KR20230157314A - Dispersible formulations of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and Its purpose - Google Patents

Abstract

The present disclosure relates to 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 Its purpose

The present disclosure is directed to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro) for use in administering to a patient in need thereof. Dispersible formulations of -4-iodo-phenylamino)-benzamide and methods for preparing such dispersible formulations. The present disclosure further provides N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benz dispersible formulations containing amides; Dispersibility containing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Method of manufacturing the dosage form; and N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) to a subject in need thereof. -Relates to methods and uses of treating tumors, cancer, or neurodevelopmental (Rasopathy) disorders by administering benzamide.

Neurofibromatosis Type 1 (“NF1”) is characterized by diverse and progressive cutaneous, neurological, skeletal and neoplastic manifestations for which there are no standard drug treatment options available. Neurofibroma is a benign peripheral nerve sheath tumor composed of a mixture of Schwann cells, fibroblasts, perineuronal cells, and mast cells and occurs in 20 to 50% of NF1 patients (Tucker, et al. (2011) J. Histochem Cytochem. 59(6):584-590). When a neurofibroma extends longitudinally along a nerve and contains multiple bundles, it is classified as a plexiform neurofibroma (PN). Plexiform neurofibromas rarely regress spontaneously, and in many patients their growth continues indefinitely. Pseudomytic neurofibromas represent a major cause of morbidity and disfigurement in individuals with NF1 and, when symptomatic, are associated with increased mortality (Rasmussen, et al. (2001) Am. J. Hum. Genet. 68(5) :1110-1118; Prada, et al. (2012) J. Pediat. 160(3):461-467). As tumor growth progresses, these lesions can cause functional impairment, pain, cosmetic disfigurement, and can compress the airway or spinal cord. Additionally, PNs have the potential to undergo malignant transformation giving rise to malignant peripheral nerve sheath tumors (MPNSTs).

Previous longitudinal retrospective studies have demonstrated age-dependent differences in plexiform neurofibromas and a high inverse correlation of PN growth 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 serial MRI of 34 patients (median 10 years, range 1 to 47 years) with measurable PN during a median follow-up of 6 years (range 1 to 15 years). This study observed that the difference between initial and final two-dimensional estimated tumor size was significantly greater in young subjects compared to elderly subjects; 3.2 cm2 vs. 0.2 cm2, respectively (p = 0.031). Additionally, the tumor growth rate in patients younger than 10 years old (0.7 cm2/year) was significantly greater than that in patients older than 10 years old (0.03 cm2/year, p=0.014). Similarly, in an observational study of 49 patients aged 3 to 25 years (median 8.3 years), Dombi et al observed that PN volume increased more rapidly than body weight over time (p = 0.026). Additionally, patients younger than the median age of 8.3 years tended to have a greater increase in annual PN volume compared to older children; Annual volume change was 21.1% vs. 8.4%, respectively (p = 0.001). This trend applies when PN growth rate is expressed in relation to the rate of increase in body size.

Based on the findings of Tucker and Dombi, Nguyen et al performed a retrospective study of 71 patients with evaluable PN over a median follow-up period of 2.2 years (range 1.1 to 4.9 years). The growth rate of individual tumors was inversely correlated with age at initial examination (Spearman's rho = -0.33, p < 0.001) but not with tumor volume at initial MRI examination. Additionally, tumors that increased by more than 20% per year occurred significantly more frequently in children than in adults (p < 0.001). In summary, results from three independent retrospective reviews of PN volume clearly indicate that PN growth rate in NF1 patients is inversely correlated with age, suggesting individual age-dependent tumor differences and unmet need in the pediatric population. indicates.

These observations suggest that the youngest patients may derive the greatest clinical benefit from therapy. However, the youngest potential patients with urgent medical needs for treatment may have difficulty receiving treatment because they may not be able to swallow capsules or tablets whole. Therefore, age-appropriate pediatric formulations that allow for precise dosing and improved compliance are needed to optimize efficacy and safety in this population.

Moreover, patients who require treatment but have difficulty swallowing (“dysphagia”) would benefit from a non-capsule or tablet formulation that can be administered orally. Dysphagia can be caused by a variety of conditions that affect one or more components of the swallowing process. This includes physical damage to the tongue, pharynx, larynx, esophagus or trachea due to trauma, infection or proliferative disease; Treatment for these conditions; Congenital anatomical defects, such as cleft palate; underdevelopment at a young age; Weakness in old age; Dementia, memory loss, or cognitive decline; or any condition that otherwise weakens or damages the muscles or nerves used in the swallowing process, such as Parkinson's disease, stroke, or neurological disease.

N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (“mirdamethi NIPS” or “PD-0325901”) is a small molecule drug designed to inhibit mitogen-activated protein kinase kinase 1 (“MEK1”) and mitogen-activated protein kinase kinase 2 (“MEK2”). MEK1 and MEK2 are proteins that play important roles in the mitogen-activated protein kinase (“MAPK”) signaling pathway. The MAPK pathway is important for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Mirdametinib is a very potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2. By its basis of action, mirdametinib significantly inhibits the phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby impairing the growth of tumor cells both in vitro and in vivo. Additionally, evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide has already been It is listed. WO2002/006213 describes crystal forms I and II and is incorporated by reference. Form I is characterized by an XRPD containing peaks at one or more of 10.6, 13.7, 19.0, and 23.7 degrees 2θ; Form II is characterized by XRPD containing peaks at 5.5 and/or 19.6 degrees 2θ. Form I is characterized by a melting point of approximately 117°C to 118°C as determined by DSC, and Form II is characterized by a melting point of 89°C to 90°C.

U.S. Patent No. 7,060,856 (the "'856 patent") describes a process for preparing Form IV, which is incorporated by reference. The '856 patent indicates that the material prepared by this method was >90% Form IV ('856 patent, Example 1). The '856 patent also states that differential scanning calorimetry ("DSC") of the prepared material shows a melting onset at 110°C and a minor peak starting at 117°C, consistent with the material being a mixture of the two forms. do. Compositions containing more than one polymorphic form are generally undesirable because of the potential for interconversion of one polymorphic form to another polymorphic form. Polymorphic interconversion can lead to differences in effective dosage or properties that affect the processability of the drug, caused by differences in solubility or bioavailability.

N-((R)-2 for use in the treatment of tumors, cancer, or neurodevelopmental disorders, when whole capsules or tablets can be safely administered to patients who have difficulty swallowing (e.g., pediatric patients or patients with dysphagia) There is a need for a dispersible formulation of ,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Given the mixture of forms apparent in Form IV previously disclosed, N-((R)-2,3-dihydroxypropoxy) to limit polymorphic interconversions between forms that may affect solubility and bioavailability. There is a need for a dispersible formulation containing essentially pure form IV of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

Figure 1A shows the essential structure of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. X-ray powder diffraction pattern (“XRPD”) corresponding to pure crystal form IV.
Figure 1B shows the essential structure of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Thermogravimetric analysis thermogram (“TGA”) and differential scanning calorimetry thermogram (“DSC”) corresponding to pure crystal form IV.
Figure 2 shows the initially prepared N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- XRPD corresponding to a batch of essentially pure Form IV of benzamide and XRPD of a known reference standard of Form IV.
Figure 3A shows N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2) after manufacture and storage for 68 months at 25°C and relative humidity of 65% or less. XRPD corresponding to essentially pure form IV of -fluoro-4-iodo-phenylamino)-benzamide.
Figure 3B shows N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2) after manufacturing and storage for 140 months at 25°C and relative humidity of 65% or less. XRPD corresponding to essentially pure form IV of -fluoro-4-iodo-phenylamino)-benzamide.

BRIEF SUMMARY OF THE INVENTION

The present disclosure features compositions useful for treating disorders associated with aberrant MEK1 or MEK2 activity, such as tumors, cancers, or neurodevelopmental disorders, such as neurofibromatosis type 1, in a subject in need thereof. In some aspects, the methods and compositions described herein are useful in patients who have difficulty swallowing whole capsules or tablets, such as pediatric patients or subjects experiencing dysphagia, such as esophageal cancer, Parkinson's disease, amyotrophic lateral sclerosis, stroke, dysphagia. It is useful in the treatment of patients with achalasia or esophageal stricture. In some aspects, the composition comprises N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benz Includes Form I, Form II or Form IV of the amide.

pharmaceutical composition

In some aspects, the present disclosure provides an amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluorocarbons of formula (I): It relates to a pharmaceutical composition comprising rho-4-iodo-phenylamino)-benzamide:

The pharmaceutical composition is dispersible in a drinkable liquid (eg, water) or orodispersible in the subject's saliva.

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

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2, and 14.6 ± 0.2 degrees 2theta. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2, 14.6 ± 0.2 and 25.0 ± 0.2 degrees 2theta.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form is characterized by an XRPD pattern substantially as shown in Figure 1A.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form is characterized by a DSC profile that does not include an endotherm, starting at about 117°C.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form has (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, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.

In some aspects, the crystal form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benz Amide is anhydrous.

In some aspects, the crystal form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benz The amide is form IV. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form is essentially pure Form IV.

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

In some aspects, the XRPD pattern is (a) (b) mirror, mirror exit slot (0.2 mm), 2.5° Soller slit, configured around the incident beam side as the beam knife and (b) anti-scatter slit (8 mm) and diffracted beam side as the 2.5° Soller slit, (b) a) incident beam side with variable diverging slit (10 mm illumination length), 0.04㎭ Soller slit, fixed anti-scatter slit (0.50°) and 10 mm beam mask and (b) with LYNXEYE ^TM detector. Together with Cu Kα (40 kV/40 mA) radiation and a variable anti-scatter slit (10 mm observation length) with an increment size of 0.03° 2θ and a 0.04 m Soller slit or relative to the diffraction beam side, such as the BRUKER ^® D8 ^® ADVANCE ^TM system. Generated using a ^{PANALYTICAL ®} Here 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 temperature increase rate of about 15° C./min.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form is characterized by an XRPD pattern with peaks at 10.6 ± 0.2, 13.7 ± 0.2, 19.0 ± 0.2 and 23.7 ± 0.2 degrees 2theta. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form is 10.6 ± 0.2, 13.7 ± 0.2, 14.6 ± 0.2, 17.3 ± 0.2, 18.0 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.3 ± 0.2, 20.1 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.4 ± 0.2 , 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.1±0.2, 32.3±0.2, 32.9±0.2, 35.8±0.2 and 37.7±0.2 degrees. 2 It is characterized by an XRPD pattern with a peak at theta.

In some aspects, the crystal form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benz The amide is characterized by a DSC profile with an endotherm starting at about 117°C.

In some aspects, the crystal form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benz The amide is Form I.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form is characterized by an XRPD pattern with peaks at 5.5 ± 0.2 and 19.6 ± 0.2 degrees 2theta. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal forms are 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 are also characterized by XRPD patterns with peaks at 2 theta.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form is characterized by a DSC profile with an endotherm starting at approximately 87°C.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form 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 orally dispersible.

In some aspects, the pharmaceutical composition is a tablet, powder, granule, minitablet, or pellet (also called 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 contains a dispersible powder.

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

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

In some aspects, the pharmaceutical composition is in the form of a pellet. In some aspects, the pellets are dispersible pellets. In some aspects, the capsule or sachet includes 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 orally dispersible tablet.

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

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

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

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

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

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

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

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

In some aspects, at least one of the lubricants consists of magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glycerol dibehenate, and talc. selected from the group. In some aspects, at least one of the lubricants is magnesium stearate.

Treatment method

In some aspects, the disclosure provides a method of treating a tumor, cancer, or neurodevelopmental disorder, comprising administering to a subject in need of such treatment a pharmaceutical composition (e.g., a dispersible tablet, a powder) as described herein. and administering an acidic powder, dispersible granules, dispersible minitablets or dispersible pellets).

In some aspects, the present disclosure provides pharmaceutical compositions described herein (e.g., dispersible tablets, dispersible powders, dispersible granules, powders) for the manufacture of a medicament for treating a tumor, cancer, or neurodevelopmental disorder. Provides the use of acidic minitablets or dispersible pellets).

In some aspects, the tumor is a neurofibroma. In some aspects, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some aspects, the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, or malignant peripheral nerve sheath tumor. do. In some aspects, the tumor is a plexiform neurofibroma.

In some aspects, the subject has neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome. Have been diagnosed with a neurodevelopmental disorder selected from the group consisting of Noonan syndrome and Noonan syndrome with multiple lentigines.

In some aspects, the cancer includes skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, stomach cancer, sarcoma, It is selected from the group consisting of bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid 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 subject has a mutation or other abnormality in one or more genes, wherein the mutation or other abnormality causes gain or loss of a function characteristic of the particular cancer, and the mutation or other abnormality in one or more genes is KRAS, NRAS, A mutation or other abnormality in one or more of HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1 or NF2.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Individual doses include: more than 1 dispersible tablet, more than 1 dose of dispersible powder, more than 1 dose of dispersible granules, more than 1 dose of dispersible minitablet, more than 1 dose of dispersible It is administered as a pellet or a combination thereof. For example, a 3 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) -Benzamide may be administered as two dispersible tablets - one containing 2 mg and the other 1 mg - or as three dispersible tablets containing 1 mg each. As another example, a 1.5 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino )-Benzamide is administered in two dispersible dosage forms - one dispersible tablet containing 1 mg and individual units of dispersible powder containing 0.5 mg - or as three units of dispersible powder each containing 0.5 mg. Can be administered as a unit.

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

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) Day 21 with a total daily dose administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. It is administered in 28-day dosing cycles, including 7 non-dosing days. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) 21 consecutive days with a total daily dose administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide It is administered in 28-day dosing cycles, including 7 consecutive days on which no doses are administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) (i) 5 days during which total daily doses are administered and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- three 7-day periods, each including 2 days during which fluoro-4-iodo-phenylamino)-benzamide was not administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. It is administered in 28-day dosing cycles, including 7 non-dosing days. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) (i) 5 consecutive days with a total daily dose administered and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2 -fluoro-4-iodo-phenylamino)-benzamide three 7-day periods each containing 2 days during which no administration was administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide It is administered in 28-day dosing cycles, including 7 consecutive days on which no doses are administered.

In some aspects, the 28-day dosing cycle is repeated for 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 It is administered in a 28-day dosing cycle with 28 days on which a total daily dose is administered.

In some aspects, the subject experiences difficulty swallowing. In some aspects, the subject has dysphagia caused by one or more of a neurological disease, muscle weakness, developmental disorder, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. experience

In some aspects, the subject is a pediatric subject.

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

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

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

Method for preparing pharmaceutical compositions

In some aspects, the disclosure provides a method of making a pharmaceutical composition, the method comprising forming the pharmaceutical composition described herein.

Justice

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

In general, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used in this specification generally have the same meaning as commonly understood by a person skilled in the art to which this disclosure pertains.

In this specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. The terms “one or more” and “at least one” as well as the singular terms “one or more” may be used interchangeably herein. In certain aspects, singular expressions mean “single.” In other aspects, singular terms include “two or more” or “plural.”

Additionally, when used herein, “and/or” is to be construed as a specific disclosure of each of the two specified features or ingredients, with or without the other. Accordingly, the term “and/or” as used herein in phrases such as “A and/or B” means “A and B”, “A or B”, “A” (alone) and “B”. It is intended to include (exclusively). Similarly, the term “and/or” as used in phrases such as “A, B, and/or C” is intended to include 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 (single); B (single); and C (exclusive).

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

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

The term “pediatric” refers to a human subject under the age of 21 at the time of treatment. The term “pediatric” refers to neonates (birth through the first 28 days of life); Infants (29 days to under 2 years); Children (2 to under 12 years of age); and adolescents (ages 12 to under 21 (not including their 22nd birthday)). See, for example, Berhman R E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery M D, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams &Wilkins; 1994]. Young pediatric patients, especially newborns, infants, and children, may have difficulty swallowing entire capsules or tablets.

As used herein, the term "dispersible" means water or other drinkable liquid (e.g., a beverage other than water) or the subject's own saliva when placed in the mouth of a subject, with or without added agitation or temperature modification. refers to a composition (e.g., tablets, powders, granules, minitablets or pellets) that disintegrates and/or dissolves when combined with. In some aspects, the dispersible composition disintegrates within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another potable liquid. It dissolves. This disintegration or dissolution need not be complete. For example, a dispersible tablet may be almost completely dissolved but some undissolved particulate material may remain.

The term “orally disintegrable” refers to a composition that is capable of dissolving or disintegrating in a subject's mouth (i.e., dissolving or disintegrating in the subject's saliva) when administered orally, without first dissolving or disintegrating in a separate container.

As used herein, the terms “treat,” “treated,” and “treating” mean that the purpose is to prevent or blunt (reduce) an undesirable physiological condition, disorder, or disease or to achieve beneficial or desirable clinical effects. It refers to both therapeutic treatment and prophylactic or prophylactic measures to achieve a positive result. Accordingly, subjects in need of treatment include those already diagnosed or suspected of having the disorder. Beneficial or desired clinical outcomes include symptom relief; Reduce the severity of a condition, disorder, or disease; Stabilized (i.e., not worsening) state of a condition, disorder, or disease; Delaying or slowing the onset of a condition, disorder, or disease progression; Improvement or alleviation (whether partial or total) of a condition, disorder or disease state, whether detectable or not; Improvement in at least one measurable physical parameter that is not necessarily identifiable to the patient; or improving or ameliorating a condition, disorder or disease. Treatment involves eliciting a clinically meaningful response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival if not treated. The term “therapeutically effective amount” is meant to include an amount of a compound sufficient to prevent the onset of or alleviate to some extent one or more of the symptoms of the disorder, disease or condition being treated. The term “therapeutically effective amount” also refers to the amount of a compound sufficient to induce a biological or medical response in a cell, tissue, system, animal or human being sought by a researcher, veterinarian, physician or clinician.

In certain aspects, a subject is successfully “treated” for a tumor according to the methods described herein if the patient exhibits one or more of the following: reduction in tumor size; Alleviation of one or more symptoms associated with a specific tumor; reduction of tumor volume; improving quality of life; Progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD) ), decreased progressive disease (PD), increased time to progression (TTP), or any combination thereof. In some aspects, nationally or internationally recognized standards for treatment outcomes for the tumor in question may be used to determine whether an effective dose of mirdametinib meets these specific endpoints (e.g., CR, PFS, PR). there is.

In certain aspects, a subject is successfully “treated” for cancer, e.g., lung cancer or ovarian cancer, according to the methods described herein if the patient exhibits one or more of the following: a reduction in the number of cancer cells; or complete absence; Alleviation of one or more symptoms associated with a specific cancer; reduction of morbidity and mortality; improving quality of life; Progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD) ), decreased progressive disease (PD), increased time to progression (TTP), or any combination thereof. In some aspects, nationally or internationally recognized standards for treatment outcomes for the cancer in question may be used to determine whether an effective dose of mirdametinib meets these specific endpoints (e.g., CR, PFS, PR). there is.

The terms “pharmaceutically acceptable carrier”, “pharmaceutically acceptable excipient”, “physiologically acceptable carrier” or “physiologically acceptable excipient” means a pharmaceutically acceptable excipient, such as a liquid or solid excipient, solvent or encapsulating material. refers to an acceptable substance, composition or vehicle. In one aspect, each ingredient is compatible with the other ingredients of the pharmaceutical formulation and is compatible with the tissues or organs of humans and animals without undue toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications commensurate with a reasonable risk/benefit ratio. “Pharmaceutically acceptable” in the sense that it is suitable for use in contact. Remington: The Science and Practice of Pharmacy , ^21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients , ^5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives , ^3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004, incorporated herein by reference. Excipients include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film formers or coatings, fragrances, flavors, glidants ( flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Exemplary excipients include butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, Ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, Gelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, Includes but is not limited to vitamin E, vitamin C, and xylitol.

As used herein, the term “pharmaceutical composition” refers to a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient or a combination of multiple pharmaceutically acceptable excipients, and It may be manufactured or sold upon approval by government regulatory agencies as part of a treatment regimen for the treatment of disease in animals. Pharmaceutical compositions may be, for example, in unit dosage form (e.g., tablets (e.g., dispersible tablets), powders (e.g., dispersible powders) capsules, granules, minitablets, pellets, caplets, gelcaps, or Syrup) can be formulated for oral administration.

The terms “about” or “approximately” mean within an acceptable margin of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how that 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 terms “about” or “approximately” refer to an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length of 30, 25, 20, 15, 10, 9, 8. means a quantity, level, value, number, frequency, percentage, dimension, size, volume, weight or length that varies by , 7, 6, 5, 4, 3, 2 or 1%.

As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or formulation comprising a compound as described herein) to a subject or system. Administration to animal subjects (e.g., humans) can be by any suitable route, such as those described herein.

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

Crystal form is generally characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (peaks, typically expressed as 2-theta) is generally considered to be the fingerprint of a particular crystal form. The relative intensities of XRPD peaks can vary significantly depending on, among other things, sample preparation techniques, crystal size distribution, filters, sample mounting procedures, and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear, depending on the instrument type or settings. In some cases, any particular peak in the XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the instrument type or settings, sensitivity of the instrument, measurement conditions, and/or purity of the crystal form. In some cases, any particular peak in XRPD may appear with a symmetrical or asymmetrical shape (e.g., with a shoulder). Additionally, instrument variations and other factors can affect 2-theta values. Those skilled in the art who understand these transformations can use XRPD as well as other known physicochemical techniques to identify or confirm the defining features or characteristics of a particular crystal form.

The term “anhydrous” as applied to a compound refers to a crystal form in which the compound contains no structural water within the crystal lattice.

As used herein, the term "essentially pure" with respect to Form IV means that compositions comprising Form IV are N-((R)-2,3-dihydroxypropoxy)-3,4- Determined by observing that there is no detectable difference in XRPD and/or DSC pattern between the single Form IV crystal of difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and the crystalline composition. means that it does not contain a detectable amount of another polymorphic form (e.g., Form I or Form II). However, the "essential “Pure” Form IV may include impurities such as, but not limited to, synthetic reactants or by-products generated during chemical synthesis.

As used herein, the term "abnormality" as applied to a gene means a mutation, chromosomal loss or fusion, epigenetic chemical modification, or sequence associated with the gene compared to the sequence, expression level, or processed mRNA sequence associated with the wild-type gene; Refers to other events that change the expression level or processed mRNA sequence.

When an aspect is described herein with the term “comprising,” it is understood that other similar aspects described with the terms “consisting of” and/or “consisting essentially of” are also provided.

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 claims.

DETAILED DESCRIPTION OF THE INVENTION

N-((R)-2,3-dihydroxypropoxy)-3,4-difluoride can be safely administered to patients with swallowing difficulties (e.g., pediatric patients or patients with dysphagia). Dispersible formulations of rho-2-(2-fluoro-4-iodo-phenylamino)-benzamide (e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets or dispersible pellets) ) is described in this specification.

With respect to all pharmaceutical compounds and compositions, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The chemical and physical properties of amino)-benzamide are important for its commercial development. These properties include, but are not limited to: (1) packing properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties. , such as dissolution rate and stability (including stability under ambient conditions, especially moisture and environmental conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile. strength, compressibility, handling, flow and blend; and (6) filtration properties. These properties can affect, for example, the processing 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 In addition to pharmaceutically acceptable carriers or excipients, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered as Form I, Form II or Form IV (e.g., essentially pure Form IV).

pharmaceutical composition

In some aspects, the present disclosure provides an amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluorocarbons of formula (I): Provided is a pharmaceutical composition comprising rho-4-iodo-phenylamino)-benzamide:

The pharmaceutical composition is dispersible in a drinkable liquid (eg, water) or orally dispersible in the subject's saliva.

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

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2 and 14.6 ± 0.2 degrees 2theta. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2, 14.6 ± 0.2 and 25.0 ± 0.2 degrees 2theta.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in Figure 1A.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide has (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, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is characterized by a DSC profile that does not include an endotherm, starting at about 117°C.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is anhydrous.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is Form IV. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystalline form is essentially pure Form IV.

In some aspects, the crystalline Form IV composition included in the pharmaceutical compositions described herein is stable, as indicated by an XRPD pattern and/or DSC profile that does not substantially change over time. In some aspects, the crystalline Form IV composition has a shelf life of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months under standard warehouse conditions (15° C. to 25° C. and relative humidity of 65% or less). , 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 Displays an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 1, 14, or 15 years. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for 3 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for 6 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for one year under standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for 5 years at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for 68 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for at least 140 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal Form IV compositions exhibit substantially unchanged XRPD patterns and/or DSC profiles after storage for at least 14 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%).

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The XRPD pattern for Form IV of iodo-phenylamino)-benzamide is (a) (b) mirror, mirror exit slot (0.2 mm), 2.5° Soller slit, configured around the incident beam side as the beam knife and (b) anti-scatter slit (8 mm) and diffracted beam side as the 2.5° Soller slit, (b) a) incident beam side with variable diverging slit (10 mm illumination length), 0.04㎭ Soller slit, fixed anti-scatter slit (0.50°) and 10 mm beam mask and (b) with LYNXEYE ^TM detector. Together with Cu Kα (40 kV/40 mA) radiation and a variable anti-scatter slit (10 mm observation length) with an increment size of 0.03° 2θ and a 0.04 m Soller slit or relative to the diffraction beam side, such as the BRUKER ^® D8 ^® ADVANCE ^TM system. Generated using a ^{PANALYTICAL ®} Here 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 temperature increase rate of about 15° C./min.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystal form of iodo-phenylamino)-benzamide is characterized by an XRPD pattern with peaks at 10.6 ± 0.2, 13.7 ± 0.2, 19.0 ± 0.2 and 23.7 ± 0.2 degrees 2theta. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The crystal form is 10.6 ± 0.2, 13.7 ± 0.2, 14.6 ± 0.2, 17.3 ± 0.2, 18.0 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.3 ± 0.2, 20.1 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.4 ± 0.2 , 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.1±0.2, 32.3±0.2, 32.9±0.2, 35.8±0.2 and 37.7±0.2 degrees. 2 Characterized by an XRPD pattern with one or more peaks at theta.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is characterized by a DSC profile with an endotherm starting at about 117°C.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is Form I.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is characterized by an XRPD pattern with peaks at 5.5 ± 0.2 and/or 19.6 ± 0.2 degrees 2theta. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Crystal forms are 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 are also characterized by XRPD patterns with peaks at 2 theta.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is characterized by a DSC profile with an endotherm starting at about 87°C.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-) included in the pharmaceutical compositions described herein. The crystalline form of iodo-phenylamino)-benzamide is Form II.

In some aspects, the present disclosure provides N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) -A pharmaceutical composition comprising benzamide (e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets or dispersible pellets) is provided. 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 orally dispersible.

In some aspects, the drinkable liquid is water, milk, or juice (eg, orange juice or apple juice). In some aspects, the drinkable liquid is water. In some aspects, the drinkable liquid is 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 contains a dispersible powder.

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

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

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

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 orally dispersible tablet.

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

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

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

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

In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has about 0.1 wt/wt% to about 7 wt/wt% N-((R)-2 ,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has about 0.1 wt/wt% to about 5 wt/wt% N-((R)-2 ,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, About 0.4wt/wt%, about 0.5wt/wt%, about 0.6wt/wt%, about 0.7wt/wt%, about 0.75wt/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 1.9wt/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 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 4.8wt/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 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 6.8 wt/wt%, about 6.9 wt/wt%, or about 7 wt/wt% N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- Includes fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.5 wt/wt% of N-((R)-2,3-dihydroxy Propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet comprises about 0.8 wt/wt% of N-((R)-2,3-dihydroxy Propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, includes one or more diluents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 50 wt/wt% to about 98 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 75 wt/wt% to about 98 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition includes from about 85 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a weight of about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%. 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 95 wt/wt%, about 96 wt/wt%, about 97 wt/wt%, or about 98 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 90 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 91 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 92 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 93 wt/wt% of one or more diluents.

In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises from about 50 wt/wt% to about 98 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 75 wt/wt% to about 98 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 85 wt/wt% to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition has a weight of about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, About 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 % microcrystalline cellulose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 90 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 91 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 92 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 93 wt/wt% microcrystalline cellulose.

In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 1.0 wt/wt% to about 10 wt/wt% of one or more disintegrants. . In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants. . In some aspects, the pharmaceutical composition comprises about 1.0 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, About 1.6wt/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 3.0 wt/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 4.5wt/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 6.0wt/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%, about 7.0wt/wt%, about 7.1wt/wt%, about 7.2wt/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 8.0 wt/wt%, about 8.1wt/wt%, about 8.2wt/wt%, about 8.3wt/wt%, about 8.4wt/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 9.2wt/wt%, about 9.3wt/wt%, about 9.4wt/ wt%, about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7 wt/wt%, about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% of one or more disintegrants. Includes. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 5 wt/wt% of one or more disintegrants.

In some aspects, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium. In some aspects, the disintegrant is croscarmellose sodium. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 1.0 wt/wt% to about 10 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 3.5 wt/wt% to about 6 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 1.0 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, About 1.6wt/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 3.0 wt/wt%, about 3.1wt/wt%, about 3.2wt/wt%, about 3.3wt/wt%, about 3.4wt/wt%, 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 4.5wt/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 5.9 wt/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 6.6wt /wt%, about 6.7wt/wt%, about 6.8wt/wt%, about 6.9wt/wt%, about 7.0wt/wt%, about 7.1wt/wt%, about 7.2wt/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 8.4wt/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 9.2wt/wt%, about 9.3wt/wt%, about 9.4wt/wt%, and about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7 wt/wt%, about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 5 wt/wt% croscarmellose sodium.

In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/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%, 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%, 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 3.2 wt/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 4.5wt/wt%, about 4.6wt/ wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, includes about 2 wt/wt% of one or more flavoring agents.

In some aspects, at least one of the flavoring agents is grape flavor, bubblegum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, and vanilla flavor. It is selected from the group consisting of natural or synthetic flavors, including, but not limited to, banana flavor or cherry flavor. In some aspects, at least one of the flavoring agents is grape flavor. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 5.0 wt/wt% grape flavor. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 2.5 wt/wt% grape flavor. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/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%, 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%, 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 3.2 wt/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 4.5wt/wt%, about 4.6wt/ wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% of one or more types of grape flavor. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 2 wt/wt% of grape flavor.

In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 5 wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 2 wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/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%, 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%, 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 3.2 wt/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 4.5wt/wt%, about 4.6wt/ wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, includes about 1 wt/wt% of one or more sweeteners.

In some aspects, at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects, at least one of the sweeteners is sucralose. In some aspects, the sweetener is sucralose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 5 wt/wt% sucralose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 2 wt/wt% sucralose. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/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%, 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%, 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 3.2 wt/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 4.5wt/wt%, about 4.6wt/ wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5 wt/wt% sucralose. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 1 wt/wt% sucralose.

In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 5 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 0.1 wt/wt% to about 5 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition has a weight of 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%. wt/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%, 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%, 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 3.5 wt/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 4.5wt/wt%, about 4.6wt/wt%, about 4.7wt/wt%, about 4.8wt/wt%, about 4.9wt/ wt% or about 5 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, includes about 1 wt/wt% of one or more lubricants.

In some aspects, at least one of the lubricants is from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc. is selected from In some aspects, at least one of the lubricants is magnesium stearate. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from 0 wt/wt% to about 5 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises from about 0.1 wt/wt% to about 2 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises about 0.5 wt/wt% to about 2 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet has a 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/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 1.9wt/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 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 3.9 wt/wt%, about 4.0wt/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 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, comprises 0 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition, which is a dispersible tablet, dispersible powder, dispersible granule, dispersible minitablet, or dispersible pellet, contains about 1 wt/wt% magnesium stearate.

Treatment methods and uses

In some aspects, the disclosure provides a method of treating a tumor, cancer, or neurodevelopmental disorder, comprising administering a pharmaceutical composition described herein to a subject in need of such treatment.

In some aspects, the tumor is a neurofibroma. In some aspects, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some aspects, the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, or malignant peripheral nerve sheath tumor. do. In some aspects, the tumor is a plexiform neurofibroma.

In some aspects, the subject has a neurodevelopmental disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facial-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines. Have ever been diagnosed with a disability.

In some aspects, the cancer includes skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, stomach cancer, sarcoma, It is selected from the group consisting of bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid 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 subject has a mutation or other abnormality in one or more genes, wherein the mutation or other abnormality causes gain or loss of a function characteristic of the particular cancer, and the mutation or other abnormality in one or more genes is KRAS, NRAS, A mutation or other abnormality in one or more of HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1 or NF2.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Individual doses may be comprised of more than 1 tablet, more than 1 dose of dispersible powder, more than 1 dose of dispersible granules, more than 1 dose of minitablet, more than 1 dose of pellets, or a combination thereof. is administered. For example, a 3 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) -Benzamide may be administered as two dispersible tablets - one containing 2 mg and the other 1 mg - or as three dispersible tablets containing 1 mg each.

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

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The pharmaceutical composition comprising is administered once, twice, three or four times per day. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The total daily dose is administered twice per day.

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

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) Day 21 with a total daily dose administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. It is administered in 28-day dosing cycles, including 7 non-dosing days. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) 21 consecutive days with a total daily dose administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide It is administered in 28-day dosing cycles, including 7 consecutive days on which no doses are administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) (i) 5 days during which total daily doses are administered and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- three 7-day periods, each including 2 days during which fluoro-4-iodo-phenylamino)-benzamide was not administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. It is administered in 28-day dosing cycles, including 7 non-dosing days. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is (a) (i) 5 consecutive days with a total daily dose administered and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2 -fluoro-4-iodo-phenylamino)-benzamide three 7-day periods each containing 2 days during which no administration was administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide It is administered in 28-day dosing cycles, including 7 consecutive days on which no doses are administered.

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a 28-day dosing cycle with 28 days on which a total daily dose is administered.

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

In some aspects, the subject experiences difficulty swallowing. In some aspects, the subject has dysphagia caused by one or more of a neurological disease, muscle weakness, developmental disorder, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. experience In some aspects, the subject has been diagnosed with autism spectrum disorder. In some aspects, the subject has been diagnosed with a craniofacial disorder. In some aspects, the subject has been diagnosed with myasthenia gravis. In some aspects, the subject has been diagnosed with tardive dyskinesia.

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

In some aspects, the subject is a geriatric subject. In some aspects, the subject is over 30 years of age, over 35 years of age, over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age, over 70 years of age, over 75 years of age, over 80 years of age, Is 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 of age. In some aspects, the subject is over 60 years of age. In some aspects, the subject is over 70 years of age. In some aspects, the subject is over 80 years of age. In some aspects, the subject is over 90 years of age. In some aspects, the subject is over 100 years of age.

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

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

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

In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Administered via the pharmaceutical compositions described herein, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo -phenylamino)-benzamide is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, It is provided in a total daily dose not exceeding 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 6 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 4 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is It is administered in a total daily dose not exceeding 1 mg.

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

Example

Example 1: Preparation of seed crystals of Form IV

Step 1: Preparation of the “side chain”, PD-0337792

14.4 kg of alcohol (chemical purity 99.4%, optical purity 99.6% enantiomeric excess) was converted to 97.5 kg of 9.7% w/w PD-0337792 (IPGA) solution in toluene (overall yield approximately 60%). Triflate activation was carried out in a 200 L reactor by maintaining the temperature at -20°C during the addition of triflate anhydride. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxyphthalimide (NHP) and the reaction was allowed to occur and complete at ambient temperature. A final base deprotection was performed by adding aqueous ammonia (ca. 28% solution, 5 equivalents, 34 kg). After the reaction was completed, water was removed by distillation from toluene, and the resulting solid by-product was filtered to obtain a product solution.

Step 2: Preparation of PD-0315209

The process yielded 21.4 kg (99.4% w/w assay), which consisted of the starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 equiv) and 2-fluoro-4-iodoaniline (16.4 kg). , 1.02 equivalent) and lithium amide base (5 kg, 3.2 equivalent), it is 80% of the theoretical value. The reaction was started by adding 5% of the total solution of TFBA and FIA to the lithium amide slurry at 50°C. This reaction exhibited a minimum onset period of approximately 10 minutes, which was observed as a color change and slight exotherm. The remaining TFBA/FIA solution in THF was added slowly via pressure can over 1 hour while maintaining the reaction temperature within 45-55°C. No appreciable pressure rise (due to ammonia gas evolution) was observed during the entire operation.

Step 3: Preparation of PD-0325901

Modifications to CDI charging were made to mitigate potential gassing. Two equal fractions of CDI were added to solid FIPFA before and after solvent addition (via shot loader). The time between two solid CDI additions (4.6 kg each) should not exceed 30 minutes. The two intermediate filter cakes were then dissolved in ethanol. Prior to PD-0325901 recrystallization, excess ethanol was distilled off and replaced with toluene to approximately 5% v/v ethanol. Laboratory studies have indicated that crystallization from toluene and acetonitrile and recrystallization from ethanol in toluene cannot reduce the impurities essential for polymorph transformation. The presence of dimer impurities (PF-00191189) at levels exceeding 0.2% is known to cause the formation of undesirable polymorphs.

Crude crystallization from the final reaction mixture reduced the dimer impurity PF-00191189 to approximately 1.9%, and subsequent recrystallization further reduced it to approximately 0.4%. As a result, undesirable polymorphs were generated. The DSC pattern showed two different melting points, approximately 80°C (low melting form II) and approximately 117°C (form I). Additionally, during processing the solid crystallized at a much lower temperature than expected (actual about 10°C, expected about 40°C). Unsuccessful recrystallization is suspected to be due to changes in solvent composition due to incomplete drying of the crude material. Drying of the crude wet cake prior to ethanol dissolution was stopped after approximately 36 hours when the crude product weighed approximately 28 kg (theoretical value 26 kg).

Polymorph conversion

Approximately 7.4 kg of PD-0325901 (mixed polymorph) from the final EtOH/water crystallization and material precipitated from the previous EtOH/toluene filtrate were used for polymorph conversion. The two crops were dried on a filter until each reached a constant weight and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC, and the estimated amount was 16.4 kg PD-0325901. EtOH was removed through vacuum distillation, the solvent composition was adjusted to about 5% EtOH in toluene at 65°C, and recrystallization was started (i.e., EtOH was added dropwise at 65°C until the solid was completely dissolved).

To ensure satisfactory results, the mixture was slowly cooled to 5°C for 4 hours and then stirred for 12 hours. The resulting slurry was filtered and completely dried again in the filter until it reached a constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 with undetectable levels of the dimer impurity PF-00191189.

The dried solid (15.4 kg) was redissolved in exactly 4 volumes of EtOH (62 L) on the filter, transferred to the reactor, precipitated by slowly adding water (308 L) at 30 to 35 ° C. (about 3 hours), and heated to 20 ° C. Cooled and stirred for 12 hours. DSC analysis of a slurry sample taken at 2 hours indicates that the solid is fully in Form IV (the desired polymorph).

12.74 kg of PD-0325901 (99.4% black, 100% Form IV; Yield approximately 48%) was produced.

Example 2: Assay/Impurities and Identification of PD-0325901

PD-0325901 is separated from process impurities and degradation products by reverse phase liquid chromatography using UV detection at 275 nm. Identification of PD-0325901 is performed by obtaining infrared or proton NMR spectra in addition to HPLC retention time. For purity assessment, process impurities and degradants are identified by their characteristic relative retention times and quantified by area normalization.

Chromatographic conditions: Agilent Zorbax SB C18, 5 μm, 4.6 x 250 mm (or equivalent); The flow rate is 1.0 mℓ/min; Column temperature is 30°C; The detector wavelength is 275 nm; Diluent is 50/50 acetonitrile/water; Mobile phase A is 0.1% trifluoroacetic acid (TFA) dissolved in water; Mobile phase B is methanol; The gradient conditions are as follows. Calibration determinations are made against reference standards and reported on an anhydrous, solvent-free basis. Quantities of identified and unidentified impurities are reported as area percentage. Total impurities are the sum of all impurities present above the reporting threshold of 0.05%.

Example 3: Improved Process for Preparing Form IV

As described in Example 1, the synthetic method to prepare mirdametinib into Form IV resulted in Form IV with the dimeric impurity PF-00191189, and the product was essentially free of the undesirable polymorphs Form I and Form II. Additional steps were required to convert to pure form IV. Therefore, there was a need to develop a method to prepare essentially pure form IV without additional processing steps.

Mirdametinib manufacturing process

The route involves the proposed starting materials ( S )-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA), 2,3,4-trifluorobenzoic acid (TFBA), 2 It is a convergent four-step synthesis with six chemical steps overall using -fluoro-4-iodoaniline (FIA) and N -hydroxyphthalimide (NHP). The final step (step 4) provides essentially pure form IV of mirdametinib.

Scheme for the preparation of mirdametinib:

Step 1 (Preparation of PD-0337792 (IPGA)): Toluene (139.3 kg, 8 volumes) and (S)-(+)-2,2-dimethyl-1,3-dioxolane in a clean, dry 100 gallon reactor. -4-Methanol (SGA; 20.0 kg, 1.0 equivalent) was charged. Triethylamine (18.8 kg, 1.22 equivalents) was charged into the reactor. The reactor contents were stirred and cooled to -10±10°C. Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was added to a clean 50 L round bottom flask under nitrogen and then cooled to a temperature below -10°C. The cooled trifluoromethanesulfonic anhydride was slowly transferred to the 100 gallon reactor while maintaining the internal temperature at -10 ± 10°C. The reaction mixture was stirred at -10±10 °C for 30 minutes. Monitoring the reaction by TLC indicated that the conversion was complete. While maintaining the internal temperature at -10±10°C, anhydrous toluene (99.8 kg, 5.75 volume) was charged into the reactor, and then N-hydroxyphthalimide (26.4 kg, 1.07 equivalent) was charged into the reactor. The contents were warmed to 20 ± 5°C and stirred at this temperature for at least 5 hours until no triflate intermediate was detected by TLC. The reaction mixture was divided into two equal fractions. 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 volume).

The toluene solution was recombined in the 100 gallon reactor. The organic solution was treated with 28% ammonium hydroxide solution (41.5 kg, 7.8 equivalents). The contents were heated to 35 ± 5°C and stirred for more than 12 hours (not less than) (“NLT”). Once the reaction was complete, the lower aqueous phase was removed. The toluene solution was dried through azeotropic distillation of toluene. The toluene solution was then concentrated to the minimum stirred volume. The concentrated solution was filtered to remove by-product solids. The cake was washed with toluene and the filtrates were combined. Toluene solution assay indicated the presence of 8.6 kg (36.7% yield) of PD-0337792 (IPGA).

Step 2 (Preparation of PD-0315209): A clean, dry 100 gallon reactor was purged with nitrogen and then charged with lithium amide (LiNH2, 8.8 kg, 3.4 equiv) followed by tetrahydrofuran (THF, 56.8 kg, 3.2 vol). did. After cooling the mixture to 10 ± 10°C, additional THF (15.1 kg, 0.85 volume) was charged to the reactor, followed by a solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equiv) in THF ( 26.4 kg, 1.15 volume) was charged. The reaction mixture was heated to "not more than" 50° C. 2-fluoro-4- in THF (17.8 kg, 1 volume), maintaining the batch temperature at 50° C. NMT and stirring for 1 hour between additions. A solution of iodoaniline (FIA, 27.5 kg, 1.02 equiv) was added to the reactor in portions. After addition was completed, the reaction mixture was stirred for an additional 3 hours at 50 ± 10 ° C. Upon completion of reaction, the mixture was heated to 10 ° C. After cooling to NMT, the reaction was stopped with USP purified water (120.3 kg, 6 volumes). The reaction mixture was distilled to about 30 gallons, and then methyl t-butyl ether (MTBE, 118.6 kg, 8 volumes) was added. Then, the MTBE solution was added. The reaction was stopped with 2M hydrochloric acid solution (89.5 kg) at pH = 7. The aqueous phase was then removed. The MTBE solution was filtered through Celite and then 5% brine solution (104.1 kg, 5.2 volume), followed by 1M hydrochloric acid solution. (77.4 kg). The MTBE solution was solvent exchanged with toluene and adjusted to approximately 50 gallons. The mixture was heated to 75 ± 5° C. for 1 hour, then cooled to 20 ± 5° C. and stirred for 1 hour. The product was filtered, washed with toluene (68.1 kg, about 4 volumes), and dried under vacuum at 40°C to obtain 25.2 kg of PD-0315209 (56.4% yield).

Step 3 (Preparation of Crude PD-0325901): A clean, dry 100 gallon reactor was purged with nitrogen and then charged with PD-0315209 (18.0 kg, 1 equiv) and THF (113.0 kg, 7 volumes). The mixture was cooled to 5±5°C. N,N-diisopropylethylamine (15.1 kg, 2.55 equivalents) was charged while maintaining the temperature of NMT at 25°C. The mixture was cooled to 5±5°C and stirred for 10 minutes. A solution of PD-0337792 in toluene (total 121.7 kg, 1.3 equiv) was charged to the reactor at 5 ± 5°C, followed by 50% T3P in ethyl acetate (42.0 kg, 1.45 equiv). The reaction mixture was stirred at 10±5°C for 3 NLT hours. To complete the coupling, N,N-diisopropylethylamine (1.9 kg, 0.3 equiv) and 50% T3P in ethyl acetate (4.1 kg, 0.15 equiv) were additionally charged. The reaction was reversely stopped with 5% sodium hydroxide solution (50 kg) and then washed with 5% brine (55.4 kg). The organic solution was concentrated and then the solvent was exchanged for 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°C until the reaction was complete after 16 hours. After removing the lower aqueous material, the reaction mixture was washed with 5% brine (75.2 kg). The organic phase was concentrated and then the solvent was exchanged with toluene to an appropriate volume. The mixture was then heated to 75 ± 5°C for 30 minutes and then slowly cooled to 20°C. The solid was filtered and washed with toluene (31.1 kg, 1.7 volume).

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

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

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

Example 4: 0.5 mg and 1.0 mg dispersible tablet formulations

Examples of dispersible tablet formulations are presented in Table 1.

Example 5: Method for manufacturing mirdametinib dispersible tablets

Non-limiting examples of exemplary methods for preparing mirdametinib dispersible tablets are described herein.

Microcrystalline cellulose (approximately 30% w/w microcrystalline cellulose in the final composition) is blended in a vessel. Mirdametinib, croscarmellose and microcrystalline cellulose (approximately 50% w/w microcrystalline cellulose in the final composition) are added to the vessel and blended. Add the remaining microcrystalline cellulose to the container and blend. Intragranular magnesium stearate is added for lubrication and the blend is roller compacted into dry granules. Grape flavor and sucralose are blended into granules, and extragranular magnesium stearate is added for lubrication. The blend is compressed and checked for in-process control based on appearance, weight, thickness, hardness, friability and disintegrability. The tablets are dusted, checked for metal impurities, and then bulk packaged.

All publications, patents, and patent applications mentioned herein 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 this application is defined differently in a document incorporated herein by reference, the definition provided herein shall be used as the definition of that term.

Although the invention has been described in relation to specific aspects thereof, the invention is capable of further modifications and the present application generally falls within the known or customary practice within the technical field to which the invention pertains and adheres to the essential features set forth herein above. It will be understood that it is intended to cover any modification, use or adaptation of the principles as may be applied and including such departures from the present disclosure as fall within the scope of the claims.

In addition to the various embodiments described herein, this disclosure includes the following embodiments numbered E1 through E141. This list of embodiments is provided as an illustrative list, and application is not limited to these embodiments.

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

The pharmaceutical composition is dispersible in a drinkable liquid or orally dispersible in the subject's saliva.

E2. In E1, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is a crystalline pharmaceutical composition.

E3. For E2, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide A pharmaceutical composition, the crystalline form of which is selected from the group consisting of:

N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- characterized by an XRPD pattern with peaks at 4.6±0.2, 7.3±0.2 and 14.6±0.2 degrees 2theta. Crystalline form of 2-(2-fluoro-4-iodo-phenylamino)-benzamide;

N-((R)-2,3-dihydroxypropoxy)-3 characterized by an XRPD pattern with peaks at one or more of 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2theta. A crystalline form of 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and

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

E4. For E2 or E3, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- A pharmaceutical composition, wherein the crystalline form of benzamide is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2 and 14.6 ± 0.2 degrees 2theta.

E5. The method of any one of E2 to E4, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl A pharmaceutical composition, wherein the crystalline form of amino)-benzamide is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2, 14.6 ± 0.2 and 25.0 ± 0.2 degrees 2theta.

E6. The method of any one of E2 to E5, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl A pharmaceutical composition, wherein the crystalline form of amino)-benzamide is characterized by an XRPD pattern substantially as shown in Figure 1A.

E7. The method of any one of E2 to E6, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl A pharmaceutical composition, wherein the crystalline form of amino)-benzamide is characterized by one or both of the following:

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

b) DSC profile substantially as shown in Figure 1B.

E8. The method of any one of E2 to E7, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl A pharmaceutical composition, wherein the crystalline form of amino)-benzamide is characterized by a DSC profile that does not include an endotherm starting at about 117°C.

E9. The method of any one of E2 to E8, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl A pharmaceutical composition, wherein the crystalline form of amino)-benzamide does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.

E10. The method of any one of E2 to E9, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The crystalline form of amino)-benzamide is a pharmaceutical form that exhibits substantially unchanged XRPD patterns and/or DSC profiles after storage for 3 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). Composition.

E11. The method of any one of E2 to E10, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The crystalline form of amino)-benzamide is a pharmaceutical product that exhibits substantially unchanged XRPD patterns and/or DSC profiles after storage for 6 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). Composition.

E12. The method of any one of E2 to E11, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The crystalline form of amino)-benzamide is a pharmaceutical form that exhibits substantially unchanged XRPD patterns and/or DSC profiles after storage for one year at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). Composition.

E13. The method of any one of E2 to E12, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The crystalline form of amino)-benzamide is a pharmaceutical form that exhibits substantially unchanged XRPD patterns and/or DSC profiles after storage for 68 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). Composition.

E14. The method of any one of E2 to E13, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The crystalline form of amino)-benzamide exhibits a substantially unchanged XRPD pattern and/or DSC profile after storage for at least 140 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of up to 65%). Academic composition.

E15. The pharmaceutical composition of any of E2 to E14, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature ramp rate of about 15° C./min.

E16. The pharmaceutical composition according to any one of E2 to E15, wherein the crystalline form is anhydrous.

E17. The pharmaceutical composition according to any one of E2 to E16, wherein the crystalline form is Form IV.

E18. For E2 or E3, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- A pharmaceutical composition, wherein the crystalline form of benzamide is characterized by an XRPD pattern with peaks at one or more of 10.6 ± 0.2, 13.7 ± 0.2, 19.0 ± 0.2, and 23.7 ± 0.2 degrees 2theta.

E19. The method of any one of E2, E3 to E18, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo The crystal forms of -phenylamino)-benzamide are 10.6±0.2, 13.7±0.2, 14.6±0.2, 17.3±0.2, 18.0±0.2, 18.2±0.2, 19.0±0.2, 19.3±0.2, 20.1±0.2, 21.0±0.2 , 21.9±0.2, 22.4±0.2, 23.7±0.2, 24.0±0.2, 24.9±0.2, 26.3±0.2, 27.6±0.2, 28.0±0.2, 30.1±0.2, 32.1±0.2, 32.3±0.2, 32.9±0.2, 35.8 A pharmaceutical composition characterized by an XRPD pattern having peaks at one or more of ±0.2 and 37.7±0.2 degrees 2theta.

E20. The pharmaceutical composition according to any one of E2, E3, E18 and E19, wherein the crystalline form is characterized by a DSC profile with an endotherm starting at about 117°C.

E21. The pharmaceutical composition according to any one of E2, E3 and E18 to E20, wherein the crystalline form is Form I.

E22. For E2 or E3, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- A pharmaceutical composition, wherein the crystalline form of benzamide is characterized by an XRPD pattern with peaks at 5.5 ± 0.2 and/or 19.6 ± 0.2 degrees 2theta.

E23. The method of any one of E2, E3 to E22, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo The crystal forms of -phenylamino)-benzamide are 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 2theta.

E24. The method of any one of E2, E3, E22 and E23, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- A pharmaceutical composition, wherein the crystalline form of iodo-phenylamino)-benzamide is characterized by a DSC profile with an endotherm starting at about 87°C.

E25. The pharmaceutical composition according to any one of E2, E3 and E22 to E24, wherein the crystalline form is Form II.

E26. The pharmaceutical composition according to any one of E1 to E25, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

E27. The pharmaceutical composition according to any one of items E1 to E26, wherein the pharmaceutical composition is for oral administration.

E28. The pharmaceutical composition according to any one of E1 to E27, wherein the pharmaceutical composition is orally dispersible.

E29. The pharmaceutical composition according to any one of E1 to E28, wherein the pharmaceutical composition is a capsule, tablet, powder, granule, minitablet or pellet.

E30. The pharmaceutical composition of E29, wherein the pharmaceutical composition is a powder.

E31. The pharmaceutical composition of E30, wherein the powder is a dispersible powder.

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

E33. The pharmaceutical composition of E29, wherein the pharmaceutical composition is in the form of granules.

E34. The pharmaceutical composition of E33, wherein the granules are dispersible granules.

E35. The pharmaceutical composition of E33 or E34, wherein the capsule or sachet comprises granules or dispersible granules.

E36. The pharmaceutical composition of E29, wherein the pharmaceutical composition is in the form of minitablets.

E37. The pharmaceutical composition according to E36, wherein the minitablet is a dispersible minitablet.

E38. The pharmaceutical composition of E36 or E37, wherein the capsule or sachet comprises minitablets or dispersible minitablets.

E39. The pharmaceutical composition of E29, wherein the pharmaceutical composition is in the form of a pellet.

E40. The pharmaceutical composition of item E39, wherein the pellets are dispersible pellets.

E41. The pharmaceutical composition of E39 or E40, wherein the capsule or sachet comprises minitablets or dispersible minitablets.

E42. The pharmaceutical composition of E29, wherein the pharmaceutical composition is a tablet.

E43. The pharmaceutical composition of E42, wherein the pharmaceutical composition is a dispersible tablet.

E44. In any one of E1 to E43,

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

Each component of the pharmaceutical composition is a pharmaceutical composition as follows:

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

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

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

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

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

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

E45. In any one of E1 to E43,

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

Each component of the pharmaceutical composition is a pharmaceutical composition as follows:

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

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

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

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

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

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

E46. The method of E44 or E45, wherein the pharmaceutical composition comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition comprising -iodo-phenylamino)-benzamide.

E47. The method of E44 or E45, wherein the pharmaceutical composition comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition comprising -iodo-phenylamino)-benzamide.

E48. The method of E44 or E45, wherein the pharmaceutical composition comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition comprising -iodo-phenylamino)-benzamide.

E49. The method of E44 or E45, wherein the pharmaceutical composition comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition comprising -iodo-phenylamino)-benzamide.

E50. The method of E44 or E45, wherein the pharmaceutical composition comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition comprising -iodo-phenylamino)-benzamide.

E51. The method of any one of E44 to E50, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate and dibasic calcium phosphate. Selected pharmaceutical composition.

E52. The pharmaceutical composition of E51, wherein at least one of the diluents is microcrystalline cellulose.

E53. The method of any one of E44 to E52, wherein at least one of the disintegrants consists of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose and alginic acid. A pharmaceutical composition selected from the group.

E54. The pharmaceutical composition of E53, wherein at least one of the disintegrants is croscarmellose sodium.

E55. The method of any one of E44 to E54, wherein the flavoring agent is grape flavor, bubble gum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, and peach flavor. , a pharmaceutical composition selected from the group consisting of natural or synthetic flavors, including, but not limited to, vanilla flavor, banana flavor, or cherry flavor.

E56. The pharmaceutical composition of E55, wherein at least one of the flavoring agents is grape flavor.

E57. The pharmaceutical composition according to any one of E44 to E56, wherein at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose and aspartame.

E58. The pharmaceutical composition of E57, wherein at least one of the sweeteners is sucralose.

E59. The method of any one of E44 to E58, wherein at least one of the lubricants is magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated A pharmaceutical composition selected from the group consisting of vegetable oils and talc.

E60. The pharmaceutical composition of E59, wherein at least one of the lubricants is magnesium stearate.

E61. The pharmaceutical composition according to any one of E1 to E60, wherein the drinkable liquid is water, milk or juice.

E62. The pharmaceutical composition of any one of E1 to E60, wherein the pharmaceutical composition is dispersible in saliva of the subject.

E63. 1. A method of treating a tumor, cancer, or neurodevelopmental disorder, comprising administering to a subject in need of such treatment the pharmaceutical composition of any of E1 to E62.

E64. The method of E63, wherein the tumor is a neurofibroma.

E65. The method of E64, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1.

E66. The method of any one of E63 to E65, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, and malignant peripheral nerve temporal layer tumor.

E67. The method of E66, wherein the tumor is a plexiform neurofibroma.

E68. In E67, the subject has a neuropathy selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facial-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines. Have ever been diagnosed with a developmental disability, how.

E69. In E63, the cancer is skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, stomach cancer, and sarcoma. , a method selected from the group consisting of bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.

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

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

E72. The method of E69, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

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

E74. The method of any one of E63 to E73, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Individual doses of amino)-benzamide may include more than 1 tablet, more than 1 dose of dispersible powder, more than 1 dose of dispersible granules, more than 1 dose of minitablet, more than 1 dose of dispersible powder. Administered as a pellet or combination thereof.

E75. The method of any one of E63 to E74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered for (a) 21 days with a total daily dose administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Administered in a 28-day dosing cycle including 7 non-dosing days.

E76. The method of any one of E63 to E74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered (a) for 21 consecutive days with a total daily dose administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days on which no dosing is administered.

E77. The method of any one of E63 to E74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered (a) for (i) 5 days for a total daily dose administered and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro -3 7-day periods, each including 2 days during which no -2-(2-fluoro-4-iodo-phenylamino)-benzamide was administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Administered in a 28-day dosing cycle including 7 non-dosing days.

E78. The method of any one of E63 to E74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered (a) for (i) 5 consecutive days, with a total daily dose administered, and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoride. three 7-day periods, each containing 2 days during which no rho-2-(2-fluoro-4-iodo-phenylamino)-benzamide was administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days on which no dosing is administered.

E79. The method of any one of E63 to E74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a 28-day dosing cycle comprising 28 days during which a total daily dose is administered.

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

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

E82. For E81, the subject has dysphagia caused by one or more of a neurological disease, muscle weakness, developmental disorder, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. How to experience.

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

E84. The method according to any one of E63 to E83, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Method, wherein the total daily dose of amino)-benzamide is administered twice daily.

E85. The method of E84, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The total daily dose is administered twice a day in a dose of about 0.1 mg to about 10 mg each.

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

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

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

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

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

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

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

E93. The method according to any one of E63 to E83, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The method wherein the total daily dose of amino)-benzamide is administered once daily.

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

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

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

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

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

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

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

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

E102. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 20 mg.

E103. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 10 mg.

E104. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 8 mg.

E105. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 6 mg.

E106. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 4 mg.

E107. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 2 mg.

E108. The method of any one of E63 to E101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 1 mg.

E109. Use of the pharmaceutical composition of any of E1 to E62 for the manufacture of a medicament for the treatment of tumors, cancer or neurodevelopmental disorders.

E110. The use of E109, wherein the tumor is a neurofibroma.

E111. The use of E110, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1.

E112. The method of any of E109 to E111, wherein the tumor is cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, or malignant peripheral nerve sheath tumor. Use selected from the group consisting of.

E113. The use of E112, wherein the tumor is a plexiform neurofibroma.

E114. In E109, the subject has neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan Have been diagnosed with a neurodevelopmental disorder selected from the group consisting of Noonan syndrome and Noonan syndrome with multiple lentigines.

E115. In E109, the cancer is skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, stomach cancer, and sarcoma. Use selected from the group consisting of bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer and serous carcinoma of the peritoneum.

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

E117. The method of 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. , Usage.

E118. The use of E115, 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.

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

E120. The method according to any one of E109 to E119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Individual doses of amino)-benzamide may include more than 1 tablet, more than 1 dose of dispersible powder, more than 1 dose of dispersible granules, more than 1 dose of minitablet, more than 1 dose of dispersible powder. Use, administered as pellets or combinations thereof.

E121. The method according to any one of E109 to E119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered for (a) 21 days with a total daily dose administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Used in a 28-day dosing cycle including 7 non-dosing days.

E122. The method according to any one of E109 to E119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered for (a) 21 consecutive days with a total daily dose; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days without administration.

E123. The method according to any one of E109 to E119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered (a) for (i) 5 days for a total daily dose administered and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro -3 7-day periods, each including 2 days during which no -2-(2-fluoro-4-iodo-phenylamino)-benzamide was administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Used in a 28-day dosing cycle including 7 non-dosing days.

E124. The method according to any one of E109 to E119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered (a) for (i) 5 consecutive days, with a total daily dose administered, and (ii) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoride. three 7-day periods, each containing 2 days during which no rho-2-(2-fluoro-4-iodo-phenylamino)-benzamide was administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days without administration.

E125. The method according to any one of E109 to E119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a 28-day dosing cycle comprising 28 days during which a total daily dose is administered.

E126. The use of E124 or E125, wherein the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.

E127. The use according to any one of E109 to E126, wherein the subject experiences dysphagia.

E128. For E127, the subject has dysphagia caused by one or more of a neurological disease, muscle weakness, developmental disorder, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. To experience, use.

E129. Use according to any one of E109 to E128, wherein the subject is a pediatric subject.

E130. The method according to any one of E109 to E129, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The total daily dose of amino)-benzamide is administered twice daily.

E131. The method of E130, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The total daily dose is administered twice a day in a dose of about 0.1 mg to about 10 mg each.

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

E133. The method of E131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The total daily dose is administered twice a day in a dose of about 0.5 mg each.

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

E135. The method of E131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The total daily dose is administered twice a day at a dose of about 2 mg each.

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

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

E138. The method of E131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The total daily dose is administered twice a day at a dose of about 10 mg each.

E139. The method according to any one of E109 to E129, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl The total daily dose of amino)-benzamide is administered once daily.

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

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

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

E143. The method of E140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide The total daily dose is administered in a dose of about 2 mg once a day.

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

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

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

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

E148. The method according to any one of E109 to E147, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 20 mg.

E149. The method according to any one of E109 to E148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 10 mg.

E150. The method according to any one of E109 to E148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 8 mg.

E151. The method according to any one of E109 to E148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 6 mg.

E152. The method according to any one of E109 to E148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide is administered in a total daily dose not exceeding 4 mg.

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

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

Claims (154)

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

The pharmaceutical composition is dispersible in a drinkable liquid or orodispersible in the saliva of the subject. The method of claim 1, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- A pharmaceutical composition, wherein the benzamide is in crystalline form. The method of claim 2, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- A pharmaceutical composition, wherein the crystalline form of benzamide is selected from the group consisting of:
a) N-((R)-2,3-dihydroxypropoxy)-3,4-difluorine characterized by an XRPD pattern with peaks at 4.6±0.2, 7.3±0.2 and 14.6±0.2 degrees 2theta. Crystalline form of rho-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b) N-((R)-2,3-dihydroxypropoxy) characterized by an XRPD pattern with peaks at one or more of 10.6±0.2, 13.7±0.2, 19.0±0.2 and 23.7±0.2 degrees 2theta. Crystalline form of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and
c) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro, characterized by an XRPD pattern with peaks at at least one of 5.5 ± 0.2 and 19.6 ± 0.2 degrees 2theta. Crystalline form of -2-(2-fluoro-4-iodo-phenylamino)-benzamide. The method of claim 2 or 3, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A pharmaceutical composition, wherein the crystalline form of phenylamino)-benzamide is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2 and 14.6 ± 0.2 degrees 2theta. The method according to any one of claims 2 to 4, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition, wherein the crystalline form of -iodo-phenylamino)-benzamide is characterized by an XRPD pattern with peaks at 4.6 ± 0.2, 7.3 ± 0.2, 14.6 ± 0.2 and 25.0 ± 0.2 degrees 2theta. The method of any one of claims 2 to 5, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition, wherein the crystalline form of -iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in Figure 1A. The method of any one of claims 2 to 6, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition, wherein the crystalline form of -iodo-phenylamino)-benzamide is characterized by one or both of the following:
a) TGA profile substantially as shown in Figure 1B; and/or
b) DSC profile substantially as shown in Figure 1B. The method of any one of claims 2 to 7, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition, wherein the crystalline form of -iodo-phenylamino)-benzamide is characterized by a DSC profile that does not include an endotherm, starting at about 117°C. The method of any one of claims 2 to 8, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A pharmaceutical composition, wherein the crystalline form of -iodo-phenylamino)-benzamide does not contain any detectable amount of Form I or Form II by XRPD and/or DSC. The method of any one of claims 2 to 9, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The crystalline form of -iodo-phenylamino)-benzamide has an XRPD pattern and/or DSC profile that remains substantially unchanged after storage for 3 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of not more than 65%). A pharmaceutical composition representing. The method of any one of claims 2 to 10, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The crystalline form of -iodo-phenylamino)-benzamide has an XRPD pattern and/or DSC profile that remains substantially unchanged after storage for 6 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of not more than 65%). A pharmaceutical composition representing. The method of any one of claims 2 to 11, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The crystalline form of -iodo-phenylamino)-benzamide has an XRPD pattern and/or DSC profile that remains substantially unchanged after storage for one year under standard warehouse conditions (15° C. to 25° C. and relative humidity of not more than 65%). A pharmaceutical composition representing. The method of any one of claims 2 to 12, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The crystalline form of -iodo-phenylamino)-benzamide has an XRPD pattern and/or DSC profile that remains substantially unchanged after storage for 68 months at standard warehouse conditions (15° C. to 25° C. and relative humidity of not more than 65%). A pharmaceutical composition representing. The method of any one of claims 2 to 13, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The crystalline form of -iodo-phenylamino)-benzamide shows an XRPD pattern and/or DSC that is substantially unchanged after storage for at least 140 months at standard warehouse conditions (15°C to 25°C and relative humidity of less than 65%). A pharmaceutical composition exhibiting a profile. 15. The pharmaceutical composition of any one of claims 2 to 14, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature increase rate of about 15° C./min. 16. The pharmaceutical composition according to any one of claims 2 to 15, wherein the crystalline form is anhydrous. 17. The pharmaceutical composition according to any one of claims 2 to 16, wherein the crystalline form is Form IV. The method of claim 2 or 3, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A pharmaceutical composition, wherein the crystalline form of phenylamino)-benzamide is characterized by an XRPD pattern with peaks at one or more of 10.6 ± 0.2, 13.7 ± 0.2, 19.0 ± 0.2 and 23.7 ± 0.2 degrees 2theta. The method of any one of claims 2, 3 and 18, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- The crystalline forms of fluoro-4-iodo-phenylamino)-benzamide are 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, 3 2.3± A pharmaceutical composition characterized by an XRPD pattern having peaks at one or more of 0.2, 32.9 ± 0.2, 35.8 ± 0.2 and 37.7 ± 0.2 degrees 2theta. 20. The pharmaceutical composition according to any one of claims 2, 3, 18 or 19, wherein the crystalline form is characterized by a DSC profile with an endotherm starting at about 117°C. 21. The pharmaceutical composition according to any one of claims 2, 3 and 18-20, wherein the crystalline form is Form I. The method of claim 2 or 3, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A pharmaceutical composition, wherein the crystalline form of phenylamino)-benzamide is characterized by an XRPD pattern with peaks at 5.5 ± 0.2 and/or 19.6 ± 0.2 degrees 2theta. The method according to any one of claims 2, 3 to 22, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- The crystalline forms of fluoro-4-iodo-phenylamino)-benzamide are 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, Characterized by an XRPD pattern with peaks at one or more of 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 2theta. Composition. The method of any one of claims 2, 3, 22 and 23, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2 A pharmaceutical composition, wherein the crystalline form of -(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC profile with an endotherm starting at about 87°C. 25. The pharmaceutical composition according to any one of claims 2, 3 and 22-24, wherein the crystalline form is Form II. 26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers. 27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the pharmaceutical composition is for oral administration. 28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the pharmaceutical composition is orally dispersible. 29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the pharmaceutical composition is a capsule, tablet, powder, granule, minitablet or pellet. 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 according to claim 30 or 31, wherein the capsule or sachet comprises a powder or a dispersible powder. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in granule form. 34. The pharmaceutical composition according to claim 33, wherein the granules are dispersible granules. 35. The pharmaceutical composition according to claim 33 or 34, wherein the capsule or sachet comprises granules or dispersible granules. 30. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition is in the form of minitablets. 37. The pharmaceutical composition according to claim 36, wherein the minitablet is a dispersible minitablet. 38. The pharmaceutical composition according to claim 36 or 37, wherein the capsule or sachet comprises minitablets or dispersible minitablets. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in pellet form. 40. The pharmaceutical composition of claim 39, wherein the pellets are dispersible pellets. 41. The pharmaceutical composition according to claim 39 or 40, wherein the capsule or sachet comprises minitablets or dispersible minitablets. 30. 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. According to any one of claims 1 to 43,
From about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) -Including benzamide;
Each component of the pharmaceutical composition is a pharmaceutical composition as follows:
a. From about 0.1 wt/wt% to about 7 wt/wt% N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-io do-phenylamino)-benzamide;
b. From about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. About 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. From about 0 wt/wt% to about 5 wt/wt% of one or more lubricants. According to any one of claims 1 to 43,
From about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) -Including benzamide;
Each component of the pharmaceutical composition is a pharmaceutical composition as follows:
a. From about 0.5 wt/wt% to about 1.2 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide;
b. About 85 wt/wt% to about 95 wt/wt% of one or more diluents;
c. About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and
f. About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants. 46. The method of claim 44 or 45, wherein the pharmaceutical composition comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- A pharmaceutical composition comprising fluoro-4-iodo-phenylamino)-benzamide. 46. The method of claim 44 or 45, wherein the pharmaceutical composition comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- A pharmaceutical composition comprising fluoro-4-iodo-phenylamino)-benzamide. 46. The method of claim 44 or 45, wherein the pharmaceutical composition comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- A pharmaceutical composition comprising fluoro-4-iodo-phenylamino)-benzamide. 46. The method of claim 44 or 45, wherein the pharmaceutical composition comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- A pharmaceutical composition comprising fluoro-4-iodo-phenylamino)-benzamide. 46. The method of claim 44 or 45, wherein the pharmaceutical composition comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- A pharmaceutical composition comprising fluoro-4-iodo-phenylamino)-benzamide. 51. The method of any one of claims 44 to 50, wherein at least one of the diluents is microcrystalline cellulose, lactose, mannitol, starch, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate and dibasic phosphoric acid. A pharmaceutical composition selected from the group consisting of calcium. 52. The pharmaceutical composition of claim 51, wherein at least one of the diluents is microcrystalline cellulose. 53. The method of any one of claims 44 to 52, wherein at least one of the disintegrants is croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl A pharmaceutical composition selected from the group consisting of cellulose and alginic acid. 54. The pharmaceutical composition of claim 53, wherein at least one of the disintegrants is croscarmellose sodium. The method of any one of claims 44 to 54, wherein at least one of the flavoring agents is grape flavor, bubble gum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, and grapefruit flavor. A pharmaceutical composition selected from the group consisting of natural or synthetic flavors, including, but not limited to, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor. 56. The pharmaceutical composition of claim 55, wherein at least one of the flavoring agents is grape flavor. 57. The method of any one of claims 44 to 56, wherein at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose and aspartame. Pharmaceutical composition. 58. The pharmaceutical composition of claim 57, wherein at least one of the sweeteners is sucralose. 59. The method of any one of claims 44 to 58, wherein at least one of the lubricants is magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, calcium stearate, zinc stearate, beeswax, colloid. A pharmaceutical composition selected from the group consisting of 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 according to any one of claims 1 to 60, wherein the drinkable liquid is water, milk or juice. 61. The pharmaceutical composition according to any one of claims 1 to 60, wherein the pharmaceutical composition is dispersible in the subject's saliva. A method of treating a tumor, cancer, or neurodevelopmental (Rasopathy) disorder, comprising administering the pharmaceutical composition of any one of claims 1 to 62 to a subject in need of such treatment. 64. The method of claim 63, wherein the tumor is a neurofibroma. 65. The method of claim 64, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1. 66. The method of any one of claims 63 to 65, wherein the tumor is cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, or malignant peripheral nerve temporal layer tumor. peripheral nerve sheath tumor), method. 67. The method of claim 66, wherein the tumor is a plexiform neurofibroma. 68. The method of claim 67, wherein the subject has neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome. , who has been diagnosed with a neurodevelopmental disorder selected from the group consisting of Noonan syndrome and Noonan syndrome with multiple lentigines. The method of claim 63, wherein the cancer is skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, and stomach cancer. , sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum, method. 70. The method of claim 69, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. 70. The method of claim 69, wherein the lymphoma is 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. Chosen method. 70. The method of claim 69, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer. 73. The method of any one of claims 63 to 72, wherein the subject has a mutation or other abnormality in one or more genes, wherein the mutation or other abnormality causes gain or loss of a function characteristic of a particular cancer, and The method wherein the mutation or other abnormality in one or more of the genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2. 74. The method of any one of claims 63 to 73, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 Individual doses of -iodo-phenylamino)-benzamide may be comprised of more than 1 tablet, more than 1 dose of dispersible powder, more than 1 dose of dispersible granules, more than 1 dose of minitablet, 1 A method, wherein more than one dose is administered as pellets or a combination thereof. 75. The method of any one of claims 63 to 74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered for (a) 21 days with a total daily dose administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Administered in a 28-day dosing cycle including 7 non-dosing days. 75. The method of any one of claims 63 to 74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered (a) for 21 consecutive days with a total daily dose; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days on which no dosing is administered. 75. The method of any one of claims 63 to 74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -Iodo-phenylamino)-benzamide is administered on (a) (i) 5 days for a total daily dose and (ii) N-((R)-2,3-dihydroxypropoxy)-3, Three 7-day periods, each including 2 days during which 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Administered in a 28-day dosing cycle including 7 non-dosing days. 75. The method of any one of claims 63 to 74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -Iodo-phenylamino)-benzamide is administered on (a) (i) 5 consecutive days for a total daily dose and (ii) N-((R)-2,3-dihydroxypropoxy)-3 , three 7-day periods each containing 2 days during which 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days on which no dosing is administered. 75. The method of any one of claims 63 to 74, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising 28 days on which the total daily dose is administered. The method of any one of claims 78 or 79, wherein the 28-day dosing cycle is repeated for 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 is suffering from one or more of the following: neurological disease, muscle weakness, developmental disorder, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. How to experience dysphagia. 81. 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 to 83, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The total daily dose of -iodo-phenylamino)-benzamide is administered twice a day. 85. The method of claim 84, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method of claim 1, wherein the total daily dose of benzamide is administered in a dose of about 0.1 mg to about 10 mg twice daily. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The total daily dose of benzamide is administered at a dose of about 0.25 mg twice daily. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered at a dose of about 0.5 mg twice a day each. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method according to claim 1, wherein the total daily dose of benzamide is administered at a dose of about 1 mg each twice a day. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method according to claim 1, wherein the total daily dose of benzamide is administered at a dose of about 2 mg twice daily. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method according to claim 1, wherein the total daily dose of benzamide is administered at a dose of about 4 mg twice daily. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method according to claim 1, wherein the total daily dose of benzamide is administered at a dose of about 5 mg twice daily. 86. The method of claim 85, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The total daily dose of benzamide is administered at a dose of about 10 mg twice a day each. 84. The method of any one of claims 63 to 83, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 A method wherein the total daily dose of -iodo-phenylamino)-benzamide is administered once a day. 93. The method of claim 93, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method of claim 1, wherein the total daily dose of benzamide is administered in a dose of about 0.1 mg to about 20 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method of claim 1, wherein the total daily dose of benzamide is administered in a dose of about 0.5 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered in a dose of about 1 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered in a dose of about 2 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered in a dose of about 4 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered in a dose of about 8 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered in a dose of about 10 mg once daily. 95. The method of claim 94, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- The method wherein the total daily dose of benzamide is administered in a dose of about 20 mg once daily. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg. 102. The method of any one of claims 63 to 101, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg. Use of the pharmaceutical composition of any one of claims 1 to 62 for the manufacture of a medicament for the treatment of tumors, cancer or neurodevelopmental disorders. 109. The use of claim 109, wherein the tumor is a neurofibroma. 111. The use of claim 110, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1. 112. The method of any one of claims 109-111, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma, or malignant peripheral nerve temporal layer tumor. , Usage. 113. The use of claim 112, wherein the tumor is a plexiform neurofibroma. 109. The method of claim 109, wherein the subject is from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facial-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines. For those who have been diagnosed with selected neurodevelopmental disorders. The method of claim 109, wherein the cancer is skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, and stomach cancer. , sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum, Usage. 116. The use of claim 115, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myelogenous leukemia. 115. The method of claim 115, wherein the lymphoma is 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. Selected use. 116. The use of claim 115, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer. 119. The method of any one of claims 09 to 118, wherein the subject has a mutation or other abnormality in one or more genes, wherein the mutation or other abnormality causes gain or loss of a function characteristic of a particular cancer, and The use wherein the mutation or other abnormality in one or more of the genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1 or NF2. 120. The method of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 Individual doses of -iodo-phenylamino)-benzamide may be comprised of more than 1 tablet, more than 1 dose of dispersible powder, more than 1 dose of dispersible granules, more than 1 dose of minitablet, 1 Use, administered as pellets or combinations thereof in greater than a dose. 120. The method of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered for (a) 21 days with a total daily dose administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Used in a 28-day dosing cycle including 7 non-dosing days. 120. The method of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered (a) for 21 consecutive days with a total daily dose; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days without administration. 120. The method of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -Iodo-phenylamino)-benzamide is administered on (a) (i) 5 days for a total daily dose and (ii) N-((R)-2,3-dihydroxypropoxy)-3, Three 7-day periods, each including 2 days during which 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered; and (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Used in a 28-day dosing cycle including 7 non-dosing days. 120. The method of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -Iodo-phenylamino)-benzamide is administered on (a) (i) 5 consecutive days for a total daily dose and (ii) N-((R)-2,3-dihydroxypropoxy)-3 , three 7-day periods each containing 2 days during which 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered; Then (b) N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Administered in a 28-day dosing cycle comprising 7 consecutive days without administration. 120. The method of any one of claims 109 to 119, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising 28 days on which the total daily dose is administered. 126. Use according to claim 124 or 125, wherein the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles. 127. Use according to any one of claims 109 to 126, wherein the subject experiences dysphagia. 128. The method of claim 127, wherein the subject is suffering from one or more of the following: neurological disease, muscle weakness, developmental disorder, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. For those experiencing difficulty swallowing. 128. The use of any one of claims 109-128, wherein the subject is a pediatric subject. 129. The method of any one of claims 109 to 129, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The total daily dose of -iodo-phenylamino)-benzamide is administered twice a day. 131. The method of claim 130, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 0.1 mg to about 10 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 0.25 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 0.5 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 1 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 2 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 4 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 5 mg twice a day each. 132. The method of claim 131, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered at a dose of about 10 mg twice a day each. 129. The method of any one of claims 109 to 129, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 The total daily dose of -iodo-phenylamino)-benzamide is administered once a day. 139. The method of claim 139, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 0.1 mg to about 20 mg once daily. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 0.5 mg once a day. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 1 mg once a day. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 2 mg once a day. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 4 mg once daily. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 8 mg once a day. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 10 mg once a day. 141. The method of claim 140, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Use wherein the total daily dose of benzamide is administered in a dose of about 20 mg once a day. 148. The method of any one of claims 109 to 147, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg. 149. The method of any one of claims 109 to 148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg. 149. The method of any one of claims 109 to 148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg. 149. The method of any one of claims 109 to 148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg. The method of any one of claims 1109 to 148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg. 149. The method of any one of claims 109 to 148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg. 149. The method of any one of claims 109 to 148, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 -iodo-phenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.