WO2023196412A1

WO2023196412A1 - Liquid formulations comprising mitogen-activated protein kinase kinase (mek) inhibitors and methods using same

Info

Publication number: WO2023196412A1
Application number: PCT/US2023/017606
Authority: WO
Inventors: Charles Petrie
Original assignee: Nobias Therapeutics, Inc.
Priority date: 2022-04-06
Filing date: 2023-04-05
Publication date: 2023-10-12

Abstract

The present disclosure provides compositions comprising a Mitogen-Activated Protein Kinase Kinase (MEK) inhibitor. In certain embodiments, the MEK inhibitor is binimetinib. In certain embodiments, the MEK inhibitor is ATR-002 (zapnometinib). The present disclosure further provides methods of treating, preventing, and/or ameliorating a lymphatic and/or vascular anomaly, or cancer, in a subject in need thereof, the method comprising administering to the subject a composition of the present disclosure. In certain embodiments, the lymphatic anomaly is generalized lymphatic anomaly (GLA). In certain embodiments, the vascular anomaly is a venous anomaly and/or malformation or an arterial anomaly and/or malformation.

Description

TITLE OF THE INVENTION Liquid Formulations Comprising Mitogen-Activated Protein Kinase Kinase (MEK) Inhibitors and Methods Using Same

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/327,838, filed April 6, 2022, which is incorporated herein by reference in its entirety.

BACKGROUND

Anomalies of the circulatory system (e.g. vascular and/or lymphatic anomalies) are abnormalities or disorders which may comprise abnormal growth and/or impaired function of arteries, veins, capillaries, and lymphatic vessels, inter alia. Such anomalies may be benign and/or cosmetic in nature (e.g., infantile hemangioma), or may be life-threatening by disrupting circulation of oxygen in the blood (e.g., arteriovenous malformation).

Lymphatic vessels are an integral component of the body’s lymphatic system, which play a critical role in maintaining the circulation of bodily fluids, absorbing dietary fats in the small intestine, and defending the body against disease. Generalized lymphatic anomaly (GLA), or lymphangiomatosis, is a lymphatic anomaly which is characterized by the abnormal growth of lymphatic vessels in the lungs, soft tissue, and bones. Such overgrowth results in lymphatic malformations (i.e. cysts) which may result in, or contribute to, medical issues. The standard of care for the treatment of GLA is reduction of the symptoms, as there is currently no cure.

Recent studies have demonstrated that aberrations of the PI3K/mT0R and Ras/Mitogen- Activated Protein Kinase (MAPK) signaling pathways result in impaired expansion and remodeling of a mature lymphatic network, thereby identifying MAPK as a potential target for the treatment of GLA. Mitogen- Activated Protein Kinase Kinase (MEK) inhibitors, including binimetinib, have been successfully used to treat certain types of cancer due to their ability to affect the MAPK/ERK pathway.

Thus, there is a need in the art for compositions comprising MEK inhibitors for the treatment, prevention, and/or amelioration of one or more vascular and/or lymphatic anomalies, non-limiting examples including lymphatic, venous, and/or arterial malformations and/or anomalies. Tn certain embodiments, the lymphatic anomaly is GLA. The present disclosure addresses this need.

BRIEF DESCRIPTION OF THE FIGURES

The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

FIG. 1 shows a representative chromatogram of the injection of the binimetinib working standard.

FIG. 2 provides a calibration curve generated by injecting varying amounts of the 0.1 mg/mL binimetinib standard.

FIG. 3 provides a graph showing the linearity of the UPLC method.

FIG. 4 shows a representative chromatogram of the injection of the ATR-002 working standard.

FIG. 5 provides a calibration curve generated by injecting varying amounts of the 0.1 mg/mL ATR-002 standard.

BRIEF SUMMARY

In one aspect, the present disclosure provides a composition comprising polyethylene glycol (PEG) and ATR-002. In another aspect, the present disclosure provides a composition consisting essentially of polyethylene glycol (PEG) and ATR-002. In another aspect, the present disclosure provides a composition consisting of polyethylene glycol (PEG) and ATR-002. In certain embodiments, the PEG is PEG-200. In certain embodiments, the PEG is PEG-400. In certain embodiments, the PEG is PEG-600.

In one aspect, the present disclosure provides a composition comprising a MEK (Mitogen- Activated Protein Kinase Kinase) inhibitor, glycerol, and polyethylene glycol (PEG).

In another aspect, the present disclosure provides a composition comprising a MEK inhibitor, a hydroxypropyl-P-cyclodextrin (HPBCD) solution, water, and polyethylene glycol (PEG).

In another aspect, the present disclosure provides a composition comprising a MEK inhibitor, a polyacrylic acid solution, a NaOH solution, and water. Tn certain embodiments, the MEK inhibitor is zapnometinib (ATR-002). Tn certain embodiments, the MEK inhibitor is binimetinib.

In another aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating a lymphatic and/or vascular anomaly in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of the present disclosure.

In another aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g, 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise.

In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

Description

The present invention relates in part to the inventor’s unexpected discovery of the high solubility of MEK inhibitors, in particular binimetinib and/or ATR-002 (zapnometinib), in polyethylene glycol (PEG). In certain embodiments, the PEG is PEG-200. In certain embodiments, the PEG is PEG-400. In certain embodiments, the PEG is PEG-600. The solubility of binimetinib and/or ATR-002 in PEG was found to be significantly greater than that which one of ordinary skill in the art would have reasonably expected in view of the solubility of the compounds in structurally similar organic solvents (e.g., glycerol or propylene glycol). Further, the solubility of ATR-002 in PEG is particularly high in the absence of any additional solvents, including but not limited to glycerol.

Definitions

The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

The term “ameliorate” as used herein refers to a moderation in the severity of a disease, condition, and/or disorder by reducing the intensity of the symptoms thereof.

In one aspect, the terms “co-administered” and “co-administration” as relating to a subject refer to administering to the subject a compound and/or composition of the invention along with a compound and/or composition that may also treat or prevent a disease or disorder contemplated herein. In certain embodiments, the co-administered compounds and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

As used herein, a “disease” is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate.

As used herein, a “condition” or “disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.

The term “hydroxypropyl-P-cyclodextrin” or “HPBCD” as used herein refers to a macrocyclic ring of glucose subunits j oined by a-1,4 glycosidic bonds.

The term “MEK inhibitor” as used herein refers to a chemical or drug that inhibits at least one of the mitogen-activated protein kinase kinase enzymes (e.g., MEK1 and/or MEK2).

The term “PEG” or “polyethylene glycol” as used herein refers to a polyether compound of formula H(OCH2CH2)nOH, wherein n is a number from 2 to 100 or more, which is commonly used as an excipient in pharmaceutical compositions and/or products. In certain embodiments, n is greater than 100. The term “PEG” may be used in conjunction with an integer (e.g. PEG-400), wherein the integer denotes the approximate average molecular weight of the PEG species comprising the excipient (/.e.. H(OCH2CH2)nOH, wherein n is about 8 to about 9, or on average 8.1 to 9.2, and the molar mass is about 380-420 g/mol).

As used herein, the term “pharmaceutical composition” or “composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Handbook of Pharmaceutical Excipients, 9"' Edition. Pharmaceutical Press, ISBN 9780 85711 375 7, 2020, and Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), both of which are incorporated herein by reference.

As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates), and clathrates thereof.

As used herein, a “pharmaceutically effective amount,” “therapeutically effective amount,” or “effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.

The term “prevent,” “preventing,” or “prevention” as used herein means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences. Disease, condition and disorder are used interchangeably herein.

As used herein, the terms “subject” and “individual” and “patient” can be used interchangeably, and may refer to a human or non-human mammal or a bird. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human. In certain embodiments, the human is a child.

The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free of as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

The terms “treat,” “treating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. MEK Inhibitors

In certain embodiments, the MEK inhibitor

-bromo-

2-fluorophenyl)amino)-4-fluoro-N-(2 -hydroxy ethoxy)- 1 -methyl- lH-benzo[d]imidazole-6- carboxamide (binimetinib). In certain embodiments, the MEK inhibitor is

, (S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3- hydroxy-3-(piperidin-2-yl)azetidin-l-yl)methanone (cobimetinib). In certain embodiments, the

MEK inhibitor i

-bromo-2-chlorophenyl)amino)-4-fluoro-N-

(2-hydroxyethoxy)-l-methyl-lH-benzo[d]imidazole-6-carboxamide (selumetinib). In certain embodiments, the MEK inhibitor

cyclopropyl-5- ((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl)phenyl)acetamide (trametinib). In certain embodiments, the MEK

-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide (pimasertib). In certain embodiments, the MEK inhibitor is

(R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4- iodophenyl)amino)benzamide (PD-0325901). In certain embodiments, the MEK inhibitor is

-chloro-4-iodophenyl)amino)-3,4-difluorobenzoic acid (ATR-002).

The terms “ATR-002” and “zapnometinib” may be used interchangeably herein. In certain embodiments, the MEK inhibitor

-fluoro-4- iodophenyl)amino)-N-(2 -hydroxy ethoxy )imidazo[l,5-a]pyridine-6-carboxamide (GDC-0623).

In certain embodiments, the MEK inhibitor i

difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)- 1 -(2,3 - dihydroxypropyl)cyclopropane-l -sulfonamide (refam etinib). In certain embodiments, the MEK inhibitor

dihydroxypropyl)-6-fhioro-5-((2-fluoro-

4-iodophenyl)amino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK 733). The terms “TAK 733” and “REC4881” may be used interchangeably herein. In certain embodiments, the MEK inhibitor is MSC2015103B (AS703988). In certain embodiments, the term “MEK inhibitor” further comprises one or more metabolites of the compounds described herein.

Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to ²H, ³H, ⁿC, ¹³C, ¹⁴C, ³⁶C1, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸0, ³²P, and ³⁵S. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

The compounds described herein may form salts with acids or bases, and such salts are included in the present invention. The term “salts” embraces addition salts of free acids or bases that are useful within the methods of the invention. The term “pharmaceutically acceptable salt” refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. In certain embodiments, the salts are pharmaceutically acceptable salts. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, 2- hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, salicylic, galactaric, galacturonic acid, glycerophosphonic acids and saccharin (e.g., saccharinate, saccharate). Salts may be comprised of a fraction of one, one or more than one molar equivalent of acid or base with respect to any compound of the invention.

Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, arginine, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucamine), tromethamine, and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

Compositions

In one aspect, the present disclosure provides a composition comprising a Mitogen- Activated Protein Kinase Kinase (MEK) inhibitor, glycerol, and polyethylene glycol (PEG) or N- methyl-2 -pyrrolidone (NMP).

In certain embodiments, the MEK inhibitor is selected from the group consisting of ATR- 002 (zapnometinib), binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, TAK 733 (REC4881), PD-0325901, GDC-0623, MSC2015103B (AS703988), and refametinib.

In certain embodiments, the glycerol is a solution of 85% glycerol in water (v/v). In certain embodiments, the composition comprises polyethylene glycol (PEG).

In certain embodiments, the PEG is PEG-200. In certain embodiments, the PEG is PEG- 400. In certain embodiments, the PEG is PEG-600. Tn certain embodiments, glycerol and PEG have a ratio selected from the group consisting of about 5: 1, 6:1, 7:1, 8:1, 9: 1, 10: 1, 11 : 1, 12: 1, 13:1, 14:1 and about 15: 1 (v/v). In certain embodiments, the ratio of glycerol to PEG-400 is about 9: 1 (v/v).

In certain embodiments, the MEK inhibitor is binimetinib.

In certain embodiments, the composition has a binimetinib concentration selected from the group consisting of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and about 2.0 mg/mL. In certain embodiments, the binimetinib concentration is about 1.5 mg/mL.

In certain embodiments, the PEG and glycerol have a ratio selected from the group consisting of about 1 : 1, 1 :2, 2:2, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, and 10:2 (v/v). In certain embodiments, the PEG and glycerol have a ratio of about 5:2 (v/v). In certain embodiments, the PEG and glycerol have a ratio of about 1:1 (v/v).

In certain embodiments, the composition further comprises ethanol (EtOH). In certain embodiments, the PEG and glycerol have a ratio selected from the group consisting of about 1 :2, 2:2, 3:2, and 4:2 (v/v). In certain embodiments, the PEG and glycerol have a ratio of about 2:2 (v/v). In certain embodiments, the PEG, glycerol, and EtOH have a ratio of about 9:9:9 (v/v).

In certain embodiments, the MEK inhibitor is ATR-002 (zapnometinib).

In certain embodiments, the composition has a ATR-002 concentration ranging from about 5 mg/mL to about 25 mg/mL. In certain embodiments, the ATR-002 concentration is about 15 mg/mL.

In certain embodiments, the composition comprises NMP.

In certain embodiments, the glycerol and NMP have a ratio selected from the group consisting of about 50: 1, 49: 1, 48: 1, 47: 1, 46:1, 45:1, 44:1, 43: 1, 42: 1, 41: 1, 40: 1, 39: 1, 38:1, 37: 1, 36: 1, 35: 1, 34:1, 33:1, 32:1, 31 : 1 and about 30: 1 (v/v). In certain embodiments, the glycerol to NMP ratio is about 39: 1 (v/v).

In certain embodiments, the composition has a binimetinib concentration selected from the group consisting of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, and about 1.5 mg/mL. In certain embodiments, the binimetinib concentration is 1.549 mg/mL.

In certain embodiments, the binimetinib concentration is about 1.0 mg/mL. In certain embodiments, the binimetinib concentration is 0.967 mg/mL.

In another aspect, the present disclosure provides a composition comprising a MEK inhibitor, a hydroxypropyl-P-cyclodextrin (HPBCD) solution, water, and PEG or NMP. Tn certain embodiments, the MEK inhibitor is selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, REC4881, TAK 733, ATR-002, PD-0325901, GDC-0623, and refametinib. In certain embodiments, the MEK inhibitor is binimetinib.

In certain embodiments, the HPBCD solution has a HPBCD concentration selected from the group consisting of about 100, 125, 150, 175, 200, 225, 250, 275, and about 300 mg/mL. In certain embodiments, the HPBCD solution has a HPBCD concentration of about 200 mg/mL.

In certain embodiments, the composition comprises PEG.

In certain embodiments, the PEG is PEG-200. In certain embodiments, the PEG is PEG- 400. In certain embodiments, the PEG is PEG-600. certain embodiments, the PEG and HBCD have a ratio selected from the group consisting of about 10: 1, 9: 1, 8:1, 7: 1, 6:1, 5: 1, 4:1, 3: 1, 2:1, 1: 1, 1 :2, 1 :3, 1 :4, 1 :5, 1:6, 1 :7, 1:8, 1 :9 and about 1 : 10. In certain embodiments, the PEG and HPBCD have a ratio of about 1 :5.

In certain embodiments, the PEG, HPBCD solution, and water have a ratio of about 1 :5:4 (v/v).

In certain embodiments, the composition further comprises glycerol. In certain embodiments, the glycerol is a solution of 85% glycerol in water (v/v).

In certain embodiments, the composition comprises NMP. In certain embodiments, the NMP and HPBCD have a ratio selected from the group consisting of about 5:20, 4.5:20, 4:20, 3.5:20, 3:20, 2.5:20, 2:20, 1.5:20, 1:20, 1 :21, 1 :22, 1 :23, 1 :24, and about 1 :25 (v/v). In certain embodiments, the NMP and glycerol have a ratio selected from the group consisting of about 5: 14, 4:14, 3:14, 2: 14, 1:14, 1: 15, 1: 16, 1 : 17, and about 1: 18 (v/v). In certain embodiments, the NMP and water have a ratio selected from the group consisting of about 1 : 1, 4:5, 3:5, 2:5, 1:5, 1 :6, 1 :7, 1 :8, 1 :9, and about 1 : 10 (v/v). In certain embodiments, the NMP, HPBCD, glycerol, and water have a ratio of about 1 :20: 14:5 (v/v). In certain embodiments, the NMP, HPBCD, glycerol, and water have a ratio of about 1: 10:14: 15 (v/v).

In certain embodiments, the PEG and HPBCD have a ratio selected from the group consisting of about 0.5:5, 1 :5, 1.5:5, 2:5, 2:6, 2:7, 2:8, 2:9, and about 2:10 (v/v). In certain embodiments, the PEG and glycerol have a ratio selected from the group consisting of about 0.5:11, 1 :11, 1.5:11, 2: 11, 2: 12, 2: 13, 2: 14 and about 2:15 (v/v). In certain embodiments, the PEG-400 and water have a ratio of about 1 : 1 , 2:3, 1 :3, 1 :4, 1 :5, and about 1 :6 (v/v). Tn certain embodiments, the PEG, HPBCD, glycerol, and water have a ratio of about 2:5:11 :6 (v/v).

In certain embodiments, the composition has a binimetinib concentration selected from the group consisting of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, and about 1.5 mg/mL. In certain embodiments, the binimetinib concentration is about 1.0 mg/mL. In certain embodiments, the binimetinib concentration is 0.989 mg/mL. In certain embodiments, the binimetinib concentration is 1.041 mg/mL.

In another aspect, the present disclosure provides a composition comprising a MEK inhibitor, a polyacrylic acid solution, a NaOH solution, and water.

In certain embodiments, MEK inhibitor is selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, REC4881, TAK 733, ATR-002, PD-0325901, GDC-0623, and refametinib. In certain embodiments, the MEK inhibitor is binimetinib.

In certain embodiments, the polyacrylic acid solution comprises 2% polyacrylic acid in water (w/v). In certain embodiments, the polyacrylic acid solution further comprises about 1% to about 5% K2CO3 (w/v).

In certain embodiments, the NaOH solution comprises a IN solution of NaOH in water.

In certain embodiments, the polyacrylic acid solution and NaOH solution have a ratio which is selected from the group consisting of about 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6:1, 7: 1, 8:1, 9: 1, and about 10:1 (v/v). In certain embodiments, the polyacrylic acid solution and NaOH solution have a ratio which is about 5:1 (v/v).

In certain embodiments, the composition has a binimetinib concentration selected from the group consisting of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and about 15 mg/mL. In certain embodiments, the binimetinib concentration is about 10 mg/mL.

The present disclosure further provides a composition comprising PEG and ATR-002. In certain embodiments, the composition consists essentially of PEG and ATR-002. In certain embodiments, the composition consists of PEG and ATR-002.

In certain embodiments, the composition does not further comprise glycerol. In certain embodiments, the composition has a ratio of glycerol to PEG of 0: 1.

In certain embodiments, the PEG is PEG-200. In certain embodiments, ATR-002 has a concentration in the PEG-200 which is selected from the group consisting of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/mL of about 50 to about 100 mg/mL. Tn certain embodiments, ATR has a concentration in the PEG-200 of about 100 mg/mL.

In certain embodiments, the PEG is PEG-400. In certain embodiments, ATR-002 has a concentration in the PEG-400 which is selected from the group consisting of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/mL. In certain embodiments, ATR-002 concentration in the PEG-400 is about 74 mg/mL.

In certain embodiments, the PEG is PEG-600. In certain embodiments, ATR-002 has a concentration in the PEG-600 which is selected from the group consisting of about 75, 80, 85, 90, 95, and about 100 mg/mL.

Methods

In one aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating a lymphatic and/or vascular anomaly in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of the present disclosure.

In certain embodiments, the lymphatic anomaly is selected from the group consisting of generalized lymphatic anomaly (GLA), central collective lymphatic anomalies (CCLA), kaposiform lymphangiomatosis (KLA), kaposiform hemangioendothelioma (KHE), Gorham- Stout disease (GSD), and Noonan syndrome (NS). In certain embodiments, the lymphatic anomaly is generalized lymphatic anomaly (GLA).

In certain embodiments, the subject is further administered at least one additional agent useful for treating a lymphatic anomaly.

In certain embodiments, the vascular anomaly is a venous anomaly. In certain embodiments, the vascular anomaly is a venous malformation. In certain embodiments, the vascular anomaly is an arterial anomaly. In certain embodiments, the vascular anomaly is an arterial malformation.

In one aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of the present disclosure.

In certain embodiments, the cancer is at least one of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer, or colon cancer.

In certain embodiments, the cancer is at least one of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma and diffuse large B cell lymphoma (DLBCL).

In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the human is a child.

Pharmaceutical Compositions and Formulations

The invention provides pharmaceutical compositions comprising a MEK inhibitor, which are useful to practice methods of the invention. Such a pharmaceutical composition may consist of a MEK inhibitor, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one MEK inhibitor or a salt or solvate thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. At least MEK inhibitor may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.

In certain embodiments, the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In other embodiments, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 1,000 mg/kg/day.

The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

Pharmaceutical compositions that are useful in the methods of the invention may be suitably developed for nasal, inhalational, oral, rectal, vaginal, pleural, lymphatic, peritoneal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, epidural, intrathecal, intravenous or another route of administration. A composition useful within the methods of the invention may be directly administered to the brain, the brainstem, or any other part of the central nervous system of a mammal or bird. Other contemplated formulations include projected nanoparticles, microspheres, liposomal preparations, nanoemulsions, coated particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.

In certain embodiments, the compositions of the invention are part of a pharmaceutical matrix, which allows for manipulation of insoluble materials and improvement of the bioavailability thereof, development of controlled or sustained release products, and generation of homogeneous compositions. By way of example, a pharmaceutical matrix may be prepared using hot melt extrusion, solid solutions, solid dispersions, size reduction technologies, molecular complexes (e.g., cyclodextrins, and others), microparticulate, and particle and formulation coating processes. Amorphous or crystalline phases may be used in such processes.

The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology and pharmaceutics. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-dose or multi-dose unit.

As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.

In certain embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the invention and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers, which are useful, include, but are not limited to, PEG-200, PEG-400, PEG-600, Carbopol 97 IP, Captisol®, Lubrisol, Keptose HP Oral, glycerol, water, saline, ethanol, recombinant human albumin (e.g., RECOMB UMIN®), solubilized gelatins (e.g., GELOFUSINE®), and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), recombinant human albumin, solubilized gelatins, suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, are included in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or fragranceconferring substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic, anxiolytics or hypnotic agents. As used herein, “additional ingredients” include, but are not limited to, one or more ingredients that may be used as a pharmaceutical carrier.

The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment. Examples of preservatives useful in accordance with the invention include but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. One such preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

The composition may include an antioxidant and a chelating agent which inhibit the degradation of the compound. Antioxidants for some compounds are BHT, BHA, alphatocopherol and ascorbic acid in the exemplary range of about 0.01% to 0.3%, or BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. The chelating agent may be present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Exemplary chelating agents include edetate salts (e.g., disodium edetate) and citric acid in the weight range of about 0.01% to 0.20%, or in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are exemplary antioxidant and chelating agent, respectively, for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.

Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g, polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin, acacia, and ionic or non ionic surfactants. Known preservatives include, but are not limited to, methyl, ethyl, or //-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.

Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an “oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying. Methods for mixing components include physical milling, the use of pellets in solid and suspension formulations and mixing in a transdermal patch, as known to those skilled in the art.

Administration/Dosing

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the patient either prior to or after the onset of a disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present invention to a patient, such as a mammal, such as a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 0.01 mg/kg to 100 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

The compound may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered, in nonlimiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose is readily apparent to the skilled artisan and depends upon a number of factors, such as, but not limited to, type and severity of the disease being treated, and type and age of the animal.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease or disorder in a patient.

In certain embodiments, the compositions of the invention are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physician taking all other factors about the patient into account.

The MEK inhibitor of the formulations of the present disclosure, for administration, may be in the range of from about 1 pg to about 7,500 mg, about 20 pg to about 7,000 mg, about 40 pg to about 6,500 mg, about 80 pg to about 6,000 mg, about 100 pg to about 5,500 mg, about 200 pg to about 5,000 mg, about 400 pg to about 4,000 mg, about 800 pg to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments there-in-between.

In some embodiments, the dose of a MEK inhibitor of the invention is from about 0.5 pg and about 5,000 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In certain embodiments, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

The term “container” includes any receptacle for holding the pharmaceutical composition or for managing stability or water uptake. For example, in certain embodiments, the container is the packaging that contains the pharmaceutical composition, such as liquid (solution and suspension), semisolid, lyophilized solid, solution and powder or lyophilized formulation present in dual chambers. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating, preventing, or reducing a disease or disorder in a patient.

Route of Administration

Routes of administration of any of the compositions of the invention include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal .g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, lymphatic, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, emulsions, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees, liquids, drops, capsules, caplets and gelcaps. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic, generally recognized as safe (GRAS) pharmaceutically excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.

Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

It is to be understood that, wherever values and ranges are provided herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, all values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

EXAMPLES

Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein.

In one aspect, the development of liquid formulations comprising binimetinib is described herein. In another aspect, the development of liquid formulations comprising zapnometinib (ATR-002)is described herein.

Regarding formulations of binimetinib, to limit the volume needed and excipients administered, a dosage strength of 1 mg/mL was targeted. The formulation development described herein comprises three distinct strategies. First, the solubility of binimetinib in water- soluble organic solvents was evaluated. Second, complexation of binimetinib with hydroxypropyl-P-cyclodextrin was evaluated to produce an aqueous formulation. Third, a liquid suspension of binimetinib in Carbopol was prepared and evaluated. The concentration of binimetinib in each of the aforementioned formulations was determined using the method described herein.

The parameters evaluated with regard to each liquid formulation are physical stability (visual inspection) and chemical stability (HPLC analysis). Physical stability, as assessed by the presence or absence of visible precipitation, is described in greater detail elsewhere herein. Chemical stability was assessed using the HPLC assay described herein.

Materials and Methods

Chemicals and Reagents

Binimetinib was purchased from LC Laboratories. ATR-002 was purchased from Toronto Research Chemicals (TRC). HPLC-grade acetonitrile, and HPLC-grade water were purchased from Fisher Scientific. HPLC-grade trifluoroacetic acid (TFA) was purchased from Pierce.

Apparatus and Chromatographic Conditions

HPLC analyses were performed using a Waters Acquity H-class liquid chromatograph equipped with a vacuum degasser, a quaternary high pressure gradient pump, a refrigerated automated sample injector, column heater, and a diode array detector.

Chromatographic separations were carried out on a Waters CSH C-18 column (2.1 x 150 mm) packed with 1.7 pm C-18 particles. The column eluent was monitored at 294 nm. Data was collected and analyzed using Empower 3 software. Mobile phase A consisted of 0.1% trifluoroacetic acid (TFA) in water and mobile phase B consisted of 0.1% TFA in acetonitrile.

For binimetinib: the column was eluted with a linear gradient from 5% mobile phase B to 65% mobile phase B over 20 minutes. The flow rate was 0.3 mL/min.

For ATR-002: the column was eluted with a linear gradient from 25% mobile phase B to 75% mobile phase B over 20 minutes. The flow rate was 0.3 mL/min.

Method Reusability

A 1 mg/mL stock solution of binimetinib in DMS was prepared. From the stock solution, a working standard was prepared at 0.1 mg/mL. A representative chromatogram from the injection of the binimetinib working standard is provided in FIG. 1. A calibration curve was generated by injecting varying amounts of the 0.1 mg/mL binimetinib standard (FIG. 2). With respect to the calibration curve, the y-intercept was found to be approximately 0, permitting the use of a single point calibration. A 1 mg/mL stock solution of ATR-002 in NMP was prepared. From the stock solution, a working standard was prepared at 0.2 mg/mL in NMP. A representative chromatogram from the injection of the ATR-002 working standard is provided in (FIG. 4). A calibration curve was generated by injection varying amounts of the 0.2 mg/mL standard (FIG. 5). With respect to the calibration curve, the y-intercept was found to be approximately 0, permitting the use of a single point calibration.

Method qualification - accuracy, range, linearity, and precision

Binimetinib

Accuracy and precision of the method were determined by spike and recovery. Binimetinib was spiked into DMSO at 5 levels: 50 pg/mL, 75 pg/mL, 100 pg/mL, 150 pg/mL, and 200 pg/mL (Table 1). Linearity was determined from repeat injections of the binimetinib reference at 0.1 mg/mL and 0.01 mg/mL (Table 2 and FIG. 3). As each formulation is developed, accuracy is determined by spike and recovery in the formulation matrix.

Precision (repeatability) was determined by pooling the CV from multiple injections of the accuracy samples. As each formulation is developed, precision is determined using replicate data from the accuracy experiments (Table 1).

The results of the method qualification with regard to each specified parameter are summarized in Table 3.

Table 1. Accuracy and precision

percentage nominal; ^binj ection volume of 3 gL; Concentration (mg/mL).

Table 2. Linearity

Table 3. Method qualification results

A TR-002

Accuracy was determined by back calculating the amount injected from each point on the calibration curve. Precision was determined as the mean position from the replicate injections of the reference standard (Table 4).

Table 4. Accuracy and precision

Example 1: Solubility of binimetinib in water-soluble organic solvents

The solubility of binimetinib in propylene glycol (PG), polyethylene glycol 400 (PEG- 400), glycerol 85%, and A-methyl-2-pyrrolidone (NMP) were determined by preparing a saturated suspension of binimetinib in each solvent. The saturated suspension was mixed for 96 h, centrifuged, and the supernatant was analyzed using the UPLC method described herein to determine the solubility of binimetinib in each water-soluble organic solvent (Table 5).

Table 5. Solubility of binimetinib in water-soluble organic solvents

Formulations of binimetinib in mixtures of PG or NMP and PEG-400 in 85% glycerol were prepared, with efforts directed toward minimizing the amount of PG and NMP, as directed by FDA and EMA guidelines for pediatric formulations (Table 6).

Table 6. Formulations prepared using water-soluble organic solvents

Example 2: Solubility of hydroxypropyl-P-cyclodextrin (HPBCD)-complexed binimetinib formulations

The solubility of HPBCD-complexed binimetinib was determined as described herein. Initially, binimetinib (2 mg/mL) was suspended in 10 mM citrate (pH 4) and homogenized. The binimetinib suspension was added to an HPBCD solution as provided in Table 6. The resulting suspensions were mixed end over end for 96 h. None of the solutions achieved complete dissolution. The supernatants were analyzed by UPLC to determine the soluble fraction of binimetinib (Table 7).

Table 7. Complexation of binimetinib with hydroxypropyl-P-cyclodextrin (HPBCD)

Formulations of binimetinib in HPBCD were prepared with addition of either PEG-400 or NMP. The addition of water-soluble organic solvents allows for a more aqueous formulation (Table 8).

Table 8. Formulations of hydroxypropyl-P-cyclodextrin (HPBCD) with PEG-400 or NMP

Example 3: Suspension of binimetinib in Carbopol 971P

A stock solution of 2% Carbopol in water was prepared by slow addition of Carbopol to a rapidly stirred volume of water (80% of final volume). Once the Carbopol had been added, the volume was adjusted to the final volume. The solution was stirred at room temperature for three days.

A fine suspension of binimetinib in water was prepared by adding 200 mg of binimetinib to 10 mL of water. The suspension was homogenized with a hand homogenizer for 5 minutes.

The stock solution of Carbopol (0.5 mL) was added to 4.4 mL of water. The binimetinib suspension (5 mL) was added to the diluted Carbopol solution with stirring. After mixing for 30 min, the suspension was neutralized by addition of IN NaOH (0.1 mL) with stirring. The resulting gel was stirred for 30 min (Table 9).

Table 9. Formulation comprising binimetinib and Carbopol gel

Example 4: Solubility of ATR-002 in water-soluble organic solvents

In another aspect, the present disclosure describes the development of liquid formulations comprising zapnometinib (ATR-002). In certain embodiments, the ATR-002 formulation development targeted a dosage strength of 15 mg/mL. The solubility of ATR-002 in PEG400, 85% glycerol, and propylene glycol was determined by preparing a saturated solution of ATR- 002 in each solvent. The suspension was mixed for 96 h, centrifuged, and the supernatant analyzed using the UPLC method described herein to determine the solubility of ATR-002 in each water-soluble organic solvent (Table 10).

Table 10. Solubility of ATR-002 in water-soluble organic solvents

^aconcentration provided corresponds to the amount of ATR-002 used to prepare saturated solution, as described elsewhere herein.

ATR-002 (100 mg) was dissolved in 1 mb of PEG400 and the concentration was determined by HPLC (74 mg/mL). The 100 mg of ATR-002 had significant volume, and the resulting solution volume was likely greater than 1 mL, possibly resulting in a lower apparent concentration than targeted. The solubility of ATR-002 in PEG400 may exceed 100 mg/mL.

Formulations of ATR-002 in PEG400/85% glycerol were prepared using both the 74 mg/mL and 27 mg/mL solutions of ATR-002 in PEG400. The concentration of ATR-002 in each formulation was confirmed by UPLC (Table 11).

Table 11. Concentrations of ATR-002 in water-soluble organic solvents and/or mixtures thereof

Three formulations have been identified targeting a dose of approximately 150 mg (Tables 12-14). Table 12 provides an exemplary formulation suitable for administration of 150 mg of ATR-002 with 2 mL dose (74 mg ATR-002/mL). Table 13 provides component ratios for an exemplary formulation suitable for administration of about 150 mg of ATR-002 with a 10 mL dose (14.9 mg ATR-002/mL). Table 14 provides component ratios for an exemplary formulation suitable for administration of about 150 mg of ATR-002 with a 10 mb dose (13.9 mg ATR- 002/mL).

Table 12. Exemplary Formula 1

* concentration of dissolved ATR-002 in Exemplary Formula 1 is 74 mg/mL

Table 13. Exemplary Formula 2

* concentration of dissolved ATR-002 in Exemplary Formula 2 is 14.9 mg/mL

Table 14. Exemplary Formula 3

* concentration of dissolved ATR-002 in Exemplary Formula 3 is 13.9 mg/mL

In certain embodiments, ATR-002 has a solubility in PEG-200 of about 100 mg/mL. In certain embodiments, ATR-002 has a solubility in PEG-400 of about 100 mg/mL. In certain embodiments, ATR-002 has a solubility in PEG-600 of about 75 mg/mL to about 100 mg/mL.

Example 5: Solubility of ATR-002 in aqueous solutions

The present disclosure further provides exemplary solubility data for ATR-002 in various aqueous solutions and/or biologically relevant liquid media (z.e., simulated biological fluids) (Tables 15-16). Table 15. Solubility of ATR-002 in aqueous solutions

Table 16. Solubility of ATR-002 in biorelevant media

^aFaSSIF: fasted state simulated intestinal fluid; ^bFeSSIF: fed state simulated intestinal fluid; ^cfasted state simulated gastric fluid.

As can be seen in Table 15, ATR-002 is negligibly soluble in water as a free acid. Further, the solubility of ATR-002 in water is significantly increased under certain basic conditions. In certain embodiments, high aqueous solubility of ATR-002 is observed with aqueous solutions basified by a strong base (e.g., NaOH) or a weak base (e.g, lysine). In other embodiments, moderate solubility of ATR-002 is observed with aqueous solutions basified with a weak base (e.g., tris(hydroxymethyl)aminomethane). Tn certain embodiments, significantly greater solubility of ATR-002 is observed in fasted state and fed state simulated intestinal fluids as compared to fasted state simulated gastric fluids, at both room temperature and human body temperature. Without wishing to be bound by any theory, orally administered aqueous solutions of ATR-002 may precipitate in the acidic environment of the stomach, as evidenced by solubility values of 0.0003 mg/mL and 0.0007 mg/mL in simulated gastric fluids at 25 °C and 37 °C, respectively. Further, precipitated ATR- 002 may be redissolved in the intestine and absorbed, as evidenced by solubility values of 0.2266/0.4580 mg/mL and 0.2065/0.5396 mg/mL in fasted state/fed state intestinal fluids at room temperature and human body temperature, respectively.

Enumerated Embodiments

The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance:

Embodiment 1 provides a composition comprising a MEK (Mitogen-Activated Protein Kinase Kinase) inhibitor, glycerol, and polyethylene glycol (PEG).

Embodiment 2 provides the composition of Embodiment 1, wherein the MEK inhibitor is selected from the group consisting of ATR-002 (zapnometinib), binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, TAK 733 (REC4881), PD-0325901, GDC-0623, MSC2015103B (AS703988), and refametinib.

Embodiment 3 provides the composition of Embodiment 1 or 2, wherein the glycerol is a solution of 85% glycerol in water (v/v).

Embodiment 4 provides the composition of any one of Embodiments 1-3, wherein the composition comprises PEG.

Embodiment 5 provides the composition of Embodiment 4, wherein the PEG is selected from the group consisting of PEG-200, PEG-400, and PEG-600.

Embodiment 6 provides the composition of any one of Embodiments 1-5, wherein the glycerol and PEG have a ratio ranging from about 5: 1 to about 15:1 (v/v).

Embodiment 7 provides the composition of any one of Embodiments 1-6, wherein the ratio of glycerol to PEG is about 9:1 (v/v). Embodiment 8 provides the composition of any one of Embodiments 1 -7, wherein the MEK inhibitor is binimetinib.

Embodiment 9 provides the composition of Embodiment 8, wherein the composition has a binimetinib concentration ranging from about 1.0 mg/mL to about 2.0 mg/mL.

Embodiment 10 provides the composition of Embodiment 9, wherein the binimetinib concentration is about 1.5 mg/mL.

Embodiment 11 provides the composition of any one of Embodiments 1-5, wherein the PEG and glycerol have a ratio ranging from about 1 : 1 to about 10:2 (v/v).

Embodiment 12 provides the composition of Embodiment 11, wherein the PEG and glycerol have a ratio of about 5:2 or about 1 :1 (v/v).

Embodiment 13 provides the composition of any one of Embodiments 1-5 and 11-12, further comprising ethanol (EtOH).

Embodiment 14 provides the composition of Embodiment 13, wherein the PEG and glycerol have a ratio ranging from about 1:2 to about 4:2 (v/v).

Embodiment 15 provides the composition of Embodiment 13 or 14, wherein the PEG and glycerol have a ratio of about 2:2 (v/v).

Embodiment 16 provides the composition of Embodiment 13, wherein the PEG, glycerol, and EtOH have a ratio of about 9:9:2 (v/v).

Embodiment 17 provides the composition of any one of Embodiments 1-5 and 11-16, wherein the MEK inhibitor is ATR-002 (zapnometinib).

Embodiment 18 provides the composition of Embodiment 17, wherein the composition has a ATR-002 concentration ranging from about 5 mg/mL to about 100 mg/mL, optionally wherein the composition has a ATR-002 concentration ranging from about 5 mg/mL to about 25 mg/mL.

Embodiment 19 provides the composition of Embodiment 18, wherein the ATR-002 concentration is about 15 mg/mL.

Embodiment 20 provides a composition comprising a MEK inhibitor, a hydroxypropyl-P- cyclodextrin (HPBCD) solution, water, and PEG.

Embodiment 21 provides the composition of Embodiment 20, wherein the MEK inhibitor is selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, REC4881, TAK 733, ATR-002, PD-0325901, GDC-0623, and refametinib. Embodiment 22 provides the composition of Embodiment 20 or 21 , wherein the ETPBCD solution has a HPBCD concentration of about 200 mg/mL.

Embodiment 23 provides the composition of any one of Embodiments 20-22, further comprising glycerol.

Embodiment 24 provides the composition of Embodiment 23, wherein the glycerol is a solution of 85% glycerol in water (v/v).

Embodiment 25 provides the composition of any one of Embodiments 20-24, wherein the composition comprises PEG.

Embodiment 26 provides the composition of Embodiment 25, wherein the PEG is selected from the group consisting of PEG-200, PEG-400, and PEG-600.

Embodiment 27 provides the composition of any one of Embodiments 20-26, wherein the PEG, HPBCD solution, and water have a ratio of about 1:5:4 (v/v).

Embodiment 28 provides the composition of any one of Embodiments 23-26, wherein the PEG, HPBCD, glycerol, and water have a ratio of about 2:5: 11 :6 (v/v).

Embodiment 29 provides the composition of any one of Embodiments 20-28, wherein the MEK inhibitor is binimetinib.

Embodiment 30 provides the composition of Embodiment 29, wherein the composition has a binimetinib concentration ranging from about 0.5 mg/mL to about 1.5 mg/mL.

Embodiment 31 provides the composition of Embodiment 30, wherein the binimetinib concentration is about 1.0 mg/mL.

Embodiment 32 provides a composition comprising a MEK inhibitor, a polyacrylic acid solution, a NaOH solution, and water.

Embodiment 33 provides the composition of Embodiment 32, wherein the MEK inhibitor is selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, REC4881, TAK 733, ATR-002, PD-0325901, GDC-0623, and refametinib.

Embodiment 34 provides the composition of Embodiment 32 or 33, wherein the polyacrylic acid solution comprises 2% polyacrylic acid in water (w/v).

Embodiment 35 provides the composition of any one of Embodiments 32-34, wherein the polyacrylic acid solution comprises about 1% to about 5% K2CO3 (w/v).

Embodiment 36 provides the composition of any one of Embodiments 32-35, wherein the NaOH solution comprises a IN solution of NaOH in water. Embodiment 37 provides the composition of any one of Embodiments 32-36, wherein the polyacrylic acid solution and NaOH solution have a ratio which is about 5: 1 (v/v).

Embodiment 38 provides the composition of any one of Embodiments 32-37, wherein the MEK inhibitor is binimetinib.

Embodiment 39 provides the composition of Embodiment 38, wherein the composition has a binimetinib concentration ranging from about 5 mg/mL to about 15 mg/mL.

Embodiment 40 provides the composition of Embodiment 39, wherein the binimetinib concentration is about 10 mg/mL.

Embodiment 41 provides a composition comprising PEG and ATR-002.

Embodiment 42 provides a composition consisting essentially of PEG and ATR-002.

Embodiment 43 provides a composition consisting of PEG and ATR-002.

Embodiment 44 provides the composition of any one of Embodiments 41-43, wherein the PEG is PEG-200.

Embodiment 45 provides the composition of Embodiment 44, wherein ATR-002 has a concentration in the PEG-200 of about 100 mg/mL.

Embodiment 46 provides the composition of any one of Embodiments 41-43, wherein the PEG is PEG-400.

Embodiment 47 provides the composition of Embodiment 46, wherein ATR-002 has a concentration in the PEG-400 of about 50 to about 100 mg/mL.

Embodiment 48 provides the composition of Embodiment 46 or 47, wherein the ATR- 002 concentration in the PEG-400 is about 74 mg/mL.

Embodiment 49 provides the composition of any one of Embodiments 41-43, wherein the PEG is PEG-600.

Embodiment 50 provides the composition of Embodiment 49, wherein ATR-002 has a concentration in the PEG-600 of about 75 mg/mL to about 100 mg/mL.

Embodiment 51 provides a method of treating, preventing, and/or ameliorating a lymphatic and/or vascular anomaly in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any of Embodiments 1-50.

Embodiment 52 provides the method of Embodiment 51, wherein the lymphatic anomaly is selected from the group consisting of generalized lymphatic anomaly (GLA), central collective lymphatic anomalies (CCLA), kaposiform lymphangiomatosis (KLA), kaposiform hemangioendothelioma (KHE), Gorham-Stout disease (GSD), and Noonan syndrome (NS).

Embodiment 53 provides the method of Embodiment 52, wherein the lymphatic anomaly is GLA

Embodiment 54 provides the method of any one of Embodiments 51-53, wherein the subject is further administered at least one additional agent useful for treating a lymphatic anomaly.

Embodiment 55 provides the method of Embodiment 51, wherein the vascular anomaly is selected from the group consisting of a venous anomaly and/or malformation and an arterial anomaly and/or malformation.

Embodiment 56 provides a method of treating, preventing, and/or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of Embodiments 1-50.

Embodiment 57 provides the method of Embodiment 56, wherein the cancer is at least one of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer, or colon cancer.

Embodiment 58 provides the method of Embodiment 56 or 57, wherein the cancer is at least one of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma and diffuse large B cell lymphoma (DLBCL).

Embodiment 59 provides the method of any one of Embodiments 51-58, wherein the subject is a mammal.

Embodiment 60 provides the method of Embodiment 59, wherein the mammal is a human.

Embodiment 61 provides the method of Embodiment 60, wherein the human is a child. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.

Claims

CLAIMS What is claimed is:

1. A composition comprising a MEK (Mitogen- Activated Protein Kinase Kinase) inhibitor, glycerol, and polyethylene glycol (PEG).

2. The composition of claim 1, wherein the MEK inhibitor is selected from the group consisting of ATR-002 (zapnometinib), binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, TAK 733 (REC4881), PD-0325901, GDC-0623, MSC2015103B (AS703988), and refametinib.

3. The composition of claim 1 or 2, wherein the glycerol is a solution of 85% glycerol in water (v/v).

4. The composition of any one of claims 1-3, wherein the composition comprises PEG.

5. The composition of claim 4, wherein the PEG is selected from the group consisting of PEG-200, PEG-400, and PEG-600.

6. The composition of any one of claims 1-5, wherein the glycerol and PEG have a ratio ranging from about 5:1 to about 15: 1 (v/v).

7. The composition of any one of claims 1-6, wherein the ratio of glycerol to PEG is about 9: 1 (v/v).

8. The composition of any one of claims 1-7, wherein the MEK inhibitor is binimetinib.

9. The composition of claim 8, wherein the composition has a binimetinib concentration ranging from about 1.0 mg/mL to about 2.0 mg/mL.

10. The composition of claim 9, wherein the binimetinib concentration is about 1.5 mg/mL.

11. The composition of any one of claims 1-5, wherein the PEG and glycerol have a ratio ranging from about 1 :1 to about 10:2 (v/v).

12. The composition of claim 11, wherein the PEG and glycerol have a ratio of about 5:2 or about 1 : 1 (v/v).

13. The composition of any one of claims 1-5 and 11-12, further comprising ethanol (EtOH).

14. The composition of claim 13, wherein the PEG and glycerol have a ratio ranging from about 1 :2 to about 4:2 (v/v).

15. The composition of claim 13 or 14, wherein the PEG and glycerol have a ratio of about 2:2 (v/v).

16. The composition of claim 13, wherein the PEG, glycerol, and EtOH have a ratio of about 9:9:2 (v/v).

17. The composition of any one of claims 1-5 and 11-16, wherein the MEK inhibitor is ATR- 002 (zapnometinib).

18. The composition of claim 17, wherein the composition has a ATR-002 concentration ranging from about 5 mg/mL to about 100 mg/mL, optionally wherein the composition has a ATR-002 concentration ranging from about 5 mg/mL to about 25 mg/mL.

19. The composition of claim 18, wherein the ATR-002 concentration is about 15 mg/mL.

20. A composition comprising a MEK inhibitor, a hydroxypropyl-P-cyclodextrin (HPBCD) solution, water, and PEG.

21 . The composition of claim 20, wherein the MEK inhibitor is selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, REC4881, TAK 733, ATR-002, PD-0325901, GDC-0623, and refametinib.

22. The composition of claim 20 or 21, wherein the HPBCD solution has a HPBCD concentration of about 200 mg/mL.

23. The composition of any one of claims 20-22, further comprising glycerol.

24. The composition of claim 23, wherein the glycerol is a solution of 85% glycerol in water (v/v).

25. The composition of any one of claims 20-24, wherein the composition comprises PEG.

26. The composition of claim 25, wherein the PEG is selected from the group consisting of PEG-200, PEG-400, and PEG-600.

27. The composition of any one of claims 20-26, wherein the PEG, HPBCD solution, and water have a ratio of about 1 :5:4 (v/v).

28. The composition of any one of claims 23-26, wherein the PEG, HPBCD, glycerol, and water have a ratio of about 2 : 5 : 11 : 6 (v/v).

29. The composition of any one of claims 20-28, wherein the MEK inhibitor is binimetinib.

30. The composition of claim 29, wherein the composition has a binimetinib concentration ranging from about 0.5 mg/mL to about 1.5 mg/mL.

31. The composition of claim 30, wherein the binimetinib concentration is about 1.0 mg/mL.

32. A composition comprising a MEK inhibitor, a polyacrylic acid solution, a NaOH solution, and water.

33. The composition of claim 32, wherein the MEK inhibitor is selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimasertib, REC4881, TAK 733, ATR-002, PD-0325901, GDC-0623, and refametinib.

34. The composition of claim 32 or 33, wherein the polyacrylic acid solution comprises 2% polyacrylic acid in water (w/v).

35. The composition of any one of claims 32-34, wherein the polyacrylic acid solution comprises about 1% to about 5% K2CO3 (w/v).

36. The composition of any one of claims 32-35, wherein the NaOH solution comprises a IN solution of NaOH in water.

37. The composition of any one of claims 32-36, wherein the polyacrylic acid solution and NaOH solution have a ratio which is about 5: 1 (v/v).

38. The composition of any one of claims 32-37, wherein the MEK inhibitor is binimetinib.

39. The composition of claim 38, wherein the composition has a binimetinib concentration ranging from about 5 mg/mL to about 15 mg/mL.

40. The composition of claim 39, wherein the binimetinib concentration is about 10 mg/mL.

41. A composition comprising PEG and ATR-002.

42. A composition consisting essentially of PEG and ATR-002.

43. A composition consisting of PEG and ATR-002.

44. The composition of any one of claims 41-43, wherein the PEG is PEG-200.

45. The composition of claim 44, wherein ATR-002 has a concentration in the PEG-200 of about 100 mg/mL.

46. The composition of any one of claims 41-43, wherein the PEG is PEG-400.

47. The composition of claim 46, wherein ATR-002 has a concentration in the PEG-400 of about 50 to about 100 mg/mL.

48. The composition of claim 46 or 47, wherein the ATR-002 concentration in the PEG-400 is about 74 mg/mL.

49. The composition of any one of claims 41-43, wherein the PEG is PEG-600.

50. The composition of claim 49, wherein ATR-002 has a concentration in the PEG-600 of about 75 mg/mL to about 100 mg/mL.

51. A method of treating, preventing, and/or ameliorating a lymphatic and/or vascular anomaly in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any of claims 1-50.

52. The method of claim 51, wherein the lymphatic anomaly is selected from the group consisting of generalized lymphatic anomaly (GLA), central collective lymphatic anomalies (CCLA), kaposiform lymphangiomatosis (KLA), kaposiform hemangioendothelioma (KHE), Gorham-Stout disease (GSD), and Noonan syndrome (NS).

53. The method of claim 52, wherein the lymphatic anomaly is GLA.

54. The method of any one of claims 51 -53, wherein the subject is further administered at least one additional agent useful for treating a lymphatic anomaly.

55. The method of claim 51, wherein the vascular anomaly is selected from the group consisting of a venous anomaly and/or malformation and an arterial anomaly and/or malformation.

56. A method of treating, preventing, and/or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1-50.

57. The method of claim 56, wherein the cancer is at least one of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer, or colon cancer.

58. The method of claim 56 or 57, wherein the cancer is at least one of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NEIL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma and diffuse large B cell lymphoma (DLBCL).

59. The method of any one of claims 51-58, wherein the subject is a mammal.

60. The method of claim 59, wherein the mammal is a human.

61. The method of claim 60, wherein the human is a child.