CN117279630A

CN117279630A - Dispersible formulations of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide and uses thereof

Info

Publication number: CN117279630A
Application number: CN202180097034.5A
Authority: CN
Inventors: K·帕特森; J·刘
Original assignee: Springworths Treatment Co ltd
Current assignee: Springworths Treatment Co ltd
Priority date: 2021-02-17
Filing date: 2021-02-17
Publication date: 2023-12-22
Also published as: IL305079A; TW202245745A; AU2021428601A1; AR124908A1; EP4294525A1; JP2024507213A; WO2022177555A1; KR20230157314A; CA3207271A1

Abstract

The present disclosure relates to dispersible pharmaceutical compositions comprising N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide and optionally a pharmaceutically acceptable carrier.

Description

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

Technical Field

The present disclosure relates to dispersible formulations of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide for administration to a patient in need thereof, and methods of producing such dispersible formulations. The present disclosure also relates to dispersible formulations comprising N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; a method of producing a dispersible formulation comprising N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; and methods and uses for treating tumors, cancers, or RAS diseases (Rasopathy disorder) by administering N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide to a subject in need thereof.

Background

Type 1 neurofibromatosis ("NF 1") is characterized by a wide variety of progressive skin, nerve, bone and tumor manifestations, with no standard drug treatment options available. Neurofibromas are benign peripheral Schwann tumors, consisting of a mixture of Schwann cells, fibroblasts, fascicular cells and mast cells, and occur in 20-50% of NF1 patients (Tucker et al (2011) j. Histochem. Cytochem.59 (6): 584-590). Neurofibromas are classified as Plexiform Neurofibromas (PN) when they extend longitudinally along the nerve and involve multiple nerve bundles. Plexiform neurofibromas regress rarely spontaneously, and in many patients their growth is sustained. Plexiform neurofibromas are the leading cause of morbidity and contour injury in NF1 individuals and are associated with increased mortality when symptoms appear (Rasmussen et al (2001) am.j.hum.genet.68 (5): 1110-1118; prada et al (2012) j.pdoat.160 (3): 461-467). As the tumor grows, this lesion produces dysfunction, pain, and an appearance defect, and can stress the airway or spinal cord. In addition, PN may undergo malignant transformation, resulting in Malignant Peripheral Nerve Sheath Tumor (MPNST).

Previous longitudinal retrospective studies have demonstrated age-dependent differences in plexiform neurofibromas, PN growth being highly inversely correlated with 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 a series of MRI's for 34 patients with measurable PN (median age 10 years, ranging from 1 to 47 years) with median follow-up time period of 6 years (ranging from 1 to 15 years). This study observed that the difference between the initial and final two-dimensional estimated tumor sizes for young individuals was significantly greater than for older individuals; respectively 3.2cm ² Contrast 0.2cm ² (p=0.031). In addition, in the case of the optical fiber,<tumor growth rate (0.7 cm) in patients aged 10 ² Per year) is significantly greater than>Tumor growth rate (0.03 cm) in patients aged 10 ² Year, p=0.014). Similarly, in an observational study with 49 patients aged 3 to 25 years (median 8.3 years), dombi et al observed a faster increase in PN volume over time than body weight (p=0.026). Furthermore, patients with median ages less than 8.3 years have a greater tendency to increase in PN volume per year than older children; each year 21.1% vs. 8.4% volume change (p=0.001). This trend holds when the PN growth rate is expressed as a rate of increase relative to body size.

From the findings of Tucker and Dombi, nguyen et al performed a retrospective study on 71 patients with an evaluable PN with a median follow-up time of 2.2 years (ranging from 1.1 to 4.9 years). The growth rate of the individual tumors was inversely related to the age at the initial examination (Spearman ρ= -0.33, p < 0.001), but not to the tumor volume at the initial MRI examination. Furthermore, more than 20% of tumors grown annually are significantly more common in children than in adults (p < 0.001). In summary, findings from three independent retrospective reviews of PN volumes clearly indicate that the growth rate of PN in NF1 patients is inversely related to age, indicating the existence of discrete age-dependent tumor differences and unmet needs in the pediatric population.

These observations indicate that the youngest patient can receive the greatest clinical benefit from treatment. However, the youngest potential patient with urgent medical treatment needs may be refractory to treatment due to inability to swallow the entire capsule or tablet. Thus, there is a need for an age-appropriate pediatric formulation that allows for accurate dosing and enhanced compliance to optimize efficacy and safety in that population.

In addition, any patient in need of treatment but with dysphagia (difficulty swallowing/"dysphagia") would benefit from an orally administrable non-capsule or tablet formulation. Dysphagia may be caused by a variety of conditions affecting one or more components of the swallowing process. These conditions may include, but are not limited to: physical damage to the tongue, pharynx, larynx, esophagus or trachea caused by trauma, infection, proliferative diseases; treatment of such disorders; congenital anatomic defects such as cleft palate; hypoplasia in young age; senile body attenuation; dementia, memory loss or cognitive decline; or any disorder that weakens or damages muscles or nerves used in the swallowing process, such as Parkinson's disease, stroke, or neurological disease.

N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide ("Midamitinib" or "PD-0325901") is a small molecule drug designed to inhibit mitogen-activated protein kinase 1 ("MEK 1") and mitogen-activated protein kinase 2 ("MEK 2"). MEK1 and MEK2 are proteins that play a critical role in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Midamitinib is a highly potent and sex-specific non-ATP-competitive inhibitor of MEK1 and MEK 2. Due to its mechanism of action, midametinib significantly inhibits the phosphorylation of extracellular regulated MAP kinases ERK1 and ERK2, thereby compromising tumor cell growth in vitro and in vivo. In addition, there is evidence that inflammatory cytokine induced increases in MEK/ERK activity lead to inflammation, pain and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

Crystalline forms of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide have been previously described. WO2002/006213 describes crystalline forms I and II and is incorporated by reference. Form I is characterized by XRPD having peaks at one or more of 10.6, 13.7, 19.0, and 23.7 degrees 2Θ; form II is characterized by XRPD having peaks at 5.5 and/or 19.6 degrees 2θ. Form I is characterized by a melting point of about 117 ℃ to 118 ℃ and form II is characterized by a melting point of 89 ℃ to 90 ℃ as determined by DSC.

U.S. patent No. 7,060,856 ("the' 856 patent") describes a method of producing form IV, and is incorporated by reference. The '856 patent indicates that the material produced by this method is of greater than 90% form IV (' 856 patent, example 1). The' 856 patent also states that differential scanning calorimetry ("DSC") of the resulting material shows a small peak beginning to melt at 110℃and beginning at 117℃consistent with the material being a mixture of the two forms. Compositions containing more than one polymorphic form are generally undesirable because one polymorphic form may be converted to another polymorphic form. Interconversion of polymorphic forms can lead to differences in effective dosage or physical properties due to differences in solubility or bioavailability, thereby affecting pharmaceutical processability.

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 (e.g., pediatric patients or patients with dysphagia) who have difficulty swallowing complete capsules or tablets for use in treating tumors, cancers, or RAS diseases. In view of the apparent mixture of forms IV disclosed previously, dispersible formulations of form IV containing substantially pure N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are needed to limit polymorphic interconversions between various forms that may affect solubility and bioavailability.

Drawings

FIG. 1A is an X-ray powder diffraction pattern ("XRPD") corresponding to substantially pure crystalline form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

FIG. 1B is a thermogram and differential scanning calorimetry thermogram ("TGA") corresponding to a substantially pure crystalline form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

FIG. 2 is an XRPD of substantially pure form IV and an XRPD of known reference standard form IV corresponding to an initially prepared batch of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

FIG. 3A is an XRPD corresponding to substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide after 68 months of storage at 25℃and 65% relative humidity after production.

FIG. 3B is an XRPD corresponding to substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide after storage for 140 months at 25℃and 65% relative humidity after production.

Disclosure of Invention

The present disclosure relates to useful compositions for treating a disorder involving aberrant MEK1 or MEK2 activity, such as a tumor, cancer, or RAS disease, such as type 1 neurofibromatosis, in a subject in need thereof. In some aspects, the methods and compositions described herein can be used to treat patients who have difficulty swallowing whole capsules or tablets, for example pediatric patients or subjects with dysphagia, such as patients with esophageal cancer, parkinson's disease, amyotrophic lateral sclerosis, stroke, achalasia, or esophageal stricture. In some aspects, the composition comprises form I, form II, or form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

Pharmaceutical composition

In some aspects, the disclosure relates to pharmaceutical compositions comprising an amount of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide of formula (I)

Wherein the pharmaceutical composition is dispersible in a potable liquid (e.g., water) or is orodispersible in saliva of the subject.

In some aspects, 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 aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is selected from the group consisting of: (a) A crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide characterized by an XRPD pattern having peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 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 peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2Θ; 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 peaks at 5.5±0.2 and 19.6±0.2 degrees 2Θ.

In some aspects, 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. In some aspects, 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.

In some aspects, 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 figure 1A.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by a DSC curve that does not include an onset of endotherm at about 117 ℃.

In some aspects, 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 figure 1B; and/or (B) a DSC profile substantially as shown in figure 1B.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is free of any amount of form I or form II detectable by XRPD and/or DSC.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is anhydrous.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is form IV. In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is substantially pure form IV.

In some aspects, substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for ≡14 years under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

In some aspects, the XRPD pattern is generated using:x' Pert Pro diffractometer, using Ni filtered Cu K alpha (45 kV/40 mA) radiation and step size of 0.03 DEG 2 theta, with +.>An instant multi-band detector, (a) the configuration on the incident beam side is as follows: variable divergence slit (10 mm irradiation length), 0.04 radian Soller slit (Soller slit), fixed anti-scatter slit (0.50 °) and 10mm beam mask, and (b) configuration on the diffracted beam side is as follows: variable anti-scatter slits (10 mm observation length) and 0.04 radian soxhlet slits; or->ADVANCE ^TM System using Cu K alpha (40 kV/40 mA) radiation and a step size of 0.03 DEG 2 theta with LYNXEYE ^TM The detector, (a) is configured as follows on the incident beam side: />The mirror, mirror exit slit (0.2 mm), 2.5 ° soxhlet slit, beam knife, and (b) the configuration on the diffracted beam side is as follows: an anti-scatter slit (8 mm) and a 2.5 ° soxhlet slit; wherein the sample is mounted flat on a zero background Si wafer. In some aspects, DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

In some aspects, 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 aspects, 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 a theta degree at 10.6±0.2, 13.7±0.2, 14.6±0.2, 17.3±0.2, 18.0±0.2, 18.2±0.2, 19.0±0.2, 19.3±0.2, 20.1±0.2, 21.0±0.2, 21.9±0.2, 22.4±0.2, 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.3±0.2, 32.9±0.2, 35.8±0.2, and 37±0.2.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by a DSC curve that begins to absorb heat at about 117 ℃.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is form I.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2 and 19.6±0.2 degrees 2θ. In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 10.7±0.2, 16.5±0.2, 19.6±0.2, 22.0±0.2, 22.5±0.2, 23.6±0.2, 24.1±0.2, 25.0±0.2, 26.2±0.2, 27.6±0.2, 29.1±0.2, 30.5±0.2, 31.7±0.2, 33.3±0.2, and 39.0±0.2 degrees 2θ.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by a DSC curve that begins to absorb heat at about 87 ℃.

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

In some aspects, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is dispersible. In some aspects, the pharmaceutical composition is orodispersible.

In some aspects, the pharmaceutical composition is a tablet, powder, granule, micro-tablet, or pellet (also referred to as a bead).

In some aspects, the pharmaceutical composition is a powder. In some aspects, the pharmaceutical composition is a dispersible powder. In some aspects, the capsule or sachet comprises a dispersible powder.

In some aspects, the pharmaceutical composition is in the form of a granulate. In some aspects, the particles are dispersible particles. In some aspects, the capsule or sachet comprises dispersible particles.

In some aspects, the pharmaceutical composition is in the form of a minitablet. In some aspects, the microtablets are dispersible microtablets. In some aspects, the capsule or sachet comprises a dispersible microtablet.

In some aspects, the pharmaceutical composition is in the form of pellets. In some aspects, the pellets are dispersible pellets. In some aspects, the capsule or sachet comprises dispersible pellets.

In some aspects, the pharmaceutical composition is a tablet. In some aspects, the tablet is a dispersible tablet. In some aspects, the tablet is an orodispersible tablet.

In some aspects, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1mg to about 20mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein the components of the pharmaceutical composition are as follows: (a) About 0.1wt/wt% to about 7wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 50wt/wt% to about 98wt/wt% of one or more diluents; (c) About 1wt/wt% to about 10wt/wt% of one or more disintegrants; (d) 0wt/wt% to about 5wt/wt% of one or more flavoring agents; (e) 0wt/wt% to about 5wt/wt% of one or more sweeteners; and (f) from 0wt/wt% to about 5wt/wt% of one or more lubricants.

In some aspects, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1mg to about 20mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein the components of the pharmaceutical composition are as follows: (a) About 0.2wt/wt% to about 1.5wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 75wt/wt% to about 98wt/wt% of one or more diluents; (c) About 3wt/wt% to about 8wt/wt% of one or more disintegrants; (d) 0wt/wt% to about 5wt/wt% of one or more flavoring agents; (e) 0wt/wt% to about 5wt/wt% of one or more sweeteners; and (f) from 0wt/wt% to about 5wt/wt% of one or more lubricants.

In some aspects, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1mg to about 20mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein the components of the pharmaceutical composition are as follows: (a) About 0.5wt/wt% to about 1.2wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85wt/wt% to about 95wt/wt% of one or more diluents; (c) About 3.5wt/wt% to about 6wt/wt% of one or more disintegrants; (d) 0wt/wt% to about 2.5wt/wt% of one or more flavoring agents; (e) 0wt/wt% to about 2wt/wt% of one or more sweeteners; and (f) from about 0.5wt/wt% to about 2wt/wt% of one or more lubricants.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 3mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 4mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, the at least one diluent is selected from the group consisting of: microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate and dibasic calcium phosphate. In some aspects, at least one diluent is microcrystalline cellulose.

In some aspects, the at least one disintegrant is selected from the group consisting of: croscarmellose sodium, sodium starch glycolate, crospovidone (crospovidone), microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid. In some aspects, the at least one disintegrant is croscarmellose sodium.

In some aspects, the at least one flavoring agent is selected from the group consisting of natural or synthetic flavoring agents, including, but not limited to, grape-flavored flavoring agents, bubble gum flavoring agents, caramel-flavored flavoring agents, orange-flavored flavoring agents, lemon-flavored flavoring agents, strawberry-flavored flavoring agents, raspberry-flavored flavoring agents, peppermint-flavored flavoring agents, grapefruit-flavored flavoring agents, pineapple-flavored flavoring agents, pear-flavored flavoring agents, peach-flavored flavoring agents, vanilla-flavored flavoring agents, banana-flavored flavoring agents, or cherry-flavored flavoring agents. In some aspects, the at least one flavoring agent is a grape-flavored flavoring agent.

In some aspects, the at least one sweetener is selected from the group consisting of: sucralose, acesulfame (acesulfame), saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame (aspartame). In some aspects, the at least one sweetener is sucralose.

In some aspects, the at least one lubricant 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, glyceryl dibehenate and talc. In some aspects, the at least one lubricant is magnesium stearate.

Therapeutic method

In some aspects, the present disclosure provides methods of treating a tumor, cancer, or RAS disease comprising administering to a subject in need of such treatment a pharmaceutical composition described herein (e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets).

In some aspects, the present disclosure provides for the use of a pharmaceutical composition described herein (e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets) for the manufacture of a medicament for the treatment of a tumor, cancer, or RAS disease.

In some aspects, the tumor is a neurofibromatosis. In some aspects, the tumor is a neurofibromatosis associated with type 1 neurofibromatosis. In some aspects, the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas. In some aspects, the tumor is a plexiform neurofibromatosis.

In some aspects, the subject is diagnosed with a RAS disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, kettkoch syndrome (Costello syndrome), rasagile syndrome (Legius syndrome), noonan syndrome (Noonan syndrome), and multiple lentigo type Noonan syndrome (Noonan syndrome with multiple lentigines).

In some aspects, the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gall bladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer. In some aspects, the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In some aspects, 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 B-cell lymphoma, small lymphocytic lymphoma, and waldenstrom macroglobulinemia (waldenstrom 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.

In some aspects, the subject carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK, MEK2, RASA1, MAP2K4, NF1, or NF 2.

In some aspects, the individual doses of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are administered in the form of one or more dispersible tablets, one or more dispersible powders, one or more dispersible granules, one or more dispersible microtablets, one or more dispersible pellets, or a combination thereof. For example, a 3mg dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be administered in the form of two dispersible tablets (one containing 2mg and the other containing 1 mg) or in the form of three dispersible tablets (each containing 1 mg). As another example, a 1.5mg dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be administered in the form of two dispersible dosage forms (containing 1mg of one dispersible tablet and a single unit of dispersible powder containing 0.5 mg), or in the form of three units of dispersible powder (each containing 0.5 mg).

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

In some aspects, 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) administering a total daily dose for 21 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days. In some aspects, 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) administering a total daily dose for 21 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days. In some aspects, 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 period comprising (i) a total daily dose administered for 5 days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days. In some aspects, 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 period comprising (i) a total daily dose administered for 5 consecutive days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

In some aspects, the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles.

In some aspects, 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 total daily dose administered for 28 days.

In some aspects, the subject experiences dysphagia. In some aspects, the subject experiences dysphagia caused by one or more of: neurological diseases, muscle weakness, developmental disability, stroke, injury, anatomical defects, cancer treatment, allergic reactions, dementia, memory loss or cognitive decline.

In some aspects, the subject is a pediatric subject.

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

In some aspects, 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 aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of from about 0.1mg to about 20mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 0.5mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 1mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 2mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 4mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 8mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 10mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 20mg once daily.

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 4 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

Method for manufacturing pharmaceutical composition

In some aspects, the present disclosure provides methods of manufacturing pharmaceutical compositions comprising forming the pharmaceutical compositions described herein.

Definition of the definition

To facilitate an understanding of the disclosure set forth herein, a number of terms are defined below.

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

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" and "an" are used interchangeably herein. In certain aspects, the term "a" or "an" means "singular. In other aspects, the term "a" or "an" includes "two or more" or "a plurality of".

Furthermore, "and/or" as used herein should be taken as specifically disclosing each of the two specified features or components, either with or without the other. Thus, the term "and/or" as used in the phrase herein, such as "a and/or B," is intended to include "a and B", "a or B", "a" (alone) and "B" (alone). Also, the term "and/or" as used in a phrase such as "A, B and/or C" is intended to cover 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).

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

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

The term "pediatric" refers to a human subject less than 21 years of age at the time of treatment. The term "pediatric" may be further divided into various sub-populations, including: neonates (from birth to 28 days); infants (29 days to less than two years old); children (two years to less than 12 years old); and teenagers (12 to 21 years old (up to but not including 22 years of birth)). See, for example, berhman R E, kliegman R, arvin AM, nelson W E.Nelson Textbook of Pediatrics, 15 th edition, philadelphia: W.B.Saunders Company,1996; rudolph A M et al, rudolph's Pediatrics, 21 st edition, new York: mcGraw-Hill,2002; and Avery M D, first L r.petiatric Medicine, 2 nd edition, baltimore: williams & Wilkins;1994. especially pediatric patients, such as newborns, infants and young children, may have difficulty swallowing whole capsules or tablets.

The term "dispersible" as used herein refers to a composition (e.g., a tablet, powder, granule, micro-tablet, or pellet) that disintegrates and/or dissolves with or without agitation or temperature correction when combined with water or another drinkable liquid (e.g., a non-aqueous beverage), or when placed in the mouth of a subject in combination with the subject's own saliva. In some aspects, the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after combination with water or another potable liquid. Such disintegration or dissolution need not be complete. For example, dispersible tablets may be almost completely dissolved, but may retain some undissolved particulate matter.

The term "orodispersible" refers to a composition that dissolves or disintegrates in the mouth of a subject (i.e., dissolves or disintegrates in the saliva of a subject) if administered orally without first dissolving or disintegrating in a separate container.

As used herein, the terms "treatment" and "treating" refer to both therapeutic treatment and prophylactic or defensive measures, wherein the aim is to prevent or slow down (alleviate) an undesired physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. Thus, a subject in need thereof includes those diagnosed or suspected of having a disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; the extent of the disorder, condition or disease is reduced; the condition, disorder or disease state is stable (i.e., not worsening); the onset of the condition, disorder or disease process is delayed or slowed; the condition, disorder or disease state is ameliorated or resolved (partially or fully), whether detectable or undetectable; at least one measurable physical parameter improvement, not necessarily discernible by the patient; or improvement or amelioration of the condition, disorder or disease. Treatment involves eliciting a clinically significant response without undue adverse side effects. Treatment also includes extending survival compared to the expected survival without treatment. The term "therapeutically effective amount" is intended to include an amount of a compound that, upon administration, is sufficient to prevent or to alleviate to some extent one or more symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or clinician.

In certain aspects, according to the methods described herein, a tumor of a subject is successfully "treated" if the patient exhibits one or more of the following: tumor size is reduced; one or more symptoms associated with a particular tumor are alleviated; tumor volume decreases; quality of life is improved; increased Progression Free Survival (PFS), disease Free Survival (DFS), total survival (OS), metastasis Free Survival (MFS), complete Response (CR), minimal Residual Disease (MRD), partial Response (PR), stable Disease (SD), progressive Disease (PD) decrease, disease Time To Progression (TTP) increase, or any combination thereof. In some aspects, national or internationally recognized treatment outcome criteria for a given tumor may be used to determine whether an effective amount of midametinib meets any of these particular endpoints (e.g., CR, PFS, PR).

In certain aspects, according to the methods described herein, a subject's cancer (e.g., lung cancer or ovarian cancer) is successfully "treated" if the patient shows one or more of the following: a reduced or complete absence of cancer cells; one or more symptom relief associated with a particular cancer; morbidity and mortality are reduced; quality of life is improved; increased Progression Free Survival (PFS), disease Free Survival (DFS), total survival (OS), metastasis Free Survival (MFS), complete Response (CR), minimal Residual Disease (MRD), partial Response (PR), stable Disease (SD), progressive Disease (PD) decrease, disease Time To Progression (TTP) increase, or any combination thereof. In some aspects, national or internationally recognized therapeutic outcome criteria for a given cancer may be used to determine whether an effective amount of midametinib meets any of these particular endpoints (e.g., CR, PFS, PR).

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, the components are "pharmaceutically acceptable" in the following sense: is compatible with the other ingredients of the pharmaceutical formulation and is suitable for contact with tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio. See Remington, the Science and Practice of Pharmacy, 21 st edition, lippincott Williams & Wilkins, philiadelphia, PA,2005; handbook of Pharmaceutical Excipients, 5 th edition, rowe et al, the Pharmaceutical Press and the American Pharmaceutical Association:2005; and Handbook of Pharmaceutical Additives, 3 rd edition, ash and Ash editions, gower Publishing Company:2007; pharmaceutical Preformulation and Formulation, gibson, CRC Press LLC: boca Raton, FL,2004 (incorporated herein by reference). Excipients may include (for example): anti-adherent agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), softeners, emulsifiers, fillers (diluents), film formers or coatings, 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): dibutyl hydroxy toluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, calcium sulfate, croscarmellose, crospovidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl p-hydroxybenzoate, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone (povidone), pregelatinized starch, propyl p-hydroxybenzoate, retinyl palmitate, shellac, silica, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin a, vitamin E, vitamin C and xylitol.

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

The term "about" or "approximately" means within an acceptable error range for the particular value being measured by one of ordinary skill in the art, which depends in part on the manner in which the value is measured or determined. In some aspects, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some aspects, the term "about" or "approximately" means that an amount, level, value, number, frequency, percentage, dimension, size, quantity, weight, or length varies by up to 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, quantity, weight, or length.

As used herein, the term "administering" refers to administering a composition (e.g., a compound or formulation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be performed by any suitable route, such as the routes described herein.

As used herein, the term "crystalline" refers to a solid state form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound or salt, hydrate or solvate thereof result from different packing of solid state molecules, which results in different crystal symmetry and/or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline forms, optical and electrical properties, stability and solubility. See, for example, remington's Pharmaceutical Sciences, 18 th edition, mack Publishing, easton PA,173 (1990); the United States Pharmacopeia, 23 rd edition, 1843-1844 (1995) (incorporated herein by reference).

The crystalline form is typically characterized by X-ray powder diffraction (XRPD). XRPD reflectance patterns (peaks, usually expressed in degrees 2- θ) are generally considered fingerprints 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 procedures, and the particular instrument employed. In some cases, new peaks may be observed or existing peaks may disappear, depending on instrument type or setup. In some cases, any particular peak in the XRPD pattern may exhibit a single peak, a double peak, a triple peak, a quadruple peak, or multiple peaks, depending on the instrument type or setting, instrument sensitivity, measurement conditions, and/or purity of the crystalline form. In some cases, any particular peak in the XRPD may appear in a symmetrical shape or an asymmetrical shape, e.g., with a shoulder. In addition, instrument variations and other factors may affect the 2-theta value. Those skilled in the art who understand these variations are able to distinguish or determine defined characteristics or features of a particular crystalline form using XRPD, as well as using other known physicochemical techniques.

The term "anhydrate" when applied to a compound refers to a crystalline form of the compound that does not contain structural water within the crystal lattice.

As used herein, the term "substantially pure" with respect to form IV means that the composition comprising form IV does not contain a detectable amount of another polymorphic form (e.g., form I or form II), as determined by the absence of a detectable difference observed in the XRPD and/or DSC pattern between single form IV crystals and crystalline compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. However, the "substantially pure" form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may contain impurities such as, but not limited to, synthetic reactants or byproducts generated during chemical synthesis.

As used herein, the term "aberration" when applied to a gene refers to a mutation, chromosome loss or fusion, epigenetic chemical modification, or other event that alters a sequence associated with a gene, expression level, or processing an mRNA sequence relative to a sequence associated with a wild-type gene, expression level, or processing an mRNA sequence.

It should be understood that wherever aspects are described herein using the word "comprising," other similar aspects described in terms of "consisting of" and/or "consisting essentially of" are also provided.

The details of one or more aspects are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.

Detailed Description

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 that are difficult to swallow (e.g., pediatric patients or patients with dysphagia).

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 exploitation. These properties include (but are not limited to): (1) filling 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 under ambient conditions, especially for moisture and stability under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handleability, flow and blending; and (6) filtration properties. These properties can affect, for example, handling and storage of the compounds and pharmaceutical compositions comprising the compounds. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered as form I, form II, or form IV (e.g., substantially pure form IV) of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide in combination with a pharmaceutically acceptable carrier or excipient.

Pharmaceutical composition

In some aspects, the present disclosure provides pharmaceutical compositions comprising an amount of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide of formula (I)

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In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide included in the pharmaceutical compositions described herein is crystalline. In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is selected from the group consisting of: (a) A crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide characterized by an XRPD pattern having peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 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 peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2Θ; 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 peaks at 5.5±0.2 and 19.6±0.2 degrees 2Θ.

In some aspects, 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 XRPD patterns having peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ. In some aspects, 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.

In some aspects, 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.

In some aspects, 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 figure 1B; and/or (B) a DSC profile substantially as shown in figure 1B.

In some aspects, 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 include an onset of endotherm at about 117 ℃.

In some aspects, 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 free of any amount of form I or form II detectable by XRPD and/or DSC.

In some aspects, 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.

In some aspects, 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 aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is substantially pure form IV.

In some aspects, the crystalline form IV composition included in the pharmaceutical compositions described herein is stable, as evidenced by a substantially constant XRPD pattern and/or DSC profile over time. In some aspects, the crystalline form IV composition exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 140 months, 12 years, 13 years, 14 years, or 15 years under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after 5 years of storage under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, crystalline form IV compositions of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibit XRPD patterns and/or DSC curves that are substantially unchanged after storage for ≡14 years under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

In some aspects, the following is used to generate N- ((R) -2, 3-bis included in the pharmaceutical compositions described hereinXRPD pattern of form IV of hydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide:x' Pert Pro diffractometer, using Ni filtered Cu K alpha (45 kV/40 mA) radiation and step size of 0.03 DEG 2 theta, with +.>An instant multi-band detector, (a) the configuration on the incident beam side is as follows: a variable divergence slit (10 mm irradiation length), a 0.04 radian soiler slit, a fixed anti-scatter slit (0.50 °) and a 10mm beam mask, and (b) the configuration on the diffracted beam side is as follows: variable anti-scatter slits (10 mm observation length) and 0.04 radian soxhlet slits; or (b)ADVANCE ^TM System using Cu K alpha (40 kV/40 mA) radiation and a step size of 0.03 DEG 2 theta with LYNXEYE ^TM The detector, (a) is configured as follows on the incident beam side: />The mirror, mirror exit slit (0.2 mm), 2.5 ° soxhlet slit, beam knife, and (b) the configuration on the diffracted beam side is as follows: an anti-scatter slit (8 mm) and a 2.5 ° soxhlet slit; wherein the sample is mounted flat on a zero background Si wafer.

In some aspects, DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide included in the pharmaceutical compositions described herein is characterized by an XRPD pattern having peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2θ. In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having one or more peaks at 10.6±0.2, 13.7±0.2, 14.6±0.2, 17.3±0.2, 18.0±0.2, 18.2±0.2, 19.0±0.2, 19.3±0.2, 20.1±0.2, 21.0±0.2, 21.9±0.2, 22.4±0.2, 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.1±0.2, 32.3±0.2, 32.9±0.2, 35.0.2, 35±0.7±0.2, and θ 2.2.

In some aspects, 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 begins to absorb heat at about 117 ℃.

In some aspects, 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.

In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide included in the pharmaceutical compositions described herein is characterized by an XRPD pattern having peaks at 5.5±0.2 and/or 19.6±0.2 degrees 2θ. In some aspects, the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 10.7±0.2, 16.5±0.2, 19.6±0.2, 22.0±0.2, 22.5±0.2, 23.6±0.2, 24.1±0.2, 25.0±0.2, 26.2±0.2, 27.6±0.2, 29.1±0.2, 30.5±0.2, 31.7±0.2, 33.3±0.2, and 39.0±0.2 degrees 2θ.

In some aspects, 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 begins to absorb heat at about 87 ℃.

In some aspects, 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.

In some aspects, the present disclosure provides pharmaceutical compositions (e.g., dispersible tablets, dispersible powders, 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 aspects, the pharmaceutical composition (e.g., dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet) further comprises one or more pharmaceutically acceptable carriers.

In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is orodispersible.

In some aspects, the potable liquid is water, milk, or juice (e.g., orange or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is fruit juice.

In some aspects, the pharmaceutical composition is a tablet, powder, granule, minitablet, or pellet.

In some aspects, the pharmaceutical composition is a powder. In some aspects, the powder is a dispersible powder. In some aspects, the capsule or sachet comprises a dispersible powder.

In some aspects, the pharmaceutical composition is a tablet. In some aspects, the tablet is a dispersible tablet. In some aspects, the dispersible tablet is an orodispersible tablet.

In some aspects, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1mg to about 20mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein the components of the pharmaceutical composition are as follows: (a) About 0.1wt/wt% to about 7wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 50wt/wt% to about 98wt/wt% of one or more diluents; (c) About 1wt/wt% to about 10wt/wt% of one or more disintegrants; (d) 0wt/wt% to about 5wt/wt% of one or more flavoring agents; (e) 0wt/wt% to about 5wt/wt% of one or more sweeteners; and (f) from about 0wt/wt% to about 5wt/wt% of one or more lubricants.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, or about 10mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 3mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 4mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 6mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 7mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 8mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 9mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 10mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 11mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 12mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 13mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 14mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 15mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 16mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 17mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 18mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 19mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 20mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1wt/wt% to about 7wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1wt/wt% to about 5wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise about 0.1wt/wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%; about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4wt/wt%, about 4.1wt/wt%, about 4.2wt/wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5wt/wt%, about 4.6wt/wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9 wt%, about 5wt/wt%, about 5.1 wt%, about 5.2wt/wt%, about 5.3 wt%, about 5.4 wt%, about 5.5.5 wt%, about 5.6 wt%, about 5.7 wt%, about 5.8 wt% About 5.9wt/wt%, about 6wt/wt%, about 6.1wt/wt%, about 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%, or about 7wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.5wt/wt% N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.8wt/wt% N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises one or more diluents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 50wt/wt% to about 98wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 75wt/wt% to about 98wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises from about 85wt/wt% to about 95wt/wt% of one or more diluents. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise about 50wt/wt%, about 51wt/wt%, about 52wt/wt%, about 53wt/wt%, about 54wt/wt%, about 55wt/wt%, about 56wt/wt%, about 57wt/wt%, about 58wt/wt%, about 59wt/wt%, about 60wt/wt%, about 61wt/wt%, about 62wt/wt%, about 63wt/wt%, about 64wt/wt%, about 65wt/wt%, about 66wt/wt%, about 67wt/wt%, about 68wt/wt%, about 69wt/wt%, about 70wt/wt%, about 71wt/wt% >, about 72wt/wt%, about 73wt/wt%, about 74wt/wt%, about 75wt/wt%, about 76wt/wt%, about 77wt/wt%, about 78wt/wt%, about 79wt/wt%, about 80wt/wt%, about 81wt/wt%, about 82wt/wt%, about 83wt/wt%, about 84wt/wt%, about 85wt/wt%, about 86wt/wt%, about 87wt/wt%, about 88wt/wt%, about 89wt/wt%, about 90wt/wt%, about 91wt/wt%, about 92wt/wt%, about 93wt/wt%, about 94wt/wt%, about 95wt/wt%, about 96wt/wt%, about 97wt/wt% or about 98wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 90wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 91wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 92wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 93wt/wt% of one or more diluents.

In some aspects, the at least one diluent 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 aspects, at least one diluent is microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 50wt/wt% to about 98wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 75wt/wt% to about 98wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 85wt/wt% to about 95wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 50wt/wt%, about 51wt/wt%, about 52wt/wt%, about 53wt/wt%, about 54wt/wt%, about 55wt/wt%, about 56wt/wt%, about 57wt/wt%, about 58wt/wt%, about 59wt/wt%, about 60wt/wt%, about 61wt/wt%, about 62wt/wt%, about 63wt/wt%, about 64wt/wt%, about 65wt/wt%, about 66wt/wt%, about 67wt/wt%, about 68 wt%, about 69 wt%, about 70wt/wt%, about 71wt/wt%, about 72wt/wt%, about 73wt/wt%, about 74wt/wt%, about 75 wt%, about 76wt/wt%, about 77wt/wt%, about 78wt/wt%, about 79wt/wt%, about 80wt/wt%, about 81 wt%, about 82 wt%, about 83wt/wt%, about 84wt/wt%, about 85 wt%, about 87 wt%, about 86 wt%, about 88 wt%, about 92 wt%, about 94 wt%, or about 95 wt% of the microcrystalline. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 90wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 91wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 92wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 93wt/wt% microcrystalline cellulose.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 1.0wt/wt% to about 10wt/wt% of one or more disintegrants. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 3.5wt/wt% to about 6wt/wt% of one or more disintegrants. In some aspects of the present invention, the pharmaceutical composition comprises about 1.0wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, about 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2.0wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1 wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 4.9 wt%, about 0 wt%, about 4.8 wt%, and about 0 wt%; about 4.1wt/wt%, about 4.2wt/wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5wt/wt%, about 4.6wt/wt%, about 4.7wt/wt%, about 4.8wt/wt%, about 4.9wt/wt%, about 5.0wt/wt%, about 5.1wt/wt%, about 5.2wt/wt%, about 5.3wt/wt%, about 5.4wt/wt%, about 5.5wt/wt%, about 5.6wt/wt%, about 5.7wt/wt%, about 5.8wt/wt%, about 5.9wt/wt%, about 6.0 wt%, about 6.1wt/wt%, about 6.2wt/wt%, about 6.3wt/wt%, about 6.4 wt%, about 6.5wt/wt%, about 6.6.7 wt%, about 6.8 wt%, about 6.9 wt%, about 7 wt%, about 7.7 wt%, about 1 wt%, about 1.7 wt% About 7.3wt/wt%, about 7.4wt/wt%, about 7.5wt/wt%, about 7.6wt/wt%, about 7.7wt/wt%, about 7.8wt/wt%, about 7.9wt/wt%, about 8.0wt/wt%, about 8.1wt/wt%, about 8.2wt/wt%, about 8.3wt/wt%, about 8.4 wt%, about 8.5wt/wt%, about 8.6wt/wt%, about 8.7wt/wt%, about 8.8wt/wt%, about 8.9wt/wt%, about 9.0wt/wt%, about 9.1wt/wt%, about 9.2 wt%, about 9.3wt/wt%, about 9.4wt/wt%, about 9.5 wt%, about 9.6 wt%, about 9.7wt/wt%, about 9.8 wt%, about 9.9wt/wt%, or about 10.0 wt% of one or more disintegrants. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 5wt/wt% of one or more disintegrants.

In some aspects, the at least one disintegrant is selected from the group consisting of: croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid. In some aspects, the at least one disintegrant is croscarmellose sodium. In some aspects, the disintegrant is croscarmellose sodium. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 1.0wt/wt% to about 10wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 3.5wt/wt% to about 6wt/wt% croscarmellose sodium. In some aspects of the present invention, the pharmaceutical composition comprises about 1.0wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, about 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2.0wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4wt/wt%, 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4.0 wt%, about 4 wt%, and about 4 wt%; about 4.1wt/wt%, about 4.2wt/wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5wt/wt%, about 4.6wt/wt%, about 4.7wt/wt%, about 4.8wt/wt%, about 4.9wt/wt%, about 5wt/wt%, about 5.1wt/wt%, about 5.2wt/wt%, about 5.3wt/wt%, about 5.4wt/wt%, about 5.5wt/wt%, about 5.6wt/wt%, about 5.7wt/wt%, about 5.8wt/wt%, about 5.9wt/wt%, about 6.0wt/wt%, about 6.1wt/wt%, about 6.2wt/wt%, about 6.3wt/wt%, about 6.4wt/wt%, about 6.5wt/wt%, about 6.6.7 wt/wt%, about 6.8 wt%, about 6.9 wt%, about 7.7 wt%, about 1 wt%, about 2.7 wt%, about 1 wt% About 7.3wt/wt%, about 7.4wt/wt%, about 7.5wt/wt%, about 7.6wt/wt%, about 7.7wt/wt%, about 7.8wt/wt%, about 7.9wt/wt%, about 8.0wt/wt%, about 8.1wt/wt%, about 8.2wt/wt%, about 8.3wt/wt%, about 8.4 wt%, about 8.5wt/wt%, about 8.6wt/wt%, about 8.7wt/wt%, about 8.8wt/wt%, about 8.9wt/wt%, about 9.0wt/wt%, about 9.1wt/wt%, about 9.2 wt%, about 9.3wt/wt%, about 9.4wt/wt%, about 9.5 wt%, about 9.6 wt%, about 9.7wt/wt%, about 9.8 wt%, about 9.9wt/wt%, or about 10.0 wt% croscarmellose sodium. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 5wt/wt% croscarmellose sodium.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 5wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 2.5wt/wt% of one or more flavoring agents. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise 0wt/wt%, about 0.1wt/wt%, about 0.2wt/wt%, about 0.3wt/wt%, about 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.8 wt%, about 0.9wt/wt%, about 1wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, or about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4.0wt/wt%, about 4.1wt/wt%, about 4.2 wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5 wt%, about 4.6 wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9 wt% or about 5.0 wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 2wt/wt% of one or more flavoring agents.

In some aspects, the at least one flavoring agent is selected from the group consisting of natural or synthetic flavoring agents, including, but not limited to, grape-flavored flavoring agents, bubble gum flavoring agents, caramel-flavored flavoring agents, orange-flavored flavoring agents, lemon-flavored flavoring agents, strawberry-flavored flavoring agents, raspberry-flavored flavoring agents, peppermint-flavored flavoring agents, grapefruit-flavored flavoring agents, pineapple-flavored flavoring agents, pear-flavored flavoring agents, peach-flavored flavoring agents, vanilla-flavored flavoring agents, banana-flavored flavoring agents, or cherry-flavored flavoring agents. In some aspects, the at least one flavoring agent is a grape-flavored flavoring agent. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 5.0wt/wt% grape flavor. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 2.5wt/wt% grape flavor. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise 0wt/wt%, about 0.1wt/wt%, about 0.2wt/wt%, about 0.3wt/wt%, about 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.8 wt%, about 0.9wt/wt%, about 1wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, or about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4.0wt/wt%, about 4.1wt/wt%, about 4.2 wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5 wt%, about 4.6 wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9 wt% or about 5.0 wt% of the grape flavoring agent. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 2wt/wt% grape flavor.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 5wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 2wt/wt% of one or more sweeteners. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise 0wt/wt%, about 0.1wt/wt%, about 0.2wt/wt%, about 0.3wt/wt%, about 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.8 wt%, about 0.9wt/wt%, about 1wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, or about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4.0wt/wt%, about 4.1wt/wt%, about 4.2 wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5 wt%, about 4.6 wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9 wt% or about 5.0 wt% of one or more sweeteners. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1wt/wt% of one or more sweeteners.

In some aspects, the at least one sweetener is selected from the group consisting of: sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects, the at least one sweetener is sucralose. In some aspects, the sweetener is sucralose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 5wt/wt% sucralose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 2wt/wt% sucralose. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise 0wt/wt%, about 0.1wt/wt%, about 0.2wt/wt%, about 0.3wt/wt%, about 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.8 wt%, about 0.9wt/wt%, about 1wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, or about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4.0wt/wt%, about 4.1wt/wt%, about 4.2 wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5 wt%, about 4.6 wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9wt/wt%, or about 5 wt% sucralose. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1wt/wt% sucralose.

In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 5wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1wt/wt% to about 5wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.5wt/wt% to about 2wt/wt% of one or more lubricants. In some aspects of the present invention, the pharmaceutical composition comprises 0wt/wt%, about 0.1wt/wt%, about 0.2wt/wt%, about 0.3wt/wt%, about 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.8wt/wt%, about 0.9wt/wt%, about 1wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, about 1.6wt/wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9 wt%, about 2wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4.0wt/wt%, about 4.1wt/wt%, about 4.2wt/wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5 wt%, about 4.6wt/wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9wt/wt%, or about 5wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1wt/wt% of one or more lubricants.

In some aspects, the at least one lubricant is selected from the group consisting of: magnesium stearate, sodium stearyl fumarate, glyceryl behenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide and talc. In some aspects, the at least one lubricant is magnesium stearate. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from 0wt/wt% to about 5wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.1wt/wt% to about 2wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises from about 0.5wt/wt% to about 2wt/wt% magnesium stearate. In some aspects of the present invention, pharmaceutical compositions as dispersible tablets, dispersible powders, dispersible granules, dispersible microtablets or dispersible pellets comprise 0wt/wt%, about 0.1wt/wt%, about 0.2wt/wt%, about 0.3wt/wt%, about 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.8 wt%, about 0.9wt/wt%, about 1wt/wt%, about 1.1wt/wt%, about 1.2wt/wt%, about 1.3wt/wt%, about 1.4wt/wt%, about 1.5wt/wt%, about 1.6 wt%, about 1.7wt/wt%, about 1.8wt/wt%, about 1.9wt/wt%, about 2wt/wt%, about 2.1wt/wt%, about 2.2wt/wt%, about 1.5 wt%, or about 2.3wt/wt%, about 2.4wt/wt%, about 2.5wt/wt%, about 2.6wt/wt%, about 2.7wt/wt%, about 2.8wt/wt%, about 2.9wt/wt%, about 3.0wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, about 3.5wt/wt%, about 3.6wt/wt%, about 3.7wt/wt%, about 3.8wt/wt%, about 3.9wt/wt%, about 4.0wt/wt%, about 4.1wt/wt%, about 4.2 wt%, about 4.3wt/wt%, about 4.4wt/wt%, about 4.5 wt%, about 4.6 wt%, about 4.7wt/wt%, about 4.8 wt%, about 4.9 wt% or about 5 wt% magnesium stearate. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises 0wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition as a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 1wt/wt% magnesium stearate.

Therapeutic methods and uses

In some aspects, the present disclosure provides methods of treating a tumor, cancer, or RAS disease comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.

In some aspects, the subject is diagnosed with a RAS disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, kettkov syndrome, rasagile syndrome, noonan syndrome and multiple lentigo noonan syndrome.

In some aspects, the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gall bladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer. In some aspects, the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In some aspects, 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 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.

In some aspects, the individual doses of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are administered in the form of one or more tablets, one or more dispersible powders, one or more dispersible granules, one or more microtablets, one or more pellets, or a combination thereof. For example, a 3mg dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be administered in the form of two dispersible tablets (one containing 2mg and the other containing 1 mg) or in the form of three dispersible tablets (each containing 1 mg).

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 0.1mg to about 20mg per dose of the pharmaceutical composition described herein. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, or about 20mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 0.5mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 1mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 2mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 3mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 4mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 5mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 10mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 20mg per dose.

In some aspects, a 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 per day. In some aspects, 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 aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, or 10 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

In some aspects, the subject experiences dysphagia. In some aspects, the subject experiences dysphagia caused by one or more of: neurological diseases, muscle weakness, developmental disability, stroke, injury, anatomical defects, cancer treatment, allergic reactions, dementia, memory loss or cognitive decline. In some aspects, the subject is diagnosed with a pan-autism disorder. In some aspects, the subject is diagnosed with a craniofacial disorder. In some aspects, the subject is diagnosed with myasthenia gravis. In some aspects, the subject is diagnosed with tardive dyskinesia.

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

In some aspects, the subject is an elderly subject. In some aspects, 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 aspects, the subject is over 50 years old. In some aspects, the subject is over 60 years old. In some aspects, the subject is over 70 years old. In some aspects, the subject is over 80 years old. In some aspects, the subject is over 90 years old. In some aspects, the subject is over 100 years old.

In some aspects, if N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is to be administered more than once in a day, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be divided such that the patient receives a different dose at each administration. For example, if the total daily dose of (R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is 2mg, the patient may receive 0.5mg (e.g., as a 0.5mg dispersible tablet) in the morning and 1.5mg (e.g., as a 0.5mg dispersible tablet and a 1mg dispersible tablet) in the evening, administered twice daily.

In some aspects, 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 aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of about 0.1mg to about 10mg twice daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, or about 10mg per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 0.25mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 0.5mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 1mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 2mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 4mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 5mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 10mg.

In some aspects, 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 aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of from about 0.1mg to about 20mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, or about 20mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 0.5mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 1mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 2mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 4mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 8mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 10mg once daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 20mg once daily.

In some aspects, 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 of no more than 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, or 20 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 4 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

In some aspects, the present disclosure provides the use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a tumor, cancer, or RAS disease.

Examples

Example 1: seed production of form IV

Step 1: preparation of PD-0337792 "side chain

14.4kg of alcohol (99.4% chemical purity, 99.6% enantiomeric excess) were converted to 97.5kg of a 9.7% w/w PD-0337792 (IPGA) solution in toluene (about 60% overall yield). Triflate activation was performed in a 200L reactor by maintaining the temperature below-20 ℃ during the addition of the triflic anhydride. The resulting activated alcohol was then transferred to a 400L reactor containing solid N-hydroxyphthalimide (NHP) and the reaction was allowed to proceed to completion at ambient temperature. The final base deprotection was carried out by adding ammonia (about 28% solution, 5 eq, 34 kg). After the reaction was completed, water was removed from toluene by distillation, and the resulting solid by-product was filtered to produce a product solution.

Step 2: preparation of PD-0315209

The process yielded 21.4kg (99.4% w/w analysis) which was 80% of theory from the starting materials 2,3, 4-trifluorobenzoic acid (12 kg,1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg,1.02 eq.) with lithium amide base (5 kg,3.2 eq.). The reaction was initiated by adding 5% TFBA and FIA total solution to the lithium amide slurry at 50 ℃. This reaction exhibited a minimum onset of about 10 minutes, which can be observed by color change and slight exotherm. The remaining TFBA/FIA solution in THF was slowly added over one hour via a pressure pot while maintaining the reaction temperature within 45-55 ℃. No significant pressure rise (due to ammonia gas release) was observed during the whole operation.

Step 3: preparation of PD-0325901

CDI charges are modified to reduce potential gas generation. Two aliquots of CDI were added to the solid FIPFA (via an injection loader) before and after solvent addition. The time between two solid CDI additions (4.6 kg each) should not exceed 30 minutes. The two intermediate filter cakes were then dissolved with ethanol. The excess ethanol was distilled and replaced with toluene to about 5% v/v ethanol prior to recrystallisation of PD-0325901. Laboratory studies have shown that recrystallization from toluene and acetonitrile and ethanol from toluene does not reduce the impurities that are necessary for polymorph conversion. It is known that the presence of dimer impurity (PF-00191189) at levels greater than 0.2% results in the formation of undesirable polymorphs.

Coarse crystallization from the final reaction mixture reduced the dimer impurity PF-00191189 to about 1.9% and subsequent recrystallization further reduced it to about 0.4%. As a result, an undesirable polymorph is produced. DSC patterns indicate two different melting points, about 80 ℃ (low melting point form II) and about 117 ℃ (form I). Further, during the treatment, the solid crystallized at a significantly lower temperature than expected (actually about 10 ℃, about 40 ℃ expected). The unsuccessful recrystallization is suspected to be due to a change in solvent composition resulting from incomplete drying of the crude. After about 36 hours, when the crude product was about 28kg (theoretical 26 kg), the drying of the crude wet cake before ethanol dissolution was stopped.

Polymorph transition

About 7.4kg of PD-0325901 (mixed polymorph) from final EtOH/water crystals and precipitated material from early EtOH/toluene filtrate were subjected to polymorph conversion. Both batches were dried separately in filters to constant weight and each batch was dissolved in EtOH. The combined EtOH solutions were analyzed by HPLC and gave 16.4kg of estimated PD-0325901. After removal of EtOH via vacuum distillation and adjustment of the solvent composition to about 5% EtOH in toluene at 65 ℃ (i.e. EtOH was added drop wise at 65 ℃ until the solid was completely dissolved), recrystallization was started.

A slow 4 hour cooling ramp to 5 ℃ was performed followed by stirring for 12 hours to ensure satisfactory results. The resulting slurry was filtered and dried again in the filter to a constant weight (about 3 days). The purified solid showed 99.8% pure PD-0325901, free of detected levels of dimeric impurity PF-00191189.

The dried solid (15.4 kg) was redissolved in just 4 volumes of EtOH (62L), transferred from the filter to the reactor and precipitated by slow (about 3 h) addition of water (308L) at 30-35 ℃, cooled to 20 ℃ and stirred for 12h. DSC analysis of the slurry samples taken at 2h showed that the solid was entirely form IV (the desired polymorph).

21.4kg PD-0315209, 9.7kg CDI (1.05 eq.) were used, 91kg 9.7% PD-0337792 in toluene (1.1 eq.) and gave 12.74kg PD-0325901 (analysis 99.4%,100% form IV, yield about 48%).

Example 2: analysis/impurity and identification of PD-0325901

PD-0325901 is separated from process impurities and degradants by reverse phase liquid chromatography (275 nm UV detection). PD-0325901 was identified by obtaining infrared or proton NMR spectra in addition to HPLC residence time. For purity assessment, process impurities and degradants were identified by characteristic relative residence times and quantified by area normalization.

Chromatographic conditions: agilent Zorbax SB C18,5 μm, 4.6x250 mm (or equivalent); the flow rate is 1.0mL/min; the column temperature was 30 ℃; the detector wavelength was 275nm; the diluent is 50/50 acetonitrile/water; mobile phase a was 0.1% aqueous trifluoroacetic acid (TFA); mobile phase B is methanol; and gradient conditions below. Analysis was determined against a reference standard and reported on an anhydrous, solvent-free basis. Quantification of specified and unspecified impurities is reported as area percent. The total impurity is the sum of all impurities present above the reported threshold (0.05%).

Time (minutes)	0	15	40	45	46
						Mobile phase B%	70	70	100	100	70

Example 3: improved process for preparing form IV

As described in example 1, the synthetic process that produces midametinib in form IV produces form IV containing dimeric impurity PF-00191189 and requires further steps to convert the product to substantially pure form IV free of the undesired polymorphs form I and form II. Therefore, there is a need to develop a process that yields substantially pure form IV without additional processing steps.

Midamitinib manufacturing process

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) were used, this route being a convergent four-step synthesis with six chemical steps in total. The final step (step 4) provides a substantially pure form IV of midametinib.

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; 20.0kg,1.0 eq). The reactor was charged with triethylamine (18.8 kg,1.22 eq). The reactor contents were stirred and cooled to-10±10 ℃. Trifluoromethanesulfonic anhydride (43.5 kg,1.02 eq.) was added to a clean 50-L round bottom flask under nitrogen followed by cooling to a temperature of less than or equal to-10 ℃. The cooled trifluoromethanesulfonic anhydride was slowly transferred to a 100 gallon reactor while maintaining the internal temperature at-10±10 ℃. The reaction mixture was stirred at-10.+ -. 10 ℃ for 30 minutes. Reaction monitoring by TLC indicated completion of conversion. The reactor was charged with anhydrous toluene (99.8 kg,5.75 volumes) while maintaining the internal temperature at-10.+ -. 10 ℃ and then with N-hydroxyphthalimide (26.4 kg,1.07 eq). The contents were warmed to 20±5 ℃, followed by stirring at this temperature for at least 5 hours until no triflate intermediate was detected by TLC. The reaction mixture was divided into two equal parts. Each toluene solution was quenched with USP purified water (66 kg,6.7 volumes). The toluene solution was then washed twice with USP purified water (66 kg,6.7 volumes).

The toluene solution was recombined into a 100 gallon reactor. The organic solution was treated with 28% ammonium hydroxide solution (41.5 kg,7.8 eq). The contents were heated to 35±5 ℃, followed by stirring for not less than ("NLT") 12 hours. After the reaction was completed, 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 stirring volume. The concentrated solution was filtered to remove by-product solids. The filter cake was washed with toluene and the filtrates were combined. Analysis of the toluene solution indicated the presence of 8.6kg (36.7% yield) of PD-0337792 (IPGA).

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

Step 3 (preparation of crude PD-0325901): the clean, dry 100 gallon reactor was purged with nitrogen, followed by charging with PD-0315209 (18.0 kg,1 eq.) and THF (113.0 kg,7 volumes). The mixture was cooled to 5±5 ℃. N, N-diisopropylethylamine (15.1 kg,2.55 eq.) was charged and the temperature NMT was maintained at 25 ℃. The mixture was cooled to 5±5 ℃ and then stirred for 10 minutes. The reactor was charged with a solution of PD-0337792 in toluene (121.7 kg,1.3 eq. Total) at 5.+ -. 5 ℃ before 50% T3P (42.0 kg,1.45 eq.) in ethyl acetate. The reaction mixture was stirred NLT for 3 hours at 10.+ -. 5 ℃. N, N-diisopropylethylamine (1.9 kg,0.3 eq.) and 50% T3P in ethyl acetate (4.1 kg,0.15 eq.) were again charged to promote coupling completion. The reaction was quenched back into 5% sodium hydroxide solution (50 kg) followed by washing with 5% brine (55.4 kg). The organic solution was concentrated and then subjected to solvent exchange with toluene. Acetonitrile (43.0 kg,2.4 volumes) was added to the reactor followed by 2M hydrochloric acid (117.6 kg,5.1 equivalents). The mixture was stirred at 25.+ -. 5 ℃ 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 is concentrated and then solvent exchanged with toluene to the appropriate volume. The mixture was then heated to 75±5 ℃ for 30 minutes, followed by slow cooling to 20 ℃. The solid was filtered and then washed with toluene (31.1 kg,1.7 volumes).

The crude solids were charged back to the 100 gallon reactor, followed by 5% ethanol (170.0 kg) in toluene. The mixture was heated to 75±5 ℃ for 60 minutes to give a solution, followed by slow cooling to 20 ℃. The solid was filtered and then washed twice with toluene (31 kg,1.7 volumes). The wet cake was dried under vacuum at 45 ℃ to give 8.2kg of crude PD-0325901 (37.1% yield).

Step 4 (preparation of substantially pure form IV of midametinib): the clean, dry 100 gallon reactor was purged with nitrogen, then charged with USP purified water (164.1 kg,20 volumes), followed by ethanol (200 gauge, 20.8kg,3.25 volumes). The solution was heated to 35±5 ℃. In a separate vessel, crude PD-0325901 (8.1 kg,1 eq.) was dissolved in ethanol (200 proof, 40.5kg,6.3 vol.). A portion of this solution (14.4 kg) was added to the 100 gallon reactor over 60 minutes. PD-0325901 form IV seed crystals (82.6 g,1% wt) as prepared in example 1 were added to the reactor to promote precipitation. The remaining crude PD-0325901/ethanol solution (34.3 kg) was added to the reactor over 90 minutes while stirring the mixture at 35.+ -. 5 ℃. The reactor contents were stirred at 35±5 ℃ for an additional 5.5 hours, followed by slow cooling to 20 ℃. The solid was then filtered, washed with USP purified water (16.5 kg,2 volumes) and dried under vacuum at 45 ℃ for 16 hours. The dried solid was screened through a 10 mesh screen to give 5.7kg of PD-0325901 form IV (70.4% yield).

The XRPD pattern of substantially pure form IV as used herein is shown in fig. 1A. TGA and DSC analyses of substantially pure form IV as used herein are shown in fig. 1B.

Example 4: dispersible tablet formulations of 0.5mg and 1.0mg

Examples of dispersible tablet formulations are shown in table 1.

Table 1.

a=based on theoretical efficacy of 1.000. The amount may be adjusted based on actual performance.

b = amount of microcrystalline cellulose the amount of example 5 can be adjusted for slight potency changes of midametinib: process for preparing Midamatinib dispersible tablet

Non-limiting examples of illustrative processes for producing a dispersible tablet of midametinib are described herein.

Microcrystalline cellulose (about 30% w/w microcrystalline cellulose in the final composition) is blended in a container. Midamatinib, croscarmellose and microcrystalline cellulose (about 50% w/w microcrystalline cellulose in the final composition) are added to the vessel and blended. The remaining microcrystalline cellulose was added to the vessel and blended. The intraparticle magnesium stearate was added for lubrication and the blend was rolled into dry pellets. Grape flavor flavoring and sucralose are blended into the granules and extra-granular magnesium stearate is added for lubrication. The blend was pressed and checked for control during appearance, weight, thickness, hardness, friability and disintegration. The tablets were dust removed and inspected for metallic impurities and then bulk packed.

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. If a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is used as the definition of that term.

While the invention has been described in connection with specific aspects thereof, it will be understood that the invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the claims.

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 in an exemplary list, and the application is not limited to these embodiments.

E1. A pharmaceutical composition comprising an amount of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide of formula (I)

Wherein the pharmaceutical composition is dispersible in a drinkable liquid or is orodispersible in saliva of a subject.

A pharmaceutical composition of e1, wherein said N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is crystalline.

A 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 selected from the group consisting of:

a crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide characterized by an XRPD pattern having peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 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 peaks at one or more of 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2Θ; and

a crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide characterized by an XRPD pattern having peaks at one or more of 5.5±0.2 and 19.6±0.2 degrees 2Θ.

A 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.

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.

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 figure 1A.

The pharmaceutical composition of any one of E2-E6, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by one or both of:

a) A TGA profile substantially as shown in figure 1B; and/or

b) A DSC profile substantially as shown in figure 1B.

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 include an onset of endotherm at about 117 ℃.

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 is free of any amount of form I or form II detectable by XRPD and/or DSC.

The pharmaceutical composition of any one of E2-E9, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

The pharmaceutical composition of any one of E2-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 under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

The pharmaceutical composition of any one of E2-E11, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

The pharmaceutical composition of any one of E2-E12, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

The pharmaceutical composition of any one of E2-E13, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

The pharmaceutical composition of any one of E2-E14, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

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

The pharmaceutical composition of any one of E2-E16, wherein the crystalline form is form IV.

A pharmaceutical composition of E2 or E3, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having peaks at one or more of 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2Θ.

A pharmaceutical composition of E19.2, E3 or E18, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having one or more degrees of theta at 10.6±0.2, 13.7±0.2, 14.6±0.2, 17.3±0.2, 18.0±0.2, 18.2±0.2, 19.0±0.2, 19.3±0.2, 20.1±0.2, 21.0±0.2, 21.9±0.2, 22.4±0.2, 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.1±0.2, 32.3±0.2, 32.1±0.2, 35.7±0.2, or more than one or more degrees of theta 2.

A pharmaceutical composition of E2, E3, E18 or E19, wherein said crystalline form is characterized by a DSC curve that begins to absorb heat at about 117 ℃.

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

A 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.

A pharmaceutical composition of E23, E3 or E22, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by an XRPD pattern having peaks at one or more of 5.5±0.2, 10.7±0.2, 16.5±0.2, 19.6±0.2, 22.0±0.2, 22.5±0.2, 23.6±0.2, 24.1±0.2, 25.0±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.

A 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 that begins to absorb heat at about 87 ℃.

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

The pharmaceutical composition of any one of E1-E25, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

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

The pharmaceutical composition of any one of E1-E27, wherein the pharmaceutical composition is orodispersible.

The pharmaceutical composition of any one of E1-E28, wherein the pharmaceutical composition is a tablet, powder, granule, micro-tablet or pellet.

A pharmaceutical composition of e30.e29, wherein the pharmaceutical composition is a powder.

A pharmaceutical composition of e31, e30, wherein said powder is a dispersible powder.

A pharmaceutical composition of E32, E30 or E31, wherein a capsule or sachet comprises said powder or dispersible powder.

A pharmaceutical composition of e29, wherein the pharmaceutical composition is in the form of particles.

A pharmaceutical composition of e34.e33, wherein said particles are dispersible particles.

A pharmaceutical composition of E33 or E34, wherein a capsule or sachet comprises said particles or dispersible particles.

A pharmaceutical composition of e36.e29, wherein the pharmaceutical composition is in the form of a minitablet.

A pharmaceutical composition of e37.e36, wherein said microtablets are dispersible microtablets.

A pharmaceutical composition of E36 or E37, wherein a capsule or sachet comprises said minitablets or dispersible minitablets.

A pharmaceutical composition of e39.e29, wherein the pharmaceutical composition is in the form of a pellet.

A pharmaceutical composition of e40.e39, wherein the pellets are dispersible pellets.

A pharmaceutical composition of E41, E39 or E40, wherein a capsule or sachet comprises said minitablets or dispersible minitablets.

A pharmaceutical composition of e42.e29, wherein the pharmaceutical composition is a tablet.

A pharmaceutical composition of e43, e42, wherein said pharmaceutical composition is a dispersible tablet.

The pharmaceutical composition of any one of E1-E43 comprising:

about 0.1mg to about 20mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

and wherein the components of the pharmaceutical composition are as follows:

a. About 0.1wt/wt% to about 7wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

b. about 50wt/wt% to about 98wt/wt% of one or more diluents;

c. about 1wt/wt% to about 10wt/wt% of one or more disintegrants;

0wt/wt% to about 5wt/wt% of one or more flavoring agents;

0wt/wt% to about 5wt/wt% of one or more sweeteners; and

f. about 0wt/wt% to about 5wt/wt% of one or more lubricants.

The pharmaceutical composition of any one of E1-E43 comprising:

and wherein the components of the pharmaceutical composition are as follows:

a. about 0.5wt/wt% to about 1.2wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

b. about 85wt/wt% to about 95wt/wt% of one or more diluents;

c. about 3.5wt/wt% to about 6wt/wt% of one or more disintegrants;

0wt/wt% to about 2.5wt/wt% of one or more flavoring agents;

0wt/wt% to about 2wt/wt% of one or more sweeteners; and

f. about 0.5wt/wt% to about 2wt/wt% of one or more lubricants.

A pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 0.5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

A pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

A pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

A pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 3mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

A pharmaceutical composition of E44 or E45, wherein the pharmaceutical composition comprises about 4mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

The pharmaceutical composition of any one of E44-E50, wherein at least one of the diluents is selected from the group consisting of: microcrystalline cellulose, lactose, mannitol, starch, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, and dibasic calcium phosphate.

A pharmaceutical composition of e52.e51, wherein at least one of the diluents is microcrystalline cellulose.

The pharmaceutical composition of any one of E44-E52, wherein at least one of the disintegrants is selected from the group consisting of: croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid.

A pharmaceutical composition of e54.e53, wherein at least one of the disintegrants is croscarmellose sodium.

The pharmaceutical composition of any one of E44-E54, wherein at least one of the flavors 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, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor.

A pharmaceutical composition of e56.e55, wherein at least one of said flavoring agents is a grape-flavored flavoring agent.

The pharmaceutical composition of any one of E44-E56, wherein at least one of the sweeteners is selected from the group consisting of: sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.

A pharmaceutical composition of e58.e57, wherein at least one of the sweeteners is sucralose.

The pharmaceutical composition of any one of E44-E58, wherein at least one of the lubricants is selected from the group consisting of: magnesium stearate, sodium stearyl fumarate, glyceryl behenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil and talc.

A pharmaceutical composition of e60 e59, wherein at least one of said lubricants is magnesium stearate.

The pharmaceutical composition of any one of E1-E60, wherein the drinkable liquid is aqueous emulsion or fruit juice.

The pharmaceutical composition of any one of E1-E60, wherein the pharmaceutical composition is dispersible in saliva of a subject.

E63. A method of treating a tumor, cancer or RAS disease comprising administering to a subject in need of such treatment a pharmaceutical composition of any one of E1-E62.

A method of e64, e63, wherein said tumor is a neurofibroma.

A method of e65, e64, wherein said tumor is a neurofibromatosis associated with type 1 neurofibromatosis.

The method of any one of E63-E65, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

A method of e67, e66, wherein said tumor is plexiform neurofibromatosis.

A method of e68, e67, wherein said subject is diagnosed with RAS disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, kettkov syndrome, rasagile syndrome, noonan syndrome and multiple lentigo noonan syndrome.

A method of e69.e63, wherein the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gall bladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

A method of e70.e69, wherein the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

A method of e71.e69, 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 B-cell lymphoma, small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

A method of e72, 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.

The method of any one of E63-E72, wherein the subject carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

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 in the form of one or more tablets, one or more dispersible powders, one or more dispersible granules, one or more microtablets, one or more pellets, or a combination thereof.

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

The method of any one of E63-E74, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) administering a total daily dose for 21 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

The method of any one of E63-E74, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) a total daily dose administered for 5 days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

The method of any one of E63-E74, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) a total daily dose administered for 5 consecutive days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

The method of any one of E63-E74, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising a total daily dose administered for 28 days.

The method of any one of E80.E78-E79, wherein the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles.

The method of any one of E81, E63-E80, wherein the subject experiences dysphagia.

A method of e82.e81, wherein the subject experiences dysphagia caused by one or more of: neurological diseases, muscle weakness, developmental disability, stroke, injury, anatomical defects, cancer treatment, allergic reactions, dementia, memory loss or cognitive decline.

The method of any one of E83, E63-E80, wherein the subject is a pediatric subject.

E84. The method of any one of claims 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.

The method of e85.e84, wherein said total daily dose of said N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in an amount of from about 0.1mg to about 10mg per dose.

The method of e86.e85, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, at a dose of about 0.25mg each time.

The method of e87.e85, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, at a dose of about 0.5mg each time.

The method of e88, 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 daily, each dose being about 1mg.

The method of e89, 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 daily, each dose being about 2mg.

A method of e90, 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 daily, each dose being about 4mg.

The method of e91.e85, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, about 5mg each dose.

The method of e 92.85, 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 daily, each dose being about 10mg.

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

A method of e94, e93, wherein said total daily dose of said N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of from about 0.1mg to about 20mg once daily.

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 at a dose of about 0.5mg once daily.

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 at a dose of about 1mg once daily.

The method of e97, 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 at a dose of about 2mg once daily.

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 at a dose of about 4mg once daily.

The method of e 99.94, wherein said total daily dose of said N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 8mg once daily.

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 at a dose of about 10mg once daily.

The method of e101, 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 at a dose of about 20mg once daily.

The method of any one of E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20mg.

E103. The method of any one of claims E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 10 mg.

E104. The method of any one of claims E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg.

The method of any one of E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 6 mg.

The method of any one of E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 4 mg.

The method of any one of E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg.

The method of any one of E63-E101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

Use of a pharmaceutical composition of any one of E1-E62 for the manufacture of a medicament for the treatment of a tumor, cancer or RAS disease.

Use of e110.E109, wherein the tumor is a neurofibromatosis.

Use of e111.E110, wherein the tumor is a neurofibromatosis associated with a type 1 neurofibromatosis.

Use of any one of E109-E111, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

Use of e113, e112, wherein the tumor is plexiform neurofibromatosis.

Use of e114.e109, wherein the subject is diagnosed with RAS disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, kettkov syndrome, rasagile syndrome, noonan syndrome and multiple lentigo noonan syndrome.

Use of e115.E109, wherein the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gall bladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

Use of e116.E115, wherein the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

Use of e117.e115, 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 B-cell lymphoma, small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

Use of e118, 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.

The use of any one of E109-E118, wherein the subject carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

The use of any one of E109-E119, wherein the individual doses of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are administered in the form of one or more tablets, one or more dispersible powders, one or more dispersible granules, one or more microtablets, one or more pellets, or a combination thereof.

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

The use of any one of E109-E119, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) administering a total daily dose for 21 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

The use of any one of E109-E119, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) a total daily dose administered for 5 days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

The use of any one of E109-E119, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) a total daily dose administered for 5 consecutive days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

The use of any one of E109-E119, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising a total daily dose administered for 28 days.

The use of any one of E124-E125, wherein the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles.

The use of any one of E109-E126, wherein the subject experiences dysphagia.

Use of e128.e127, wherein the subject experiences dysphagia caused by one or more of: neurological diseases, muscle weakness, developmental disability, stroke, injury, anatomical defects, cancer treatment, allergic reactions, dementia, memory loss or cognitive decline.

The use of any one of E129, E109-E128, wherein the subject is a pediatric subject.

The use of any one of E109-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.

Use of e131.e130, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in an amount of about 0.1mg to about 10mg per dose.

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 daily, each dose being about 0.25mg.

Use of e133.E131, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, at a dose of about 0.5mg each time.

Use of e134.e131, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 1mg.

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 daily, each dose being about 2mg.

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 daily, each dose being about 4mg.

Use of e137.e131, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily, each dose being about 5mg.

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 daily, each dose being about 10mg.

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

Use of e140.E139, wherein said total daily dose of said N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of from about 0.1mg to about 20mg once daily.

Use of e141.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 at a dose of about 0.5mg once daily.

Use of e142, 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 at a dose of about 1mg once daily.

Use of e143, 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 at a dose of about 2mg once daily.

Use of e144, 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 at a dose of about 4mg once daily.

Use of e145, 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 at a dose of about 8mg once daily.

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 at a dose of about 10mg once daily.

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 daily at a dose of about 20mg.

The use of any one of E109-E147, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20mg.

The use of any one of E109-E148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10mg.

The use of any one of E109-E148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 8mg.

The use of any one of E109-E148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 6 mg.

The use of any one of E109-E148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 4 mg.

The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg.

The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

Claims

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

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. 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 selected from the group consisting of:

a) A crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide characterized by an XRPD pattern having peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 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 peaks at one or more of 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2Θ; 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 peaks at one or more of 5.5±0.2 and 19.6±0.2 degrees 2Θ.

4. The pharmaceutical composition of claim 2 or 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 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2Θ.

5. The pharmaceutical composition of any one of claims 2-4, 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 having peaks at 4.6±0.2, 7.3±0.2, 14.6±0.2, and 25.0±0.2 degrees 2Θ.

6. The pharmaceutical composition of any one of claims 2-5, 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 figure 1A.

7. The pharmaceutical composition of any one of claims 2-6, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by one or both of:

a) A TGA profile substantially as shown in figure 1B; and/or

b) A DSC profile substantially as shown in figure 1B.

8. The pharmaceutical composition of any one of claims 2-7, 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 curve that does not include an onset of endotherm at about 117 ℃.

9. The pharmaceutical composition of any one of claims 2-8, wherein the crystalline form of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is free of any amount of form I or form II detectable by XRPD and/or DSC.

10. The pharmaceutical composition of any one of claims 2-9, 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 DSC profile that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

11. The pharmaceutical composition of any one of claims 2-10, 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 DSC profile that is substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

12. The pharmaceutical composition of any one of claims 2-11, 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 DSC profile that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

13. The pharmaceutical composition of any one of claims 2-12, 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 DSC profile that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

14. The pharmaceutical composition of any one of claims 2-13, 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 DSC profile that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

15. The pharmaceutical composition of any one of claims 2-14, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

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

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

18. The pharmaceutical composition of claim 2 or 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 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2Θ.

19. The pharmaceutical composition of claim 2,3, or 18, 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 one or more degrees of theta 2 at 10.6±0.2, 13.7±0.2, 14.6±0.2, 17.3±0.2, 18.0±0.2, 18.2±0.2, 19.0±0.2, 19.3±0.2, 20.1±0.2, 21.0±0.2, 21.9±0.2, 22.4±0.2, 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.1±0.2, 32.3±0.2, 20.1±0.2, 21.0.2, 23.7±0.2, 24.9±0.2.

20. The pharmaceutical composition of claim 2,3, 18 or 19, wherein the crystalline form is characterized by a DSC curve that begins to absorb heat at about 117 ℃.

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

22. The pharmaceutical composition of claim 2 or 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 5.5±0.2 and/or 19.6±0.2 degrees 2Θ.

23. The pharmaceutical composition of claim 2,3, or 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 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. The pharmaceutical composition of claim 2,3, 22 or 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 that begins to absorb heat at about 87 ℃.

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

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

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

28. The pharmaceutical composition of any one of claims 1-27, wherein the pharmaceutical composition is orodispersible.

29. The pharmaceutical composition of any one of claims 1-28, wherein the pharmaceutical composition is a tablet, powder, granule, micro-tablet, or pellet.

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

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

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

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

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

35. The pharmaceutical composition of claim 33 or 34, wherein a capsule or sachet comprises the particles or dispersible particles.

36. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of a minitablet.

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

38. The pharmaceutical composition of claim 36 or 37, wherein a capsule or sachet comprises the minitablet or dispersible minitablet.

39. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of pellets.

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

41. The pharmaceutical composition of claim 39 or 40, wherein a capsule or sachet comprises the minitablet or dispersible minitablet.

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

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

44. The pharmaceutical composition of any one of claims 1-43, comprising:

and wherein the components of the pharmaceutical composition are as follows:

b. about 50wt/wt% to about 98wt/wt% of one or more diluents;

c. about 1wt/wt% to about 10wt/wt% of one or more disintegrants;

0wt/wt% to about 5wt/wt% of one or more flavoring agents;

0wt/wt% to about 5wt/wt% of one or more sweeteners; and

f. about 0wt/wt% to about 5wt/wt% of one or more lubricants.

45. The pharmaceutical composition of any one of claims 1-43, comprising:

and wherein the components of the pharmaceutical composition are as follows:

b. about 85wt/wt% to about 95wt/wt% of one or more diluents;

c. About 3.5wt/wt% to about 6wt/wt% of one or more disintegrants;

0wt/wt% to about 2.5wt/wt% of one or more flavoring agents;

0wt/wt% to about 2wt/wt% of one or more sweeteners; and

f. about 0.5wt/wt% to about 2wt/wt% of one or more lubricants.

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

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

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

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

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

51. The pharmaceutical composition of any one of claims 44-50, 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.

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

53. The pharmaceutical composition of any one of claims 44-52, 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. The pharmaceutical composition of claim 53, wherein at least one of the disintegrants is croscarmellose sodium.

55. The pharmaceutical composition of any one of claims 44-54, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavoring agents, including but not limited to grape-flavored flavoring agents, bubble gum flavoring agents, caramel-flavored flavoring agents, orange-flavored flavoring agents, lemon-flavored flavoring agents, strawberry-flavored flavoring agents, raspberry-flavored flavoring agents, peppermint-flavored flavoring agents, grapefruit-flavored flavoring agents, pineapple-flavored flavoring agents, pear-flavored flavoring agents, peach-flavored flavoring agents, vanilla-flavored flavoring agents, banana-flavored flavoring agents, or cherry-flavored flavoring agents.

56. The pharmaceutical composition of claim 55, wherein at least one of the flavoring agents is a grape-flavored flavoring agent.

57. The pharmaceutical composition of any one of claims 44-56, 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. The pharmaceutical composition of claim 57, wherein at least one of the sweeteners is sucralose.

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, glyceryl behenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil and talc.

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

61. The pharmaceutical composition of any one of claims 1-60, wherein the drinkable liquid is water emulsion or juice.

62. The pharmaceutical composition of any one of claims 1-60, wherein the pharmaceutical composition is capable of being dispersed in saliva of a subject.

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

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

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

66. The method of any one of claims 63-65, wherein the tumor is a cutaneous neurofibroma, plexiform neurofibroma, optic-circuit glioma, low-grade glioma, high-grade glioma, or malignant peripheral-schwannoma.

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

68. The method of claim 67, wherein the subject is diagnosed with RAS disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, kettkov syndrome, rasagile syndrome, noonan syndrome and multiple lentigo noonan syndrome.

69. 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 neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gall bladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

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

71. 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 B-cell lymphoma, small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

72. 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. The method of any one of claims 63-72, wherein the subject carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

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 in the form of one or more tablets, one or more dispersible powders, one or more dispersible granules, one or more microtablets, one or more pellets, or a combination thereof.

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) administering a total daily dose for 21 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

76. 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) administering a total daily dose for 21 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

77. 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 period comprising (i) a total daily dose administered for 5 days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

78. 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 period comprising (i) a total daily dose administered for 5 consecutive days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

79. 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 total daily dose administered for 28 days.

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

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

82. The method of claim 81, wherein the subject experiences dysphagia caused by one or more of: neurological diseases, muscle weakness, developmental disability, stroke, injury, anatomical defects, cancer treatment, allergic reactions, dementia, memory loss or cognitive decline.

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

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

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 daily at a dose of about 0.25mg each time.

87. 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 daily at a dose of about 0.5mg each time.

88. 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 daily, each dose being about 1mg.

89. 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 daily, each dose being about 2mg.

90. 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 daily, each dose being about 4mg.

91. 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 daily, each dose being about 5mg.

92. 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 daily, each dose being about 10mg.

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

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 at a dose of from about 0.1mg to about 20mg once daily.

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 at a dose of about 0.5mg once daily.

96. 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 at a dose of about 1mg once daily.

97. 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 at a dose of about 2mg once daily.

98. 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 at a dose of about 4mg once daily.

99. 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 at a dose of about 8mg once daily.

100. 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 at a dose of about 10mg once daily.

101. 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 at a dose of about 20mg once daily.

102. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20mg.

103. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10mg.

104. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 8 mg.

105. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 6 mg.

106. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 4 mg.

107. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg.

108. The method of any one of claims 63-101, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.

109. Use of the pharmaceutical composition of any one of claims 1-62 for the manufacture of a medicament for treating a tumor, cancer or RAS disease.

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

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

112. The use of any one of claims 109-111, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

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

114. The use of claim 109, wherein the subject is diagnosed with RAS disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, kettkov syndrome, rasagile syndrome, noonan syndrome and multiple lentigo noonan syndrome.

115. 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 neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gall bladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

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

117. 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 B-cell lymphoma, small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

118. 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. The use of any one of claims 09-118, wherein the subject carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

120. The use of any one of claims 109-119, wherein the individual dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in the form of one or more tablets, one or more dispersible powders, one or more dispersible granules, one or more microtablets, one or more pellets, or a combination thereof.

121. The use of any one of claims 109-119, 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) administering a total daily dose for 21 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

122. The use of any one of claims 109-119, 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) administering a total daily dose for 21 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

123. The use of any one of claims 109-119, 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 period comprising (i) a total daily dose administered for 5 days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

124. The use of any one of claims 109-119, 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 period comprising (i) a total daily dose administered for 5 consecutive days and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide administered for 2 consecutive days; thereafter (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 consecutive days.

125. The use of any one of claims 109-119, 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 total daily dose administered for 28 days.

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

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

128. The use of claim 127, wherein the subject experiences dysphagia caused by one or more of: neurological diseases, muscle weakness, developmental disability, stroke, injury, anatomical defects, cancer treatment, allergic reactions, dementia, memory loss or cognitive decline.

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

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

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

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 daily at a dose of about 0.25mg each time.

133. 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 daily at a dose of about 0.5mg each time.

134. 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 daily, each dose being about 1mg.

135. 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 daily, each dose being about 2mg.

136. 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 daily, each dose being about 4mg.

137. 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 daily at a dose of about 5mg each time.

138. 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 daily at a dose of about 10mg each time.

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

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 at a dose of from about 0.1mg to about 20mg once daily.

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 at a dose of about 0.5mg once daily.

142. 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 at a dose of about 1mg once daily.

143. 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 at a dose of about 2mg once daily.

144. 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 at a dose of about 4mg once daily.

145. 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 at a dose of about 8mg once daily.

146. 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 at a dose of about 10mg once daily.

147. 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 at a dose of about 20mg once daily.

148. The use of any one of claims 109-147, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20 mg.

149. The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg.

150. The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 8 mg.

151. The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 6 mg.

152. The use of any one of claims 1109-148 wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 4 mg.

153. The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 2 mg.

154. The use of any one of claims 109-148, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 1 mg.