg.

149. 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg.

150. 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg.

151. 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg.

152. The use of any one of claims 1109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg.

153. 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg.

154. 149. The use of any one of claims 109 to 148, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

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