Composition of the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and its uses

Abstract

The present disclosure relates to a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an essentially pure form IV; b) a pharmaceutical composition comprising the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an essentially pure form IV and optionally a pharmaceutically acceptable carrier; and c) a method for treating a tumor, cancer, or RAS disorder by administering the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an essentially pure form IV to a subject in need thereof.

Description

Technology Field

[0001] The present disclosure relates to a) a crystalline composition in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is in which form IV is essentially pure; b) a pharmaceutical composition comprising the crystalline composition in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is in which form IV is essentially pure, and optionally, a pharmaceutically acceptable carrier; and c) a method for treating a tumor, cancer, or RAS disorder by administering the crystalline composition in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is in which form IV is essentially pure to a subject in need thereof. Background Technology

[0002] N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide ("mirdametinib" or "PD-0325901") is a small molecule drug designed to inhibit mitogen-activated protein kinase 1 ("MEK1") and mitogen-activated protein kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that play a major role 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 highly potent and specific allosteric non-ATP competitive inhibitor of MEK1 and MEK2. Due to its mechanism of action, mirdametinib significantly inhibits the phosphorylation of the extracellularly regulated MAP kinases ERK1 and ERK2, leading to impaired growth of tumor cells in vitro and in vivo. Additionally, there is evidence that increased MEK / ERK activity induced by inflammatory cytokines contributes to inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

[0003] The crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide have been previously described. WO2002 / 006213 describes crystalline forms I and II. U.S. Patent No. 7,060,856 ("'856 Patent") describes a method for preparing form IV. The '856 Patent indicates that the material prepared by this method was more than 90% form IV ('856 Patent, Example 1). The '856 Patent also shows that differential scanning calorimetry ("DSC") of the prepared material shows melting initiation at 110°C as well as a small peak initiation at 117°C, which is consistent with the material being a mixture of the two forms.

[0004] WO 2006 / 134469 ("'469 PCT Publication") also describes a method for synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. '469 PCT Publication reports that it yields a product consistent with polymorphic form IV disclosed in U.S. Patent Application No. 10 / 969,681, registered as a patent in '856.

[0005] Compositions containing more than one polymorphic form are generally undesirable because there is a possibility that one polymorphic form may interconvert to another. Polymorphic interconversion can result in differences in effective dose or physical properties that affect the processability of the drug due to differences in solubility or bioavailability. Therefore, a composition containing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in essentially pure form IV is required for use in the treatment of tumors, cancer, or RAS disorders. Brief explanation of the drawing

[0006] Figure 1a is the X-ray powder diffraction pattern ("XRPD") corresponding to the essentially pure crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Figure 1b shows the thermal gravitational analysis ("TGA") and differential scanning calorimetry ("DSC") corresponding to the essentially pure crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. FIG. 2 is an XRPD corresponding to a batch of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as initially manufactured, and an XRPD of a known reference standard of form IV. Figure 3a is an XRPD corresponding to the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after storage for 68 months after preparation at 25°C and 65% relative humidity. Figure 3b is the XRPD corresponding to the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after storage for 140 months after preparation at 25°C and 65% relative humidity. Specific details for implementing the invention

[0007] The present disclosure features a useful composition and method for treating disorders involving abnormal MEK1 or MEK2 activity in subjects requiring treatment, such as cancer, tumors, or RAS disorders like neurofibromatosis type 1.

[0008] In some aspects, the present disclosure relates to a crystalline composition of the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of the following formula (I):

[0009] Chemical formula (I)

[0010] .

[0011] In some aspects, the crystalline composition of essentially pure N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide does not contain any amount of type I or type II detectable by XRPD and / or DSC.

[0012] In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 3 months under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 6 months under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 1 year under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 5 years under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for 68 months under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for ≥140 months under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after storage for ≥14 years under standard warehouse conditions (15°C–25°C and ≤65% relative humidity).

[0013] In some aspects, the XRPD pattern is composed of (a) a variable divergence slit (irradiation length 10 mm), a 0.04 rad Soller slit, a fixed anti-scattering slit (0.50°), and a 10 mm beam mask on the incident beam side, and (b) a variable anti-scattering slit (observation length 10 mm) and a 0.04 rad Soller slit on the diffracted beam side, a PANALYTICAL® X'Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV / 40 mA) radiation and a step size of 0.03° 2θ accompanied by an X'CELERATOR® Real Time Multi-Strip detector, or (a) a Goebel mirror, a mirror exit slit (0.2 mm), a 2.5° Soller slit, and a beam knife on the incident beam side, and (b) an anti-scattering slit (8 mm) and a 2.5° Soller slit on the diffracted beam side, It was generated using a BRUKER® D8® ADVANCE™ system with Cu Kα (40 kV / 40 mA) radiation accompanied by a LYNXEYETM detector and a step size of 0.03° 2θ; where 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.

[0014] In some aspects, the crystalline composition contains ≤ 0.2% of dimeric impurity PF-00191189:

[0015] .

[0016] In some aspects, the crystalline composition contains about 0.05 weight% to about 0.19 weight% of dimeric impurity PF-00191189. In some aspects, the crystalline composition does not contain a detectable amount of dimeric impurity PF-00191189.

[0017] In some aspects, the present disclosure provides a pharmaceutical composition comprising the crystalline composition described herein and a pharmaceutically acceptable carrier. In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is in the form of a solid dosage. In some aspects, the pharmaceutical composition is a tablet or a capsule. In some aspects, the pharmaceutical composition is a tablet.

[0018] In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; (d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and a gelatin capsule encapsulating component ad. In some aspects, the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; (d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and (e) a gelatin capsule encapsulating component ad. In some aspects, the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt / wt% to about 7.(b) a crystalline composition of 0 wt / wt% N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; and (d) a gelatin capsule encapsulating component ac.

[0019] In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose.

[0020] In some aspects, at least one of the disintegrants is selected from the group consisting of sodium croscarmellose, sodium starch glycolate, crospovidone, and alginate. In some aspects, at least one of the disintegrants is sodium croscarmellose.

[0021] In some aspects, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate.

[0022] In some aspects, the present disclosure provides a method for treating cancer, tumor, or RAS disorder, comprising administering the pharmaceutical composition described herein to a subject in need of treatment.

[0023] 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 schwann tumor. In some aspects, the tumor is a plexiform neurofibroma.

[0024] In some aspects, the subject was diagnosed with a RAS disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, heart-face-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigo.

[0025] In some aspects, cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum. In some aspects, leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia. In some aspects, lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, 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.

[0026] In some aspects, the subject has a mutation or other abnormality in one or more genes that causes the acquisition or loss of a characteristic function of a specific cancer, wherein the mutation or other abnormality in one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0027] In some aspects, individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as more than one capsule or tablet.

[0028] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 6 mg.

[0029] In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 0.1 mg to about 20 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 2 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 4 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 6 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 8 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as about 20 mg.

[0030] In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg, respectively. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 1 mg, respectively. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 2 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 3 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 4 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 10 mg each.

[0031] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days in which a total daily dose is administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 consecutive days in which a total daily dose is administered; Subsequently (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered.

[0032] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which a total 1-day dose is administered and (ii) 2 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which a total 1-day dose is administered and (ii) 2 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0033] In some aspects, the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.

[0034] In some aspects, the present disclosure provides the use of the pharmaceutical composition described herein for the manufacture of a drug for treating tumors, cancer, or RAS disorders.

[0035] Method for preparing a pharmaceutical composition

[0036] In some aspects, the present disclosure provides a method for preparing a pharmaceutical composition comprising forming the pharmaceutical composition described herein.

[0037] definition

[0038] To facilitate understanding of the disclosures presented herein, a number of terms are defined below.

[0039] In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the relevant technical field. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as generally understood by a person skilled in the art to which this disclosure pertains.

[0040] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the context clearly indicates otherwise. The terms “a” (or “an”), as well as “one or more” and “at least one,” may be used interchangeably herein. In a particular aspect, the term “a” or “an” means “single.” In another aspect, the term “a” or “an” includes “two or more” or “multiple.”

[0041] Furthermore, as used herein, "and / or" shall be construed as the explicit disclosure of each of two specific features or components, with or without the other. Accordingly, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A alone," and "B alone." Likewise, the term "and / or" as used in phrases such as "A, B and / or C" is intended to encompass, respectively, the following aspects: A, B and C; A, B or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0042] 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.

[0043] The term “subject” refers to an animal including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein with respect to mammalian subjects, such as human subjects, for example.

[0044] As used herein, the terms “to treat,” “being treated,” and “treating” refer to both therapeutic treatment and prophylactic or preventive measures aimed at preventing or slowing (alleviating) an undesirable physiological condition, disorder, or disease, or at obtaining a favorable or desired clinical outcome. Accordingly, those requiring treatment include those who have already been diagnosed with a disorder or are suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, the alleviation of symptoms; a reduction in the severity of the condition, disorder, or disease; a stabilized (i.e., not worsening) state of the condition, disorder, or disease; a delay or slowing of the onset of the condition, disorder, or disease progression; improvement or remission (partial or total) of the condition, disorder, or disease state, whether detectable; improvement of at least one measurable physical parameter, although not necessarily identifiable by the patient; or improvement or remission of the condition, disorder, or disease. Treatment involves inducing a clinically significant response without excessive levels of adverse effects. Treatment also includes extended survival compared to the survival expected without treatment. The term "therapeutic effective dose" means containing an amount of a compound sufficient to prevent or alleviate to some extent the occurrence of one or more symptoms of the disorder, disease, or condition being treated upon administration. The term "therapeutic effective dose" also refers to an 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.

[0045] In certain aspects, if a patient demonstrates one or more of the following, the subject is considered to have been successfully “treated” for the tumor according to the methods described herein: reduction in tumor size; relief of one or more symptoms associated with the specific tumor; reduction in tumor volume; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in disease progression (PD), increased time to progression (TTP), or any combination thereof. In some aspects, nationally or internationally accepted standards of treatment outcomes for a given tumor may be used to determine whether an effective dose of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0046] In certain aspects, if a patient demonstrates one or more of the following, the subject is successfully “treated” for cancer, e.g., lung cancer or ovarian cancer, according to the methods described herein: a reduction in the number of cancer cells or the complete absence of cancer cells; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduced disease progression (PD), increased time to progression (TTP), or any combination thereof. In some aspects, nationally or internationally accepted standards of treatment outcomes for a given cancer may be used to determine whether an effective dose of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0047] The terms “pharmaceuticalally acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable substances, compositions, or vehicles, such as liquid or solid excipients, solvents, or encapsulating materials. In one aspect, each component is “pharmaceutically acceptable” in the sense of compatibility with other components of a pharmaceutical formulation and is suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, corresponding to a reasonable benefit-risk ratio. Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; See also 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 may include, for example, anti-adhesion agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colors), softeners, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavors, fragrances, lubricants (flow enhancers), lubricants, preservatives, printing inks, absorbents, suspending agents or dispersing agents, sweeteners and water for hydration.Exemplary excipients include butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pre-gelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc. It includes, but is not limited to, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0048] As used herein, the term “pharmaceutical composition” refers to a composition containing the compound described herein formulated with pharmaceutically acceptable excipients, which may be manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of diseases in mammals. The pharmaceutical composition may be formulated for oral administration, for example, in a unit dosage form (e.g., tablet, capsule, coated tablet, gel cap, or syrup).

[0049] The term “approximately” or “roughly” means within an acceptable margin of error for a specific value determined by a person skilled in the relevant technical field, depending in part on the way the value is measured or determined. In some respects, the term “approximately” or “roughly” means within 1, 2, 3, or 4 standard deviations. In some respects, the term “approximately” or “roughly” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0050] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation containing the compound described herein) to a subject or system. Administration to animal subjects (e.g., humans) may be by any suitable route, such as as described herein.

[0051] As used herein, the term “crystalline” refers to a solid form consisting of a regular arrangement of structural units. Different crystalline forms of the same compound, or its salts, hydrates, or solvates, arise from different packing of solid molecules, which results in different crystal symmetries and / or unit cell parameters. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, PA, 173 (1990); The United States Pharmacopeia, 23rd ed., 1843–1844 (1995) (incorporated herein by reference).

[0052] Crystal morphology is generally characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflection (peaks, typically expressed as 2-theta degrees) is commonly considered the fingerprint of a specific crystal morphology. The relative intensity of XRPD peaks can vary significantly, particularly depending on 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 specific peak in the XRPD pattern may appear as a single, double, triple, quadruplet, or multiplet depending on the instrument type or settings, instrument sensitivity, measurement conditions, and / or the purity of the crystal morphology. In some cases, any specific peak in the XRPD may appear as a symmetrical shape or, for example, an asymmetrical shape with a shoulder. Additionally, instrument changes and other factors can affect the 2-theta values. A skilled technician who understands these variations can distinguish or identify features or properties that define the intrinsic meaning of a specific crystal morphology by using XRPD as well as other known physicochemical techniques.

[0053] The term "anhydride," applied to compounds, refers to a crystalline form in which the compound does not contain structural water within its crystal lattice.

[0054] As used herein, the term “essentially pure” for Form IV means that a composition containing Form IV does not contain detectable amounts of another polymorphic form (e.g., Form I or Form II), as determined by observing that there is no detectable difference in XRPD and / or DSC patterns between a single Form IV crystal and a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. However, the “essentially pure” Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide may contain, without limitation, impurities such as synthetic reactants or byproducts generated during chemical synthesis.

[0055] As used herein, the term “abnormality” applied to a gene refers to a mutation, chromosomal loss or fusion, epigenetic chemical modification, or other event that alters a sequence, expression level, or processed mRNA sequence associated with a wild-type gene relative to a sequence, expression level, or processed mRNA sequence.

[0056] For any aspect described herein with the term “comprising,” it is understood that other similar aspects described with the terms “constituted” and / or “essentially constituted” are also provided.

[0057] Details of one or more aspects are set forth in the details below. Other features, purposes, and benefits will become apparent from the details and claims.

[0058] Specific details of the invention

[0059] A method for treating a patient requiring a treatment comprising an essentially pure form IV, a composition that is essentially pure form IV, and administration of essentially pure form IV is described herein.

[0060] Crystalline composition

[0061] The present disclosure relates to an essentially pure crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. As with all pharmaceutical compounds and compositions, the chemical and physical properties of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are important for its commercial development. These properties include (1) packing properties such as molar volume, bulk density, and hygroscopicity; (2) thermodynamic properties such as melting temperature, vapor pressure, and solubility; (3) dissolution rate and stability (e.g., stability under ambient conditions, particularly moisture and storage conditions); (4) surface properties such as surface area, wettability, interfacial tension, and shape; and (5) mechanical properties such as hardness, tensile strength, compressibility, handling properties, flow, and blendability; and (6) filtration properties, but are not limited thereto. These properties may affect, for example, the processing and storage of compounds and pharmaceutical compositions containing compounds.

[0062] A crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide that improves one or more of these properties compared to other crystalline forms of the compound is preferred. Isolating a pharmaceutically acceptable crystalline form of a compound that can be manufactured and formulated on a commercial scale may be a challenge.

[0063] In some aspects, the present disclosure relates to an essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of the following formula (I):

[0064] Chemical formula (I)

[0065] .

[0066] In some aspects, the crystalline composition is stable, as evidenced by XRPD patterns and / or DSC profiles that remain substantially unchanged over time. In some aspects, the crystalline composition exhibits XRPD patterns and / or DSC profiles that remain substantially unchanged after storage under standard warehouse conditions (15°C–25°C and ≤65% relative humidity) for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 140 months, 12 years, 13 years, 14 years, or 15 years. In some aspects, the crystalline composition exhibits XRPD patterns and / or DSC profiles that remain substantially unchanged after storage for 3 months under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after 6 months of storage under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after 1 year of storage under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after 5 years of storage under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after 68 months of storage under standard warehouse conditions (15°C–25°C and ≤65% relative humidity). In some aspects, the crystalline composition exhibits XRPD patterns and / or DSC profiles that remain substantially unchanged after storage for ≥140 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).In some aspects, the crystalline composition exhibits XRPD patterns and / or DSC profiles that remain substantially unchanged after storage for ≥14 years under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).

[0067] In some aspects, the XRPD pattern is composed of (a) a variable divergence slit (irradiation length 10 mm), a 0.04 rad Soller slit, a fixed anti-scattering slit (0.50°), and a 10 mm beam mask on the incident beam side; and (b) generated using a PANALYTICAL® X'Pert Pro diffractometer using Ni-filtered Cu Kα (45kV / 40mA) radiation and a step size of 0.03° 2θ accompanied by an X'CELERATOR® Real Time Multi-Strip detector consisting of a variable anti-scattering slit (observation length 10mm) and a 0.04 rad Soller slit on the diffracted beam side, or using a BRUKER® D8® ADVANCE™ system using Cu Kα (40kV / 40mA) radiation and a step size of 0.03° 2θ accompanied by a LYNXEYETM detector consisting of a Goebel mirror, a mirror exit slit (0.2mm), a 2.5° Soller slit, and a beam knife on the incident beam side, and (b) an anti-scattering slit (8mm) and a 2.5° Soller slit on the diffracted beam side; Here, the sample is mounted flat on a zero-background Si wafer. In some aspects, a DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature increase rate of about 15°C / min.

[0068] In some aspects, the crystalline composition contains ≤ 0.2% of dimeric impurity PF-00191189:

[0069] .

[0070] In some aspects, the crystalline composition contains about 0.05 wt% to about 0.19 wt% of dimeric impurity PF-00191189. In some aspects, the crystalline composition contains about 0.05 wt% to about 0.15 wt% of dimeric impurity PF-00191189. In some aspects, the crystalline composition contains about 0.05 wt% to about 0.10 wt% of dimeric impurity PF-00191189. In some aspects, the crystalline composition does not contain a detectable amount of dimeric impurity PF-00191189.

[0071] In some aspects, the amount of the dimeric impurity PF-00191189 is determined using high-performance liquid chromatography ("HPLC"). In some aspects, reverse-phase liquid chromatography using a UV detector at 275 nm is used.

[0072] In some aspects, the crystalline composition exhibits a DSC profile that does not have an endothermic event initiated at about 117°C.

[0073] Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide features an XRPD pattern as substantially illustrated in FIG. 1a, a TGA profile as substantially illustrated in FIG. 1b; and / or a DSC profile as substantially illustrated in FIG. 1b.

[0074] Pharmaceutical composition

[0075] In some aspects, the present disclosure provides a pharmaceutical composition comprising the crystalline composition described herein and a pharmaceutically acceptable carrier. In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is a tablet or a capsule. In some aspects, the pharmaceutical composition is a tablet. In some aspects, the pharmaceutical composition is a capsule.

[0076] In some aspects, the pharmaceutical composition comprises a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.1 mg to about 10 mg. In some aspects, the pharmaceutical composition comprises a crystalline composition 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 comprises about 2 mg of a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 3 mg of a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 4 mg of a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 5 mg of a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0077] In some aspects, the pharmaceutical composition comprises a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein in an amount of about 0.25 wt / wt% to about 7 wt / wt%. In some aspects, the pharmaceutical composition comprises about 0.25 wt / wt%, about 0.3 wt / wt%, about 0.4 wt / wt%, about 0.5 wt / wt%, about 0.6 wt / wt%, about 0.7 wt / wt%, about 0.8 wt / wt%, about 0.9 wt / wt%, about 1 wt / wt%, about 1.1 wt / wt%, about 1.2 wt / wt%, about 1.3 wt / wt%, about 1.4 wt / wt%, about 1.5 wt / wt%, about 1.6 wt / wt%, about 1.7 wt / wt%, about 1.8 wt / wt%, about 1.9 wt / wt%, about 2 wt / wt%, about 2.1 wt / wt%, about 2.2 wt / wt%, approx. 2.3 wt / wt%, approx. 2.4 wt / wt%, approx. 2.5 wt / wt%, approx. 2.6 wt / wt%, approx. 2.7 wt / wt%, approx. 2.8 wt / wt%, approx. 2.9 wt / wt%, approx. 3 wt / wt%, approx. 3.1 wt / wt%, approx. 3.2 wt / wt%, approx. 3.3 wt / wt%, approx. 3.4 wt / wt%, approx. 3.5 wt / wt%, approx. 3.6 wt / wt%, approx. 3.7 wt / wt%, approx. 3.8 wt / wt%, approx. 3.9 wt / wt%, approx. 4 wt / wt%, approx. 4.1 wt / wt%, approx. 4.2 wt / wt%, approx. 4.3 wt / wt%, approx. 4.4 wt / wt%, approx. 4.5 wt / wt%, approx. 4.6 wt / wt%, approx. 4.7 wt / wt%, approx. 4.8 wt / wt%, approx. 4.9 wt / wt%, approx. 5 wt / wt%, approx. 5.1 wt / wt%, approx. 5.2 wt / wt%, approx. 5.3 wt / wt%, approx. 5.4 wt / wt%, approx. 5.5 wt / wt%, approx. 5.6 wt / wt%, approx. 5.7 wt / wt%, approx. 5.8 wt / wt%, approx. 5.9 wt / wt%, approx. 6 wt / wt%, approx. 6.1 wt / wt%, approx. 6.2 wt / wt%, approx. 6.It comprises a crystalline composition of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein in an amount of 3 wt / wt%, about 6.4 wt / wt%, about 6.5 wt / wt%, about 6.6 wt / wt%, about 6.7 wt / wt%, about 6.8 wt / wt%, about 6.9 wt / wt%, or about 7 wt / wt%. In some aspects, the pharmaceutical composition comprises about 0.5 wt / wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein. In some aspects, the pharmaceutical composition comprises about 0.8 wt / wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein.

[0078] In some aspects, the pharmaceutical composition comprises one or more diluents. In some aspects, the pharmaceutical composition comprises one or more diluents in an amount of about 70 wt / wt% to about 95 wt / wt%. In some aspects, the pharmaceutical composition comprises one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%. In some aspects, the pharmaceutical composition comprises about 70 wt / wt%, about 71 wt / wt%, about 72 wt / wt%, about 73 wt / wt%, about 74 wt / wt%, about 75 wt / wt%, about 76 wt / wt%, about 77 wt / wt%, about 78 wt / wt%, about 79 wt / wt%, about 80 wt / wt%, about 81 wt / wt%, about 82 wt / wt%, about 83 wt / wt%, about 84 wt / wt%, about 85 wt / wt%, about 86 wt / wt%, about 87 wt / wt%, about 88 wt / wt%, about 89 wt / wt%, about 90 wt / wt%, about 91 It comprises one or more diluents of wt / wt%, about 92 wt / wt%, about 93 wt / wt%, about 94 wt / wt%, or about 95 wt / wt%. In some aspects, the pharmaceutical composition comprises one or more diluents of about 90 wt / wt%. In some aspects, the pharmaceutical composition comprises one or more diluents of about 93 wt / wt%.

[0079] In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose. In some aspects, the diluent is microcrystalline cellulose.

[0080] In some aspects, the pharmaceutical composition comprises about 70 wt / wt% to about 95 wt / wt% of microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 85 wt / wt% to about 95 wt / wt% of microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 70 wt / wt%, about 71 wt / wt%, about 72 wt / wt%, about 73 wt / wt%, about 74 wt / wt%, about 75 wt / wt%, about 76 wt / wt%, about 77 wt / wt%, about 78 wt / wt%, about 79 wt / wt%, about 80 wt / wt%, about 81 wt / wt%, about 82 wt / wt%, about 83 wt / wt%, about 84 wt / wt%, about 85 wt / wt%, about 86 wt / wt%, about 87 wt / wt%, about 88 wt / wt%, about 89 wt / wt%, about 90 wt / wt%, about 91 It contains wt / wt%, about 92 wt / wt%, about 93 wt / wt%, about 94 wt / wt%, or about 95 wt / wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition contains about 90 wt / wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition contains about 93 wt / wt% microcrystalline cellulose.

[0081] In some aspects, the pharmaceutical composition comprises one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%. In some aspects, the pharmaceutical composition comprises about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, about 5 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt / wt%, about It comprises one or more disintegrants in an amount of 5.5 wt / wt%, about 5.6 wt / wt%, about 5.7 wt / wt%, about 5.8 wt / wt%, about 5.9 wt / wt%, or about 6.0 wt / wt%. In some aspects, the pharmaceutical composition comprises one or more disintegrants in an amount of about 5 wt / wt%.

[0082] In some aspects, at least one of the disintegrants is selected from the group consisting of sodium croscarmellose, sodium starch glycolate, crospovidone, and alginate. In some aspects, at least one of the disintegrants is sodium croscarmellose. In some aspects, the disintegrant is sodium croscarmellose. In some aspects, the pharmaceutical composition comprises about 3.5 wt / wt% to about 6 wt / wt% sodium croscarmellose. In some aspects, the pharmaceutical composition comprises about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, about 5 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt / wt%, about It contains 5.5 wt / wt%, about 5.6 wt / wt%, about 5.7 wt / wt%, about 5.8 wt / wt%, about 5.9 wt / wt%, or about 6.0 wt / wt% croscarmellose sodium. In some aspects, the pharmaceutical composition contains about 5 wt / wt% croscarmellose sodium.

[0083] In some aspects, the pharmaceutical composition comprises one or more lubricants in an amount of 0 wt / wt% to about 2 wt / wt%. In some aspects, the pharmaceutical composition is 0 wt / wt%, about 0.1 wt / wt%, about 0.2 wt / wt%, about 0.3 wt / wt%, about 0.4 wt / wt%, about 0.5 wt / wt%, about 0.6 wt / wt%, about 0.7 wt / wt%, about 0.8 wt / wt%, about 0.9 wt / wt%, about 1 wt / wt%, about 1.1 wt / wt%, about 1.2 wt / wt%, about 1.3 wt / wt%, about 1.4 wt / wt%, about 1.5 wt / wt%, about 1.6 wt / wt%, about 1.7 wt / wt%, about 1.8 wt / wt%, about 1.9 wt / wt%, or about 2 It comprises one or more lubricants in wt / wt%. In some aspects, the pharmaceutical composition comprises one or more lubricants in about 1 wt / wt%.

[0084] In some aspects, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate. In some aspects, the lubricant is magnesium stearate. In some aspects, the pharmaceutical composition is 0 wt / wt%, about 0.1 wt / wt%, about 0.2 wt / wt%, about 0.3 wt / wt%, about 0.4 wt / wt%, about 0.5 wt / wt%, about 0.6 wt / wt%, about 0.7 wt / wt%, about 0.8 wt / wt%, about 0.9 wt / wt%, about 1 wt / wt%, about 1.1 wt / wt%, about 1.2 wt / wt%, about 1.3 wt / wt%, about 1.4 wt / wt%, about 1.5 wt / wt%, about 1.6 wt / wt%, about 1.7 wt / wt%, about 1.8 wt / wt%, about 1.9 wt / wt%, or about 2 It contains wt / wt% magnesium stearate. In some aspects, the pharmaceutical composition contains 0 wt / wt% magnesium stearate. In some aspects, the pharmaceutical composition contains about 1 wt / wt% magnesium stearate.

[0085] In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; (d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and (e) a gelatin capsule encapsulating components (a)-(d).

[0086] In some aspects, the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; (d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and (e) a gelatin capsule encapsulating ingredients (a)-(d).

[0087] In some aspects, the capsule comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; (d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and (e) a gelatin capsule encapsulating ingredients (a)-(d).

[0088] In some aspects, the capsule comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; (d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and (e) a gelatin capsule encapsulating ingredients (a)-(d).

[0089] In some aspects, the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 2.5 wt / wt% to about 7.0 wt / wt%; (b) one or more diluents in an amount of about 85 wt / wt% to about 95 wt / wt%; (c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; and (d) a gelatin capsule encapsulating component ac.

[0090] Treatment methods

[0091] In some aspects, the present disclosure provides a method for treating a tumor, cancer, or RAS disorder, comprising administering a pharmaceutical composition described herein to a subject requiring such treatment.

[0092] 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 schwann tumor. In some aspects, the tumor is a plexiform neurofibroma.

[0093] In some aspects, the subject was diagnosed with a RAS disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, heart-face-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigo.

[0094] In some aspects, cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histoplastic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum. In some aspects, leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia. In some aspects, lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, 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.

[0095] In some aspects, the subject has a mutation or other abnormality in one or more genes that causes the acquisition or loss of a characteristic function of a specific cancer, wherein the mutation or other abnormality among one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0096] In some aspects, individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as more than one capsule or tablet. For example, a dose of 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide may be administered as two capsules—one containing 2 mg and the other containing 1 mg—or as three capsules, each containing 1 mg.

[0097] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of 0.1 mg to about 20 mg per dose of the pharmaceutical compositions described herein. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in amounts of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is available in an amount of about 1 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is available in an amount of about 2 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is available in an amount of about 3 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is available in an amount of about 4 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is available in an amount of about 10 mg per dose.

[0098] In some aspects, a pharmaceutical composition comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once, twice, three times, or four times daily. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

[0099] In some aspects, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide needs to be administered more than once a day, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide may be divided so that the patient receives the same dose at each administration. For example, if the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide needs to be 4 mg administered twice a day, the patient may receive 2 mg in the morning (e.g., as two 1 mg capsules) and 2 mg in the evening (e.g., as one 2 mg capsule).

[0100] In some aspects, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide needs to be administered more than once a day, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide may be divided so that the patient receives different doses at each administration. For example, if the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is to be 4 mg administered twice daily, the patient may be administered 1 mg in the morning (e.g., as one 1 mg capsule) and 3 mg in the evening (e.g., as one 1 mg capsule and one 2 mg capsule).

[0101] In some aspects, the present disclosure provides a method for treating a tumor, cancer, or RAS disorder, comprising administering a pharmaceutical composition described herein to a patient requiring such treatment, wherein a total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily in amounts of about 0.1 mg to about 10 mg each.

[0102] In some aspects, a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered via the pharmaceutical composition described herein, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in a total daily dose not exceeding 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 15 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 12 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 6 mg.In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 1 mg.

[0103] In some aspects, the present disclosure provides a method for treating a tumor, cancer, or RAS disorder, comprising administering a pharmaceutical composition described herein to a patient requiring such treatment, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily in a dose of about 0.1 mg to about 20 mg.

[0104] In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 3 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 5 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 7 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 9 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 10 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 11 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 12 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 13 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 14 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 15 mg.In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 16 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 17 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 18 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 19 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.

[0105] In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg, respectively. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 0.25 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 0.5 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 1 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 2 mg each.In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 3 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 4 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 5 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 6 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 7 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 8 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 9 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 10 mg each.

[0106] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days in which a total daily dose is administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 consecutive days in which a total daily dose is administered; Subsequently (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered.

[0107] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which a total 1-day dose is administered and (ii) 2 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which a total 1-day dose is administered and (ii) 2 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0108] In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle including 28 days in which a total of 1 daily dose is administered.

[0109] In some aspects, the 28-day dosing cycle is repeated for up to a total of 24 consecutive 28-day dosing cycles.

[0110] In some aspects, the present disclosure provides the use of the pharmaceutical composition described herein for the manufacture of a drug for treating cancer, tumors, or RAS disorders.

[0111] Examples

[0112]

[0113] Example 1: Preparation of Essentially Pure Form IV

[0114] Laboratory-scale production of essentially pure form IV

[0115] 2 kg PD-0325901 was prepared using the following synthesis scheme, starting with commercially available 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-iodoaniline (FIA), and chiral S-glycerol acetonide (SGA) and assembling them together.

[0116]

[0117] Step 1: Manufacture of "side chain", PD-0337792

[0118] All reactions were carried out in toluene except as otherwise noted. Triflic acid anhydride provided the best yield.

[0119]

[0120] Recognizing that triflate provides the highest yield, we investigated the possibility of eliminating the cryogenic conditions, which were likely established due to stability issues with the "methanesulfonate" intermediate. The following experiments suggest that there was no significant yield loss in experiments conducted at -20°C.

[0121]

[0122] The data presented above suggest that no adverse effects were observed after prolonged stirring of the "trifluoromethanesulfonate" intermediate prior to the addition of N-hydroxyphthalimide. Back addition of the intermediate mixture to solid NHP appears to provide the highest yield.

[0123] An additional advantage of using triflate was the easy removal of Et3N triflate salt byproducts by simply washing with water. As a result, high-purity N-hydroxyphthalimide-protected alcohol, IPGAP (PD-0333760), was produced in toluene, which can be isolated as crystals or transferred to a final deprotection reaction.

[0124] Both aqueous and anhydrous ammonia bases were investigated as deprotectants. The results were successful for both. When anhydrous ammonia was used, the phthalimide byproduct was simply filtered from the solution of the product (PD-0337792) in toluene. Similarly, when aqueous ammonia (28% solution) was used, it was filtered from the solution after performing azeotropic removal from toluene. However, anhydrous ammonia requires the reaction to be carried out in a high-pressure closed system. Experiments performed with ammonia gas spray provided acceptable yields; however, these required large volumes and the use of cryogenic condensers (to prevent gas from escaping from the reactor headspace).

[0125]

[0126] Step 2: Fluoride Replacement

[0127] Investigation of the reaction in an automated reactor revealed that the reaction is essentially capacity-controlled after the initiation period. Increasing the amount of lithium amide and the stirring speed appears to shorten the induction time. Adding water appears to extend the induction time. However, it is not certain whether this is due to the formation of lithium hydroxide.

[0128] The induction time increased when 0.1 equivalent of H2O was added. However, the trend was reversed when 0.1 equivalent of lithium hydroxide was added. The induction time decreased with increasing lithium amide equivalent and stirring.

[0129] Step 3: Amidation Coupling and Deprotection

[0130]

[0131] Acid hydrolysis (including aqueous HCl) following the CDI-assisted coupling of PD-0315209 acid and side-chain reagents has consistently yielded good results in the laboratory. The focus of development for this step was to ensure that impurity levels remained within specification limits. Known impurities in the final isolated diol products are excess PD-0315209 acid, dimeric impurities, and chiral impurities. Chiral impurities are controlled by limiting the R-enantiomer in the starting s-glycerol acetonide. Elevated levels of dimeric impurities (d) are known to cause difficulties in the polymorph conversion step. Dimeric impurities are initially formed by the reaction of imidazole (CDI-activated acid) in the presence of excess acid PD-0315209 to form dimers (a) and possibly (b), which then undergo subsequent IPGA coupling and acid hydrolysis steps to form dimers (c) and (d), respectively. Impurity d is designated as PF-00191189.

[0132]

[0133] The reaction can be easily carried out in the laboratory by charging both the solid, FIPFA, and CDI, and then charging a solvent (acetonitrile), or by charging solid CDI into a slurry of FIPFA in acetonitrile. Neither solid is initially dissolved in acetonitrile. The acid activation reaction is rapid (almost instantaneous), forming a highly soluble imidazolid product, which transforms the slurry into a clear, homogeneous solution while CO2 gas emission occurs.

[0134] Laboratory experiments generally resulted in impurity levels of less than 3%, which could be completely removed by subsequent recrystallization from a 3–5% ethanol-toluene system. Additional recrystallization was performed in a few cases where impurity levels exceeded 0.3%. Table 4 shows selected results from laboratory experiments regarding the amount of impurity removed in subsequent recrystallization and the observed elevated levels of impurities. Unpurified PD-0325901 was obtained using an acetonitrile / toluene system, and the purified product was recrystallized from a 5% ethanol / toluene system. Items 4 and 5 required the use of additional solvents to remove impurities, and Item 5 required two recrystallizations to achieve an "ND" level in polymorph conversion. A crystallization volume of 8–10 ml / g of unpurified material was selected to limit product loss while maintaining a filterable slurry and ensuring impurity removal.

[0135]

[0136] A scale-up procedure was developed to provide acceptable levels of impurities prior to polymorph transition (<0.3%) without excessive product loss during recrystallization, while considering the solid CDI addition rate. Rapid addition is desirable for minimizing impurity formation; however, addition must be performed at a rate that allows the emitted CO2 to be safely vented.

[0137] Half of the solid CDI was initially added to the PD-0325901 acid, and then the solvent was added. The remaining CDI was added through a hopper within 30 minutes so that the impurity level was less than 3%.

[0138] Polymorphic transformation

[0139] The three polymorph forms of PD-0325901 are characterized below. Form I has the highest melting point (approx. 117°C) and is enantiotropically related to Form IV (melting point 112°C), which is a more stable form below an estimated transition temperature of 73°C. Form II is a low-melting point form (melting point approx. 85°C).

[0140]

[0141] Most polymorph conversion experiments were performed using high-purity PD-0325901 containing various forms, which generally exhibited low melting points below 80°C as a result of efficient EtOH / toluene recrystallization following the isolation of crude crystals directly from the reaction mixture. These various polymorphs were completely dissolved in EtOH and then precipitated by adding water (20 volumes) at 20-25°C for a period of 15-60 minutes. Analysis of the solids sampled after stirring for less than 2 hours showed complete polymorph conversion to form IV. The only failure occurred when water was added almost immediately and all at once to the solution of PD-0325901 in EtOH (4 volumes). In this case, the undesirable polymorph form I was exclusively obtained.

[0142] One anomaly was observed in the standard procedure. One lot produced mixed polymorphs, but the level of impurities after recrystallization was not detectable. The corrective procedure for this case involves converting all low-melting-point forms (form II) to form I at a temperature close to or above 73°C, and then slowly cooling to 20°C (over a period of about 4 hours).

[0143] The EtOH / water system produces efficient polymorph conversion. Recrystallized (purified) PD-0325901, initially consisting of amphoteric polymorphs of form I (melting point approx. 117°C) and form IV (melting point approx. 112°C), was completely converted to form IV.

[0144] Manufacturing of a pilot plant of essentially pure form IV

[0145] Step 1: Manufacture of "side chain", PD-0337792

[0146] 14.4 kg of alcohol (99.4% chemical purity, 99.6% optical purity, excess enantiomer) was converted into a 9.7% w / w PD-0337792 (IPGA) solution in 97.5 kg of toluene (total yield approximately 60%). Triflate activation was performed in a 200 L reactor by maintaining the temperature below -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 allowed to complete the reaction at ambient temperature. Final base deprotection was performed by adding aqueous ammonia (approx. 28% solution, 5 equivalents, 34 kg). After the reaction was complete, water was removed from the toluene by distillation, and the resulting solid byproduct was filtered to yield a product solution.

[0147] Step 2: Manufacture of PD-0315209

[0148] This process yielded 21.4 kg (99.4% w / w calibration), which is theoretically 80%, from the starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 equivalent) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 equivalents) along with a lithium amide base (5 kg, 3.2 equivalents). The reaction was initiated by adding 5% of the total TFBA and FIA solution to the lithium amide slurry at 50°C. The reaction was proven to have a minimum initiation period of approximately 10 minutes, which was observed through a color change and slight exothermic reaction. After 1 hour, the TFBA / FIA solution in the remaining THF was slowly added via a pressure can while maintaining the reaction temperature within 45-55°C. No perceptible pressure rise (due to ammonia gas release) was observed throughout the entire operation.

[0149] Step 3: Manufacture of PD-0325901

[0150] Modifications were made to the CDI loading to mitigate potential gas generation. Two equal amounts of CDI were added to solid FIPFA before and after solvent addition (via a shot loader). The timing between the addition of the two solid CDIs (4.6 kg each) should not exceed 30 minutes. Then, two intermediate filter cakes were dissolved in ethanol. The excess ethanol was distilled and replaced with toluene so that the ethanol content was approximately 5% v / v prior to PD-0325901 recrystallization. Laboratory studies suggested that crystallization from toluene and acetonitrile, and recrystallization from ethanol in toluene, could not reduce impurities essential for polymorph conversion. The presence of dimeric impurities (PF-00191189) at levels exceeding 0.2% is known to result in the formation of undesirable polymorphs.

[0151]

[0152] Crystallization of the crude from the final reaction mixture reduced the dimeric impurity PF-00191189 to approximately 1.9%, and subsequent recrystallization further reduced it to approximately 0.4%. Consequently, unwanted polymorphs were formed. The DSC pattern exhibited two distinct 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 (actually about 10°C, expected about 40°C). The failed recrystallization is suspected to be due to changes in solvent composition resulting from the incomplete drying of the crude. Drying of the crude wet cake prior to ethanol dissolution was stopped after approximately 36 hours, when the crude product amounted to about 28 kg (theoretically 26 kg).

[0153] Polymorphic transformation

[0154] Approximately 7.4 kg of PD-0325901 (mixed polymorph) from the final EtOH / water crystallization and the material precipitated from the initial EtOH / toluene filtrate were subjected to polymorph conversion. Both harvests were individually dried in filters to a constant weight and dissolved in EtOH. The combined EtOH solution was analyzed by HPLC, yielding an estimated amount of approximately 16.4 kg of PD-0325901. EtOH was removed via vacuum distillation, and recrystallization was initiated after adjusting the solvent composition to approximately 5% EtOH in toluene at 65°C (i.e., EtOH was added dropwise at 65°C until the solid was completely dissolved).

[0155] To ensure satisfactory results, the mixture was slowly cooled to 5°C for 4 hours, followed by stirring for 12 hours. The resulting slurry was filtered and completely dried on a filter to a constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901, at a level where the dimeric impurity PF-00191189 was undetectable.

[0156] The dried solid (15.4 kg) was redissolved from the filter in exactly 4 volumes of EtOH (62 L), transferred to a reactor, precipitated by slow (about 3 hours) water addition (308 L) at 30-35°C, cooled to 20°C, and stirred for 12 hours. DSC analysis of the slurry sample taken at the 2nd hour showed that the solid was completely in form IV (desired polymorph).

[0157] 91 kg of solution of 9.7% PD-0337792 in 21.4 kg PD-0315209, 9.7 kg CDI (1.05 equivalents), and toluene (1.1 equivalents) was used, resulting in 12.74 kg of PD-0325901 (test 99.4%, 100% form IV, yield about 48%).

[0158] Example 2: Testing / Impurity and Identification of PD-0325901

[0159] PD-0325901 is separated from process impurities and decomposition products by reverse-phase liquid chromatography with UV detection at 275 nm. Identification of PD-0325901 is performed by obtaining infrared or proton NMR spectra in addition to HPLC retention times. For purity evaluation, process impurities and decomposition products are identified by their characteristic relative retention times and quantified by area normalization.

[0160] Chromatography conditions: Agilent Zorbax SB C18, 5 μm, 4.6 x 250 mm (or equivalent); flow rate: 1.0 mL / min; column temperature: 30°C; detector wavelength: 275 nm; diluent: 50 / 50 acetonitrile / water; mobile phase A: 0.1% trifluoroacetic acid (TFA) in water; mobile phase B: methanol; gradient conditions are as follows. Calibrations are determined against reference standards and reported on an anhydrous, solvent-free basis. Quantification of specific and unspecific impurities is reported as area percentage. Total impurities are the sum of all impurities present above a reporting threshold of 0.05%.

[0161] Example 3: Single-crystal X-ray diffraction analysis of Type IV

[0162] A suitable single crystal of type IV was prepared by a method involving a coupling agent different from that used in the method disclosed in Example 1. However, this crystal yielded a type IV having the same XRPD characteristics as the type IV prepared by the method of Example 1, and thus had a purity suitable for type IV analysis.

[0163] A single form IV crystal was analyzed using a Bruker D8 Venture Photon II CPAD diffractometer equipped with a CuKα INCOATEC Imus micro-focus source (λ = 1.54178 Å). The simulated PXRD pattern was calculated from the low-temperature (100 K) structure and room-temperature (298 K, 25 °C) unit cell parameters presented below. The unit cell at room temperature was initially determined by the difference vector method based on 235 reflections harvested from 151 1° diffraction frames. The unit cell parameters were subsequently refined during data integration by Saint (Bruker (2020). SAINT. Data Reduction Software) and are based on 903 reflections recorded between 19.1 and 1.1 Å resolutions. The simulated pattern matched the experimental form IV pattern shown in Fig. 1a.

[0164]

[0165]

[0166] Example 4: Capsule Formulation

[0167]

[0168] Example 5: Shape IV Stability

[0169] The stability of the Type IV material was determined by comparing the batch's XRPD spectrum with a reference standard XRPD spectrum. This analysis was performed at the time of batch emission, and the obtained XRPD spectrum corresponded to the spectrum of the reference standard for Type IV (Fig. 2). The Type IV batch was then stored at 25°C and 65% relative humidity. XRPD analysis of the stored Type IV was performed at 68 months (Fig. 3a) and again at 140 months (Fig. 3b). Undetectable changes in the XRPD spectrum over time indicated the stability of Type IV at 25°C and ≤65% relative humidity.

[0170] All publications, patents, and patent applications mentioned in this specification are incorporated herein in their entirety by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated herein as incorporated herein in its entirety by reference. Where a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein serves as the definition for such term.

[0171] Although the present invention has been described in relation to specific aspects thereof, it will be understood that further modifications may be made to the invention and that this application is intended to cover any changes, uses, or modifications, including such deviations from the disclosure, that are generally followed in principle and fall within known or customary practices within the art to which the invention pertains and are applicable to the essential features presented above, and that they follow the scope of the claimed invention.

[0172] In addition to the various embodiments described herein, the present disclosure includes the following embodiments numbered E1 through E94. This list of embodiments is presented as an exemplary list and is not limited to these embodiments.

[0173] E1. A crystalline composition that is the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of chemical formula (I):

[0174] Chemical formula (I)

[0175] .

[0176] E2. A crystalline composition of E1 that exhibits an XRPD pattern and / or DSC profile that has not substantially changed after storage for 3 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).

[0177] E3. A crystalline composition of E1 or E2 that exhibits an XRPD pattern and / or DSC profile that has not substantially changed after storage for 6 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).

[0178] E4. Any one of E1-E3 crystalline compositions exhibiting an XRPD pattern and / or DSC profile that has not substantially changed after storage for one year under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).

[0179] E5. Any one of E1-E4 crystalline compositions that exhibits an XRPD pattern and / or DSC profile that has not substantially changed after storage for 68 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).

[0180] E6. Any one of E1-E5 crystalline compositions that exhibits an XRPD pattern and / or DSC profile that has not substantially changed after storage for more than 140 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity).

[0181] E7. A crystalline composition of any one of E2-E6 produced using an XRPD pattern as follows:

[0182] (a) Composed of a variable diverging slit (irradiation length 10 mm), a 0.04 rad Soller slit, a fixed anti-scattering slit (0.50°), and a 10 mm beam mask on the incident beam side;

[0183] (b) X'CELERATOR, consisting of a variable anti-scattering slit (observation length 10 mm) and a 0.04 rad Soller slit on the diffracted beam side ® PANALYTICAL using Ni-filtered Cu Kα (45kV / 40mA) radiation and a step size of 0.03° 2θ accompanied by a Real Time Multi-Strip detector ® X'Pert Pro diffraction meter; or

[0184] (a) Composed of a Goebel mirror, a mirror exit slit (0.2 mm), a 2.5° Soller slit, and a beam knife on the incident beam side,

[0185] (b) composed of an anti-scattering slit (8 mm) and a 2.5° Soller slit on the diffraction beam side,

[0186] LYNXEYE TM BRUKER using Cu Kα (40kV / 40mA) radiation accompanied by a detector and a step size of 0.03° 2θ ® D8 ® ADVANCE TM System;

[0187] Here, the sample is mounted flat on a zero-background Si wafer.

[0188] E8. A crystalline composition of any one of E1-E7, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature increase rate of approximately 15°C / min.

[0189] E9. Any one of E1-E8 crystalline composition containing ≤ 0.2% of dimeric impurity PF-00191189:

[0190] .

[0191] E10. A crystalline composition of any one of E1-E9, wherein the crystalline composition contains about 0.05% by weight to about 0.19% by weight of dimeric impurity PF-00191189.

[0192] E11. A crystalline composition of any one of E1-E9 that does not contain a detectable amount of dimeric impurity PF-00191189.

[0193] E12. A pharmaceutical composition comprising any one of E1 to E11 crystalline compositions and a pharmaceutically acceptable carrier.

[0194] E13. The pharmaceutical composition of E12, wherein the pharmaceutical composition is for oral administration.

[0195] E14. A pharmaceutical composition of E13 in which the pharmaceutical composition is in the form of a solid dosage.

[0196] E15. Any one of E12-E14, wherein the pharmaceutical composition is a tablet or a capsule.

[0197] E16. A pharmaceutical composition of E15, wherein the pharmaceutical composition is a tablet.

[0198] E17. A pharmaceutical composition of E15, wherein the pharmaceutical composition is a capsule.

[0199] E18. A pharmaceutical composition of E17, wherein each capsule contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and each component of the capsule is as follows:

[0200] a) A crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%;

[0201] b) one or more diluents of about 85 wt / wt% to about 95 wt / wt%;

[0202] c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%;

[0203] d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and

[0204] e) Gelatin capsule encapsulating ingredient ad.

[0205] E19. A pharmaceutical composition of E17, wherein each capsule contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and each component of the capsule is as follows:

[0206] a) A crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 0.25 wt / wt% to about 1.5 wt / wt%;

[0207] b) one or more diluents of about 85 wt / wt% to about 95 wt / wt%;

[0208] c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%;

[0209] d) one or more lubricants in an amount of about 0.5 wt / wt% to about 2 wt / wt%; and

[0210] e) Gelatin capsule encapsulating ingredient ad.

[0211] E20. A pharmaceutical composition of E17, wherein each capsule contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and each component of the capsule is as follows:

[0212] a) A crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in an amount of about 2.5 wt / wt% to about 7.0 wt / wt%;

[0213] b) one or more diluents of about 85 wt / wt% to about 95 wt / wt%;

[0214] c) one or more disintegrants in an amount of about 3.5 wt / wt% to about 6 wt / wt%; and

[0215] d) Gelatin capsule encapsulating ingredient ac.

[0216] E21. A pharmaceutical composition of any one of E18 to E20, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate.

[0217] E22. A pharmaceutical composition of E21 in which at least one of the diluents is microcrystalline cellulose.

[0218] E23. A pharmaceutical composition of any one of E18 to E22, wherein at least one of the disintegrants is selected from the group consisting of sodium croscarmellose, sodium starch glycolate, crospovidone, and alginate.

[0219] E24. A pharmaceutical composition of E23 in which at least one of the disintegrants is croscarmellose sodium.

[0220] E25. A pharmaceutical composition of any one of E18 to E24, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, and talc.

[0221] E26. A pharmaceutical composition of E25 in which at least one of the lubricants is magnesium stearate.

[0222] E27. A method for treating a tumor, cancer, or RAS disorder, comprising administering any one of E12-E26 pharmaceutical compositions to a subject requiring such treatment.

[0223] E28. Method of E27, in which the tumor is a neurofibroma.

[0224] E29. Method of E28 in which the tumor is a neurofibroma associated with neurofibromatosis type 1.

[0225] E30. Any one of E27 to E29, 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 schwann tumor.

[0226] E31. Method of E30, in which the tumor is a plexiform neurofibroma.

[0227] E32. Method of E27 in which the subject is diagnosed with a RAS disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, heart-facial-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigo.

[0228] E33. The method of E27, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histocompatible neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenocystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum.

[0229] E34. Method of E33 in which the leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia and chronic myeloid leukemia.

[0230] E35. The method of E33, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.

[0231] E36. Method of E33, wherein the lung cancer is selected from a group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer and small cell lung cancer.

[0232] E37. Any one of E27-E36 methods, wherein the subject possesses a mutation or other abnormality in one or more genes, and the mutation or other abnormality causes the acquisition or loss of characteristic functions of a specific cancer, wherein the mutation or other abnormality in one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0233] E38. Any one of E27 to E37, 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.

[0234] E39. Any one of E27-E37, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 10 mg.

[0235] E40. Any one of E27-E37, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 8 mg.

[0236] E41. Any one of E27-E37, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 6 mg.

[0237] E42. Any one of E27-E41, wherein a total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily.

[0238] E43. Method of E42, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily in a dose of about 0.1 mg to about 20 mg.

[0239] E44. Method of E42, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.

[0240] E45. Method of E42, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.

[0241] E46. Method of E42, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.

[0242] E47. Method of E42, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.

[0243] E48. Method of E42, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.

[0244] E49. Any one of E27 to E42, wherein a total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

[0245] E50. Method of E49, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg each.

[0246] E51. Method of E49, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 1 mg each.

[0247] E52. Method of E49, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 2 mg each.

[0248] E53. Method of E49, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 3 mg each.

[0249] E54. Method of E49, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 4 mg each.

[0250] E55. Method of E49, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 10 mg each.

[0251] E56. Any one of E27 to E55, wherein individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are administered as one or more capsules or tablets.

[0252] E57. Any one of E27-E56 method in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days in which a total daily dose is administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0253] E58. Any one of E27 to E56, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 consecutive days in which a total daily dose is administered; followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0254] E59. A method of any one of E27 to E56 in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day cycles each comprising (i) 5 days in which a total 1-day dose is administered and (ii) 2 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0255] E60. Any one of E27 to E56, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which a total 1-day dose is administered and (ii) 2 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; subsequently (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0256] E61. Any one of E57-E60, in which a 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.

[0257] E62. Use of any one of E12-E26 pharmaceutical compositions for the manufacture of a drug for treating tumors, cancer, or RAS disorders.

[0258] E63. Use of any one of E62 where the tumor is a neurofibroma.

[0259] E64. Use of E63 in which the tumor is a neurofibroma associated with neurofibromatosis type 1.

[0260] E65. Use of any one of E62 to E64, 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 schwann tumor.

[0261] E66. Use of E65, in which the tumor is a plexiform neurofibroma.

[0262] E67. Use of E62 in a subject diagnosed with a RAS disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, heart-facial-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigo.

[0263] E68. Use of E62, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenocystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum.

[0264] E69. Use of E68, wherein the leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia and chronic myeloid leukemia.

[0265] E70. Use of E68, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.

[0266] E71. Use of E68 in which 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.

[0267] E72. Use of any one of E62 to E71, wherein the subject possesses a mutation or other abnormality in one or more genes, and thereby the mutation or other abnormality causes the acquisition or loss of characteristic functions of a specific cancer, wherein the mutation or other abnormality in one or more genes is a mutation or other abnormality in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0268] E73. Use of any one of E62-E72, administered at a total daily dose not exceeding 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0269] E74. Use of any one of E62-E72, in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered at a total daily dose not exceeding 10 mg.

[0270] E75. Use of any one of E62-E72, administered at a total daily dose not exceeding 8 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0271] E76. Use of any one of E62-E72, administered at a total daily dose not exceeding 6 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0272] E77. Use of any one of E62-E75, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily.

[0273] E78. Use of E76, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily in a dose of about 0.1 mg to about 20 mg.

[0274] E79. Use of E77, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.

[0275] E80. Use of E77, administered once daily at a total daily dose of about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0276] E81. Use of E77, administered once daily at a total daily dose of about 6 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0277] E82. Use of E77, administered once daily at a total daily dose of about 8 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0278] E83. Use of E77, in which a total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.

[0279] E84. Use of any one of E62 to E76, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily.

[0280] E85. Use of E84, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at doses of about 0.1 mg to about 10 mg each.

[0281] E86. Use of E84, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 1 mg each.

[0282] E87. Use of E84, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 2 mg each.

[0283] E88. Use of E84, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 3 mg each.

[0284] E89. Use of E84, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 4 mg each.

[0285] E90. Use of E76, in which the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice daily at a dose of approximately 10 mg each.

[0286] E91. Use of any one of E61-E90 in which an individual dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as one or more capsules or tablets.

[0287] E92. Use of any one of E62 to E91, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days in which a total daily dose is administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0288] E93. Use of any one of E62 to E91, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) 21 consecutive days in which a total daily dose is administered; followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0289] E94. Use of any one of E62 to E91, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which a total 1-day dose is administered and (ii) 2 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0290] E95. Use of any one of E62 to E91, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which a total 1-day dose is administered and (ii) 2 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered; followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is not administered.

[0291] E96. Use for any one of E92-E95, in which a 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.

Claims

Claim 1 (a) Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of formula (I): formula (I) , and (b) a composition comprising a carrier, wherein form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide features an XRPD pattern as shown in the figure below: A composition that does not contain any amount of form I or form II detectable by DSC, wherein form I is detectable by DSC through a melting point peak at 117°C and form II is detectable by DSC through a melting point peak at 90°C. Claim 2 The composition of claim 1, wherein the composition exhibits an XRPD pattern and / or DSC profile that has not substantially changed after storage for (i) 3 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity); (ii) 6 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity); (iii) 1 year under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity); (iv) 68 months under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity); or (v) 140 months or more under standard warehouse conditions (15℃-25℃ and ≤65% relative humidity). Claim 3 In claim 1, the composition contains ≤ 0.2 weight% of dimeric impurity PF-00191189 or: , or a composition in which the composition contains 0.05% to 0.19% by weight of dimeric impurity PF-00191189, or the composition does not contain a detectable amount of dimeric impurity PF-00191189. Claim 4 As the pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of chemical formula (I): chemical formula (I) Form IV of ,N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide features an XRPD pattern as shown in the figure below: ;N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide form IV does not contain any amount of form I or form II detectable by DSC, wherein form I is detectable by DSC through a melting point peak at 117°C and form II is detectable by DSC through a melting point peak at 90°C. Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete Claim 52 delete Claim 53 delete Claim 54 delete Claim 55 delete Claim 56 delete Claim 57 delete Claim 58 delete Claim 59 delete Claim 60 delete Claim 61 delete Claim 62 delete Claim 63 delete Claim 64 delete Claim 65 delete Claim 66 delete Claim 67 delete Claim 68 delete Claim 69 delete Claim 70 delete Claim 71 delete Claim 72 delete Claim 73 delete Claim 74 delete Claim 75 delete Claim 76 delete Claim 77 delete Claim 78 delete Claim 79 delete Claim 80 delete Claim 81 delete Claim 82 delete Claim 83 delete Claim 84 delete Claim 85 delete Claim 86 delete Claim 87 delete Claim 88 delete Claim 89 delete Claim 90 delete Claim 91 delete Claim 92 delete Claim 93 delete Claim 94 delete Claim 95 delete Claim 96 delete

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