Taxol conjugate compounds and pharmaceutical compositions thereof

Abstract

Provided herein are peptide-paclitaxel conjugate compounds, comprising paclitaxel conjugated to oligoarginine peptides via a disulfide linker, wherein the disulfide linker is attached to the taxol at the C2' hydroxyl position, pharmaceutical compositions thereof, methods of their preparation, and methods of their use in treatment or prevention of a proliferative, dermatological, or ophthalmological disease or disorder.

Description

TAXOL CONJUGATE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOFCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 447,609, filed February 22, 2023, which is hereby incorporated by reference in its entirety.FIELD

[0002] Provided herein are pepti de-paclitaxel conjugate compounds and pharmaceutical compositions thereof.BACKGROUND

[0003] Despite numerous advances over many years, cancer remains a global health concern. Cancer is among the leading causes of death worldwide. In 2018, there were 18.1 million new cancer cases and 9.5 million cancer-related deaths worldwide. By 2040, the number of new cancer cases per year is expected to rise to 29.5 million and the number of cancer-related deaths to 16.4 million. See National Cancer Institute (US) and World Health Organization.

[0004] Liver cancer is common in sub-Saharan Africa and Southeast Asia. In many of these countries, it is the most common type of cancer. More than 800,000 people are diagnosed with this cancer each year throughout the world. Liver cancer is also a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year.

[0005] Ovarian cancer is the fifth leading cause of cancer death in females, with an estimated 22,000 women in the United States being diagnosed, accounting for 15,500 deaths.

[0006] Gastric cancer is the 4th most common cancer worldwide and the second leading cause of cancer death. 40% of gastric cancer deaths have liver metastasis, while 53-60% have peritoneal carcinomatosis. Systemic chemotherapy provides a median survival of 7 months; however with peritoneal spread the median survival is only 1-3 months.

[0007] Colorectal cancer is the third most common cancer diagnosed in the United States. It causes about 49,700 deaths annually, making it the second most common cause of cancerdeaths. Approximately 10% of patients have peritoneal spread at the time diagnosis, and this is the second leading cause of death in patients with colorectal cancer. The median overall survival for patients with colorectal cancer with peritoneal dissemination is 24 months.

[0008] Currently, there are no chemotherapeutic agents specifically approved for intraperitoneal (IP) chemotherapy. All current IP chemotherapy clinical studies have been performed by off-label use of drugs designed for intravenous (IV) applications.

[0009] Dermatological diseases, on a global scale, are the fourth most common among all diseases, affecting almost one-third of the world population. Flohr, 2021, Brit. J. Dermatol. 184(2): 189-190. As of 2013, skin diseases contributed 1.79% to the global burden of disease. Karimkhani et al., 2017, JAMA Dermatol. 153(5):406-412.

[0010] Ophthalmological conditions affect an estimated 2.2 billion people in the world as of 2021. Almost half of these cases could have been prevented or have yet to be addressed by treatment. The global burden of eye diseases was estimated to be 4.0% of the total global disease burden in 2013 as reported in Ono etal., 2010, Am. J. Public Health 100(9):1784-1788.

[0011] There is a need for additional therapies for treating proliferative, dermatological, or ophthalmological diseases and conditions. There is also a need for new therapies effective for intraperitoneal administration for treating proliferative, dermatological, or ophthalmological diseases and disorders.SUMMARY

[0012] In one aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein n is an integer selected from 1-20. In some embodiments, n is 8. In someor a pharmaceutically acceptable salt. In some embodiments, the compound is an acetate salt.

[0013] In some embodiments, the pharmaceutical composition is a formulation further comprising mannital. In some embodiments, mannital is 2.5 wt% of the formulation. In some embodiments, the formulation is substantially free of surfactants. The formulation can be aqueous or lyophilized.

[0014] In another aspect, provided herein is an aqueous pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:and the aqueous pharmaceutical composition has a pH of less than 5.5. In some embodiments, n is 8. In some embodiments, the compound is of Formula (II),or a pharmaceutically acceptable salt. In some embodiments, the compound is an acetate salt. In some embodiments, the aqueous pharmaceutical composition further comprises mannital. In some embodiments, mannital is 2.5 wt% of the aqueous pharmaceutical composition. In some embodiments, the aqueous pharmaceutical composition is substantially free of surfactants.

[0015] In some embodiments, the aqueous pharmaceutical composition has a pH between 3 and 4, In some embodiments, the aqueous pharmaceutical composition has a pH between 3 and 5.5. embodiments, the aqueous pharmaceutical composition has a pH of about 3.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 4.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.0.

[0016] In some embodiments, the aqueous pharmaceutical composition has a pH of about or less than 5.5, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is no less than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH of about or less than 5.0, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH about or less 4.5, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueouspharmaceutical composition has a pH about or less 4.0, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH of about or less 3.5, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH of about or less 3.0, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL.

[0017] In another aspect, provided herein an aqueous pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:and the concentration of the compound, or a pharmaceutically acceptable salt thereof, is at least about 25 mg / mL. In some embodiments, n is 8. In some embodiments, the compound is of Formula (II),or a pharmaceutically acceptable salt. In some embodiments, the compound is an acetate salt. In some embodiments, the aqueous pharmaceutical composition further comprises mannital. In some embodiments, mannital is 2.5 wt% of the aqueous pharmaceutical composition. In some embodiments, the aqueous pharmaceutical composition is substantially free of surfactants.

[0018] In some embodiments, the concentration of the compound or a pharmaceutically acceptable salt thereof in the aqueous pharmaceutical composition is between 25 mg / mL and 50 mg / mL, between 50 mg / mL and 100 mg / mL, or between 100 mg / mL and 200 mg / mL. In some embodiments, the concentration of the compound described herein, or a pharmaceutically acceptable salt thereof in the aqueous pharmaceutical composition is at least about 25 mg / mL (e.g., at least about 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL or 250 mg / mL). In some embodiments, the concentration is about 25 mg / mL. In some embodiments, the concentration about 50 mg / mL. In some embodiments, the concentration is about 100 mg / mL. In some embodiments, the concentration is about 150 mg / mL. In some embodiments, the concentration is about 200 mg / mL. In some embodiments, the concentration is about 250 mg / mL.

[0019] In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 25 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 50 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 75 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 100 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 150 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound(e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 200 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 250 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0.BRIEF DESCRIPTION OF THE FIGURES

[0020] FIG. 1A is a graph of solutions of compound of Formula (II) in buffers systems (1 mg / mL) with different pH values after 24 hours. The solution samples from left to right have pH of 3, 4, 5, 6, 7, 8, and 9, respectively.

[0021] FIG. IB is a graph of solutions of compound of Formula (II) in buffers systems (10 mg / mL) with different pH values after 24 hours. The solution samples from left to right have pH of 3, 4, 5, 6, 7, 8, and 9, respectively.

[0022] FIG. 1C is a graph of solutions of compound of Formula (II) in buffers systems (100 mg / mL) with different pH values after 24 hours. The solution samples from left to right have pH of 3, 4, 5, 6, 7, 8, and 9, respectively.

[0023] FIG. ID is a graph of solutions of compound of Formula (II) in buffers systems (200 mg / mL) with different pH values after 24 hours. The solution samples from left to right have pH of 3, 4, 5, 6, 7, 8, and 9, respectively.

[0024] FIG. IE is a graph of as-prepared solutions of compound of Formula (II) in WFI (5 mg / mL) with different pH values. The solution samples from left to right have pH of 3, 4, 5, 6, 7, 8, and 9, respectively.

[0025] FIG. IF is a graph of solutions of compound of Formula (II) in buffers systems (5 mg / mL) with different pH values after 24 hours. The solution samples from left to right have pH of 3, 4, 5, 6, 7, 8, and 9, respectively.

[0026] FIG. 2 is a plot of compound of Formula (II) degradation level versus pH.

[0027] FIG. 3 is a plot of compound of Formula (II) degradation level versus storage days under different pH conditions.

[0028] FIG. 4 is a plot of compound of Formula (II) degradation level versus storage days with different initial concentrations.DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0029] Described herein are pharmaceutical compositions containing a peptide-paclitaxel conjugate compound, or a pharmaceutically acceptable salt thereof. The present application is based, at least in part, on the surprising finding that an aqueous pharmaceutical composition comprising a peptide-paclitaxel conjugate compound of formula (I), specifically, the compound of formula (II), or a pharmaceutically acceptable salt thereof demonstrate remarkable solubility and stability at one or more of the following conditions: 1) low pH (e.g., no more than about pH 5.5); 2) high concentration (e.g., at least about 25 mg / mL); and 3) in a mannitol-containing formulation . Thus, the present application provides pharmaceutical compositions, including specific formulations, suitable for the paclitaxel-peptide conjugate compounds described herein, or pharmaceutically acceptable salts thereof.Definitions

[0030] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity, and / or ready reference. The techniques and procedures described or referenced herein are generally well understood, and are commonly employed using conventional methodologies by those skilled in the art. As appropriate, procedures involving the use of commercially available kits, and reagents are generally carried out in accordance with manufacturer-defined protocols, and conditions unless otherwise noted.

[0031] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0032] The term “about” indicates and encompasses an indicated value, and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value. In certain embodiments, for example, logarithmic scales (e.g., pH), the term “about” indicates the designated value ± 0.3, ± 0.2, or ± 0.1.

[0033] When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0034] The term “protecting group,” as used herein, and unless otherwise specified, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction, or for other purposes. A wide variety of oxygen, and nitrogen protecting groups are known to those skilled in the art of organic synthesis. (See, e.g., Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, which is incorporated herein by reference).

[0035] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0036] The term “substantially free of’ or “substantially in the absence of’ with respect to a composition refers to a composition that includes at least 50%, 60%, 70%, 75%, 80%, 85%, or 90% by weight, in certain embodiments 95%, 98 %, 99%, or 100% by weight; or in certain embodiments, 95%, 98%, 99%, or 100% of the designated enantiomer or diastereomer of a compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of one of two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of one of two diastereomers. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of the opposite D-cysteine amino acid epimer.

[0037] The term “epimer” is one of a pair of diastereomers that have the opposite configuration at only one stereogenic center, or chiral center, out of at least two. For example,a compound of Formula (I) and the corresponding compound comprising a D-cysteine amino acid are epimers.

[0038] Similarly, the term “isolated” with respect to a composition refers to a composition that includes at least 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% by weight, of the compound, the remainder comprising other chemical species, enantiomers or diastereomers.

[0039] As used herein, “enantiomeric excess (ee)” refers to a dimensionless mole ratio describing the purity of chiral substances that contain, for example, a single stereogenic center. For instance, an enantiomeric excess of zero would indicate a racemic (e.g., 50:50 mixture of enantiomers, or no excess of one enantiomer over the other). By way of further example, an enantiomeric excess of ninety -nine would indicate a nearly stereopure enantiomeric compound (i.e., large excess of one enantiomer over the other). The percentage enantiomeric excess, % ee = ([(7?)-compound]-[(S)-compound]) / ([(7?)-compound]+[(S)-compound]) x 100, where the (R)- compound > (S)-compound; or % ee = ([(S)-compound]-[(7?)-compound]) / ([(S)- compound]+[(7?)-compound]) x 100, where the (S)-compound > (7?)-compound.

[0040] As used herein, “diastereomeric excess (de)” refers to a dimensionless mole ratio describing the purity of chiral substances that contain more than one stereogenic center. For example, a diastereomeric excess of zero would indicate an equimolar mixture of diastereoisomers. By way of further example, diastereomeric excess of ninety-nine would indicate a nearly stereopure diastereomeric compound (i.e., large excess of one diastereomer over the other). Diastereomeric excess may be calculated via a similar method to ee. As would be appreciated by a person of skill, de is usually reported as percent de (% de). % de may be calculated in a similar manner to % ee.

[0041] “Solvate” refers to a compound provided herein, or a salt thereof, that further includes a stoichiometric, or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0042] “Isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition, or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example,unless otherwise stated, when a position is designated specifically as hydrogen (H), the position is understood to have hydrogen at its natural isotopic composition.

[0043] “Isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance. For example, deuterium (D) enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0044] “Isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0045] As used herein, term “ECso” refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked, or potentiated by the particular test compound.

[0046] As used herein, and unless otherwise specified, the term “ICso” refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0047] As used herein, the terms “subject”, and “patient” are used interchangeably. The terms “subject”, and “subjects” refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse), and a primate (e.g., a monkey, such as a cynomolgous monkey, a chimpanzee, and a human), and in certain embodiments, a human. In certain embodiments, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.), or a pet (e.g., a dog or a cat). In certain embodiments, the subject is a human.

[0048] As used herein, the terms “therapeutic agent”, and “therapeutic agents” refer to any agent(s) which can be used in the treatment, or prevention of a disorder, or one or moresymptoms thereof. In certain embodiments, the term “therapeutic agent” includes a compound provided herein. In certain embodiments, a therapeutic agent is an agent which is known to be useful for, or has been, or is currently being used for the treatment, or prevention of a disorder, or one, or more symptoms thereof.

[0049] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g, metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. In some embodiments, the composition reduces the severity of one or more symptoms associated with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the composition. Also encompassed by “treatment” is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.

[0050] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

[0051] As used herein, an “at risk” individual is an individual who is at risk of developing cancer. An individual “at risk” may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of cancer, which are described herein. An individual having one or more of these risk factors has a higher probability of developing cancer than an individual without these risk factor(s).

[0052] “Adjuvant setting” refers to a clinical setting in which an individual has had a history of cancer, and generally (but not necessarily) been responsive to therapy, which includes, but is not limited to, surgery (e.g, surgical resection), radiotherapy, and chemotherapy. However, because of their history of the cancer, these individuals are considered at risk of development of the disease. Treatment or administration in the “adjuvant setting” refers to a subsequent mode of treatment. The degree of risk (e.g, when an individual in the adjuvant setting is considered as “high risk” or “low risk”) depends upon several factors, most usually the extent of disease when first treated.

[0053] “Neoadjuvant setting” refers to a clinical setting in which the method is be carried out before the primary / definitive therapy.

[0054] As used herein, by “pharmaceutically active compound” is meant a chemical compound that induces a desired effect, e.g, treating, stabilizing, preventing, and / or delaying cancer.

[0055] As used herein, by “combination therapy” is meant a first therapy that includes nanoparticles comprising rapamycin or a derivative thereof and a carrier protein in conjunction with a second therapy (e.g, radiation, surgery, or chemotherapeutic agent) useful for treating, stabilizing, preventing, and / or delaying cancer. Administration in “conjunction with” another compound includes administration in the same or different composition(s), either sequentially, simultaneously, or continuously. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inert substances.

[0056] As used herein, the terms “prophylactic agent”, and “prophylactic agents” as used refer to any agent(s) which can be used in the prevention of a disorder, or one or more symptoms thereof. In certain embodiments, the term “prophylactic agent” includes a compound provided herein. In certain other embodiments, the term “prophylactic agent” does not refer a compound provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent, or impede the onset, development, progression, and / or severity of a disorder.

[0057] As used herein, the phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention, or reduction of the development, recurrence, or onset of one or more symptoms associated with adisorder, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).

[0058] The term “effective amount” intends such amount of a composition (e.g. , compound of Formula (II)), first therapy, second therapy, or a combination therapy, which in combination with its parameters of efficacy and toxicity, should be effective in a given therapeutic form based on the knowledge of the practicing specialist. In various embodiments, an effective amount of the composition or therapy may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of a tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and / or delay one or more of symptoms of cancer.

[0059] In some embodiments, the amount of the composition, first therapy, second therapy, or combination therapy is an amount sufficient to decrease the size of a tumor, decrease the number of cancer cells, or decrease the growth rate of a tumor by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding tumor size, number of cancer cells, or tumor growth rate in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the treatment. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays with purified enzyme, cell-based assays, animal models, or human testing.

[0060] As is understood in the art, an “effective amount” may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a nanoparticle composition (e.g, a composition including rapamycin and a carrier protein) may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. The components (e.g, the first and second therapies) in a combination therapy of the invention may be administered sequentially, simultaneously, or continuously using the same or different routes of administration for each component. Thus, an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that when administered sequentially, simultaneously, or continuously produces a desired outcome.

[0061] A “therapeutically effective amount” refers to an amount of a composition (e.g, compound of Formula (II)), first therapy, second therapy, or a combination therapy sufficient to produce a desired therapeutic outcome (e.g, reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of cancer). For therapeutic use, beneficial or desired results include, e.g, decreasing one or more symptoms resulting from the disease (biochemical, histologic and / or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, and / or prolonging survival of patients.

[0062] A “prophy tactically effective amount” refers to an amount of a composition (e.g. compound of Formula (II)), first therapy, second therapy, or a combination therapy sufficient to prevent or reduce the severity of one or more future symptoms of cancer when administered to an individual who is susceptible and / or who may develop cancer. For prophylactic use, beneficial or desired results include, e.g, results such as eliminating or reducing the risk, lessening the severity of future disease, or delaying the onset of the disease (e.g, delaying biochemical, histologic and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during future development of the disease).

[0063] It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.Pharmaceutical Composition

[0064] In one aspect, provided herein is an aqueous pharmaceutical composition comprising a compound described herein (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (I). In some embodiments, the compound is a compound of Formula (II). In some embodiments, the aqueous pharmaceutical composition further comprises water for injection.

[0065] In some embodiments, the aqueous pharmaceutical composition has a pH of less than 7 (e.g., less than 6, less than 5.5, less than 5, less than 4.5, less than 4, or less than 3.5). In some embodiments, the aqueous pharmaceutical composition has a pH between 2 to 7 (e.g.,between 3 to 4, between 3 to 5, between 3 to 5.5, between 3 to 6, or between 3 to 7). In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 4.5 In some embodiments, the aqueous pharmaceutical composition has a pH of less than 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of no less than 2.5. In some embodiments, the aqueous pharmaceutical composition has a pH of no less than 3.0. In some embodiments, the aqueous pharmaceutical composition has a pH of no less than 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH of no less than 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH of no less than 4.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 3.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 4.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.5.

[0066] In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof in the aqueous pharmaceutical composition is between 0.1 mg / mL and 250 mg / mL (e.g., between 0.1 mg / mL and 250 mg / mL, between 1 mg / mL and 200 mg / mL, between 10 mg / mL and 100 mg / mL, between 10 mg / mL and 25 mg / mL, between 25 mg / mL and 50 mg / mL, between 25 mg / mL and 75 mg / mL, between 50 mg / mL and 100 mg / mL, between 75 mg / mL and 250 mg / mL, or between 100 mg / mL and 200 mg / mL). In some embodiments, the concentration of the compound described herein (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof in the aqueous pharmaceutical composition is greater than 25 mg / mL (e.g., greater than 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL or 250 mg / mL). In some embodiments, the concentration is about 25 mg / mL. In some embodiments, the concentration is about 50 mg / mL. In some embodiments, the concentration is about 100 mg / mL. In some embodiments, the concentration is about 150 mg / mL. In some embodiments, the concentration is about 200 mg / mL. In some embodiments, the concentration is about 250 mg / mL.

[0067] In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.5, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH of no more than 5.0, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH no more than 4.5, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH no more than 4.0, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH of no more than 3.5, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL. In some embodiments, the aqueous pharmaceutical composition has a pH of no more than 3.0, and the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is about or more than 0.1 mg / mL, 1.0 mg / mL, 5.0 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, or 200 mg / mL.

[0068] In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 25 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 50 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 75 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound(e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 100 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 150 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 200 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, the concentration of the compound (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, is at least about 250 mg / mL, and the aqueous pharmaceutical composition has a pH of no more than 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is no more than about 5.5 (such as any of 5, 4.5, 4, 3.5, or 3). In some embodiments, the concentration of the compound, or a pharmaceutically acceptable salt thereof in the formulation is at least about 25 mg / mL (such as at least about any of 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL). In some embodiments, the the formulation further comprises mannitol. In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0069] In some embodiments, there is provided a liquid formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof is at least about 25 mg / mL (such as at least about any of 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL). In some embodiments, the formulation further comprises mannitol. In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0070] In some embodiments, in conjunction with any of the embodiments above or below, the aqueous pharmaceutical composition is prepared by reconstitution of a lyophilized formulation. In some embodiments, in conjunction with any of the embodiments above orbelow, the pharmaceutically acceptable salt of compound (e.g., compound of Formula (I) or Formula (II)) is an acetate salt.

[0071] In some embodiments, in conjunction with any of the embodiments above or below, the pharmaceutical compositions provided herein are suitable to be administered by any suitable route known in the art. For example, the pharmaceutical compositions described herein are suitable for administration routes including, but are not limited to, oral, inhalation, sublingual, buccal, intraarterial, intradermal, intramuscular, intraperitoneal (I.P.), intravenous (I.V.), nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, a pharmaceutical composition provided herein is suitable for parenteral administration. In some embodiments, a pharmaceutical composition provided herein is suitable for I.P. injection. In some embodiments, a pharmaceutical formulation provided herein is suitable for I.V. injection. In some embodiments, a pharmaceutical composition provided herein is suitable for oral administration.Pharmaceutically acceptable excipients

[0072] The pharmaceutical compositions described herein can further comprise a pharmaceutically acceptable carrier. The term “carrier” includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils including petroleum, animal, vegetable, or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions, and aqueous dextrose, and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, E.W., Remington ’s Pharmaceutical Sciences.

[0073] Any suitable pharmaceutical excipient may be used, wherein a person of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition, or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific compound in thedosage form. The composition, or single unit dosage form, if desired, can also contain minor amounts of wetting, or emulsifying agents, or pH buffering agents. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference herein in its entirety.

[0074] In some embodiments, the pharmaceutical composition comprises an anti-foaming agent. Any suitable anti-foaming agent may be used. In some aspects, the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some aspects, the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long-chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof. In some embodiments, the pharmaceutical composition provided herein does not comprise any anti-foaming agent.

[0075] In some embodiments, the pharmaceutical composition comprises a co-solvent. Illustrative examples of co-solvents include, for example, ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol. In some embodiments, the pharmaceutical composition provided herein is a aqueous solution that does not comprise any co-solvent.

[0076] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include, for example, acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate. In some embodiments, the pharmaceutical composition provided herein does not comprise any buffers.

[0077] In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers, or fillers, include, for example, lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0078] In some embodiments, the pharmaceutical composition provided herein comprises mannitol. In some embodiments, the pharmaceutical composition comprises a compounddescribed herein (e.g., compound of Formula (I) or Formula (II)), and mannitol, wherein the relative weight ratio between the compound and mannitol is about 200: 1 to about 10: 1. In some embodiments, the pharmaceutical composition comprises a compound described herein (e.g., compound of Formula (I) or Formula (II)), and mannitol, wherein the relative weight ratio between the compound and mannitol is about 100 to about 20: 1. In some embodiments, the relative weight ratio between the compound and mannitol is about 100: 1, 80: 1, 60: 1, 50: 1, 45: 1, 40: 1, 35: 1, 30: 1, or 20: 1.

[0079] In some embodiments, provided herein is an aqueous pharmaceutical composition comprising a compound described herein (e.g., compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition has a pH of less than 5.5, and wherein the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.5, and the aqueous pharmaceutical composition does not comprise a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.0, and the aqueous pharmaceutical composition does not comprise a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 4.5, and the aqueous pharmaceutical composition does not comprise a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 4.0, and the aqueous pharmaceutical composition does not comprise a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 3.0, and the aqueous pharmaceutical composition does not comprise a buffer. In some embodiments, the pharmaceutical compositions comprise water for injection.

[0080] In some embodiments, the aqueous pharmaceutical composition has a concentration of the compound (e.g., compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt thereof, of greater than 0. 1 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration of greater than 1 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration of greater than 25 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration of greater than 50 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration of greater than 100 mg / mL, and thepharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration of greater than 200 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical compositions do not comprise a surfactant.

[0081] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the formulation further comprises mannitol. In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0082] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is no more than about 5.5 (such as any of 5, 4.5, 4, 3.5, or 3), wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof in the formulation is at least about 25 mg / mL (such as at least about any of 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL), and wherein the formulation further comprises mannitol. In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0083] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is about 3.0, wherein the concentration of the compound in the formulation is about 50 mg / mL, and wherein the formulation further comprises mannitol (e.g, 2.5% or 5% mannitol by weight in the formulation). In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0084] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is about 3.0, wherein the concentration of the compound in the formulation is about 110 mg / mL. In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0085] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is about 3.0, wherein the concentration of the compound in the formulation is about 110 mg / mL, and wherein the formulation further comprises benzyl alcohol (e.g., 0.5%, 1%, 1.5%, or 2% benzyl alcohol by weight in the formulation). In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0086] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is about 3.0, wherein the concentration of the compound in the formulation is about 110 mg / mL, and wherein the formulation further comprises mannitol (e.g., 2.5% or 5% mannitol by weight in the formulation) and benzyl alcohol (e.g., 0.5%, 1%, 1.5%, or 2% benzyl alcohol by weight in the formulation). In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0087] In some embodiments, there is provided a formulation of a compound of Formula (I) (such as a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is about 3.0, wherein the concentration of the compound in the formulation is about 100 mg / mL, and wherein the formulation further comprises mannitol (e.g, 2.5% or 5% mannitol by weight in the formulation), benzyl alcohol (e.g., 0.5%, 1%, 1.5%, or 2% benzyl alcohol by weight in the formulation), and EDTA (e.g., 0.05%, or 0.1% EDTA by weight in the formulation). In some embodiments, the composition is substantially free of surfactants. In some embodiments, the formulation comprises an acetate salt of the compound.

[0088] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include, for example, -alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxy stearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate. In some embodiments, the pharmaceutical composition provided herein does not comprise any surfactant.

[0089] In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include, for example, calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide. In some embodiments, the pharmaceutical composition provided herein does not comprise any anticaking agents.

[0090] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference herein in its entirety. In some embodiments, the pharmaceutical composition provided herein does not comprise any antioxidants. In some embodiments, the pharmaceutical composition provided herein does not comprise any chelating agents. In some embodiments, the pharmaceutical composition provided herein does not comprise any emulsifying agents. In some embodiments, the pharmaceutical composition provided herein does not comprise any solubilizing agents. In some embodiments, the pharmaceutical composition provided herein does not comprise any stabilizing agents.

[0091] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is saline solution, such as a sterile isotonic saline solution, or dextrose solution. In some aspects, the solvent is water for injection. In some aspects, the solvent is dextrose solution.

[0092] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous, or low moisture containing ingredients, and low moisture, or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity is made during manufacturing, packaging, and / or storage is expected.

[0093] An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged usingmaterials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0094] Lactose-free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopeia (USP) SP (III) / NF (XVI). In general, lactose-free compositions comprise an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.Parenteral Dosage Forms

[0095] In certain embodiments, the pharmaceutical compositions provided herein are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), inhalation, intramuscular, and intraarterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, emulsions, lyophilized powder ready to be reconstituted by a pharmaceutically acceptable solution for injection, and atomized droplets ready to be inhaled.

[0096] In some embodiments, in conjunction with any of the embodiments above or below, the pharmaceutical compositions provided herein are emulsions or sterile solutions suitable for parenteral administration. Such parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These pharmaceutical compositions can also contain wetting, isotonizing, emulsifying, dispersing, and stabilizing agents. Sterilization can be carried out in several ways, for example, using a bacteriological filter, via radiation, or via heating. These pharmaceutical compositions can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water, or any other injectable sterile medium.

[0097] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to Water for InjectionUSP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose, and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. In some embodiments, the aqueous pharmaceutical compositions provided herein comprise Water for Injection. In some embodiments, the aqueous pharmaceutical compositions provided herein comprise Water for Injection and have a pH value of less than 5.5.

[0098] In some embodiments, the pharmaceutical compositions provided herein are lyophilized powder ready to be reconstituted by a pharmaceutically acceptable solution (e.g.,Water for Injection) for injection. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition comprising the compound of Formula (II), water- for-inj ection, mannitol, and HC1. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition, wherein the starting solution has a pH lower than 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH lower than 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH lower than 4.5. In some embodiments, the aqueous pharmaceutical composition has a pH lower than 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH lower than 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH lower than 3.0. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition, wherein the concentration of the compound of Formula (II) is about 10 mg / mL to about 200 mg / mL. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition, the concentration of the compound of Formula (II) is about is about 50 mg / mL. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition comprises about 1.0 wt.% to about 10% wt.% mannitol. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition comprises about 1.0 wt.% to about 5% wt.% mannitol. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition comprises about 2.5 wt.% mannitol. In some embodiments, the lyophilized is prepared from an aqueous pharmaceutical composition comprising 50 mg / mL of compound of Formula (II), Water for Injection, and about 2.5 wt.% mannitol. In certain embodiments, the lyophilized is free of surfactants.

[0099] In some embodiments, the pharmaceutical compositions provided herein are lyophilized powder ready to be reconstituted by a pharmaceutically acceptable solution for injection, wherein the pharmaceutically acceptable solution comprises water-for-inj ection (WFI) and dextrose 5% in water (D5W). In some embodiments, the pharmaceutically acceptable solution is water-for-inj ection (WFI). In some embodiments, the pharmaceutically acceptable solution is D5W. In some embodiments, the lyophilized powder can be diluted no less than 5-fold, no less than 10-fold, no less than 50-fold, or no less than 100-fold by the pharmaceutically acceptable solution.

[0100] In some embodiments, the pharmaceutical compositions provided herein are lyophilized powder ready to be reconstituted by a pharmaceutically acceptable solution for injection, wherein the composition after reconstitution has a pH value of less than 5.5. In some embodiments, the composition after reconstitution has a pH value of less than 5.0. the composition after reconstitution has a pH value of less than 4.5. the composition after reconstitution has a pH value of less than 4.0.

[0101] In some embodiments, the pharmaceutical compositions provided herein are dosage forms for inhalation, wherein the compositions can be administered via non-aqueous inhalers, dry powder inhalers, or jet or ultrasonic nebulizers.Compounds of Formulae (I)-(II)

[0102] The pharmaceutical composition provided herein comprises Taxol conjugate compounds useful for treating or preventing a proliferative, dermatological, or ophthalmological disease or disorder. The compounds can be prepared, formulated, and administered as described herein, and used for therapy or diagnosis. In certain embodiments, the therapy is the treatment of a proliferative, dermatological, or ophthalmological disease or disorder.

[0103] The embodiments described herein include the recited compounds as well as pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof.

[0104] In certain embodiments, provided is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof:wherein n is an integer selected from 1-20. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10. In certain embodiments, n is 11. In certain embodiments, n is 12. In certain embodiments, n is 13. In certain embodiments, n is 14. In certain embodiments, n is 15. In certain embodiments, n is 16. In certain embodiments, n is 17. In certain embodiments, n is 18. In certain embodiments, n is 19. In certain embodiments, n is 20. In certain embodiments, n is an integer from 6-10. In preferred embodiments, n is 8.|0105| In certain embodiments, provided is a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof:

[0106] In certain embodiments, the compounds described herein have a de or % de greater than zero. For example, in certain embodiments, the compounds described herein have a de or % de of about ten. In certain embodiments, the compounds described herein have a de or % de ofabout twenty-five. In certain embodiments, the compounds described herein have a de or % de of about fifty. In certain embodiments, the compounds described herein have a de or % de of about seventy-five. In certain embodiments, the compounds described herein have a de or % de of about eighty. In certain embodiments, the compounds described herein have a de or % de of about eighty-five. In certain embodiments, the compounds described herein have a de or % de of about ninety. In certain embodiments, the compounds described herein have a de or % de of about ninety-five. In certain embodiments, the compounds described herein have a de or % de of about ninety-seven. In certain embodiments, the compounds described herein have a de or % de of about ninety-eight. In certain embodiments, the compounds described herein have a de or % de of about ninety-ninety. In certain embodiments, the compounds described herein have a de or % de of one-hundred.

[0107] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 50% free, at least about 60% free, at least about 70% free, at least about 75% free, at least about 80% free, at least about 85% free, at least about 90% free, at least about 95% free, at least about 97% free, at least about 99% free, or 100% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is about 85% - 95% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is about 90% - 95% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 85% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 90% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 95% free of the opposite D- cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 97% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is 100% free of the opposite D-cysteine amino acid epimer.|0108| In certain embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 50% free, at least about 60% free, at least about 70% free, at least about 75% free, at least about 80% free, at least about 85% free, at least about 90% free, at least about 95% free, at least about 97% free, at least about 99% free, or 100% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is about 85% - 95% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is about 90% - 95% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 85% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 90% free of the opposite D- cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 95% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is at least about 97% free of the opposite D-cysteine amino acid epimer. In one embodiment, the compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof, is 100% free of the opposite D-cysteine amino acid epimer.|0109| In certain embodiments, provided is a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof:(X) wherein the compound of Formula (X) comprises at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% by weight a compound of Formula (I):compared to the total weight of all stereoisomers of Formula (X); wherein n is an integer selected from 1-20.

[0110] In certain embodiments, the compound of Formula (X) comprises at least about 50% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 75% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 80% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 85% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 90% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 95% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 97% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 98% or more by weight of a compound of Formula (I) compared to the total weight of allstereoisomers of Formula (X). In certain embodiments, the compound of Formula (X) comprises at least about 99% or more by weight of a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X). In one embodiment, the compound of Formula (X) is 100% by weight a compound of Formula (I).

[0111] In certain embodiments, the compounds described herein have a de or % de range from about fifty to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about sixty to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about seventy to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about seventy- five to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about eighty to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about eighty-five to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about ninety to one hundred. In certain embodiments, the compounds described herein have a de or % de range from ninety- five to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about ninety-seven to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about ninety-eight to one hundred. In certain embodiments, the compounds described herein have a de or % de range from about ninety -nine to one hundred.

[0112] In some embodiments, provided herein is a pharmaceutical composition comprising compounds of any of Formulas (I)-(II), that are substantially free of a designated stereoisomer of that compound. In some embodiments, provided herein are compositions of compounds of any of Formulas (I)-(II), that are substantially free of a designated stereoisomer of that compound wherein the designated stereoisomer is the opposite D-cysteine amino acid epimer. In certain embodiments, in the methods and compounds of this disclosure, the compounds are substantially free of other stereoisomers. In certain embodiments, in the pharmaceutical composition of this disclosure, the compounds are substantially free of the opposite D-cysteine amino acid epimer. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) or (II) that is at least about 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% free of the opposite D-cysteine amino acid epimer by weight of the compound of Formula (I) or (II). In some embodiments, provided herein is a pharmaceutical composition comprising compounds of any of Formulas (I)-(II), that are substantially free ofa designated stereoisomer of that compound. In certain embodiments, in the pharmaceutical composition of this disclosure, the compounds are substantially free of other stereoisomers.Isotopically Enriched Compounds

[0113] In one aspect, provided herein is a pharmaceutical composition comprising isotopically enriched compounds including, but not limited to, isotopically enriched compounds of any of Formulas (I)-(II).

[0114] Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and / or toxicity profiles, has been previously demonstrated within some classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).[0.1.15] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites; (2) increase the half-life of the parent drug; (3) decrease the number of doses needed to achieve a desired effect; (4) decrease the amount of a dose necessary to achieve a desired effect; (5) increase the formation of active metabolites if any are formed; and / or (6) decrease the production of deleterious metabolites in specific tissues. Isotopic enrichment of a drug can also be used to create a more effective and / or safer drug for combination therapy, whether the combination therapy is intentional or not.

[0116] The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as2H,3H, "C.13C,14C13N,15O,17O,32P,35S,18F,36C1. Incorporation of heavier isotopes such as deuterium (2H or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, hence may be preferred in some instances. As used herein, each instance of replacement of a hydrogen by deuterium is also a disclosure of replacing that hydrogen with tritium. As used herein, each instance of enrichment,substitution, or replacement of an atom with corresponding isotope of that atom encompasses isotopic enrichment levels of one of about: 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the preceding percentages.

[0117] Isotopically -labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.|0118| In one embodiment, the pharmaceutical compositions provided herein comprise a compound of Formula (X) wherein the formulations comprise at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% by weight a compound of Formula (I) compared to the total weight of all stereoisomers of Formula (X).

[0119] In one embodiment, a pharmaceutical composition provided herein comprises a compound of Formula (I) wherein the composition is at least about 50% free, at least about 60% free, at least about 70% free, at least about 75% free, at least about 80% free, at least about 85% free, at least about 90% free, at least about 95% free, at least about 99% free, or 100% free by weight of the opposite D-cysteine amino acid epimer and one, or more pharmaceutically acceptable excipients as described herein. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is about 85%-95% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is about 90%-95% free by weight of the opposite D- cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is about 85% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is about 90% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is about 95% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is about 97% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (I) is 100% free by weight of the opposite D-cysteine amino acid epimer.|O120| In one embodiment, a pharmaceutical composition provided herein comprises a compound of Formula (II) wherein the formulation is at least about 50% free, at least about 60% free, at least about 70% free, at least about 75% free, at least about 80% free, at least about 85% free, at least about 90% free, at least about 95% free, at least about 99% free, or 100% free by weight of the opposite D-cysteine amino acid epimer and one, or more pharmaceutically acceptable excipients as described herein. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is about 85%-95% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is about 90%-95% free by weight of the opposite D- cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is about 85% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is about 90% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is about 95% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is about 97% free by weight of the opposite D-cysteine amino acid epimer. In one embodiment, the pharmaceutical composition that comprises a compound of Formula (II) is 100% free by weight of the opposite D-cysteine amino acid epimer. In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers, or fillers, include, for example, lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.Method of Use

[0121] Also provided herein are methods of use of pharmaceutical compositions comprising the compounds described herein. In some embodiments, the pharmaceutical compositions described herein are administered to a subject in need thereof. In some embodiments, the subject is a mammal, in certain embodiments, a human, in a pharmaceutically acceptable dosage suitable for administration form such as those known in the art, and those discussed herein, intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, inhalation, or intratumoral routes. The pharmaceutical compositions also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. In certain embodiments, the compounds are administered to amammal, in certain embodiments, a human, in a pharmaceutically acceptable dosage suitable for oral administration form such as those known in the art, and those discussed herein, for example sublingually. For example, the pharmaceutical compositions of this disclosure may be administered orally to a human as a liquid or solid form. Solid dosage forms include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as, for example, glycerol, d) disintegrating agents such as, for example, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as, for example, paraffin, f) absorption accelerators such as, for example, quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as, for example, kaolin and bentonite clay, and i) lubricants such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. In one embodiment, the oral dosage form is an oral disintegrating tablet.101221 In clinical practice the pharmaceutical compositions or compounds provided herein may be administered by any suitable route known in the art. Exemplary routes of administration of the formulations described herein include, but are not limited to, oral, inhalation, sublingual, buccal, intraarterial, intradermal, intramuscular, intraperitoneal (I.P.), intravenous (I.V.), nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, a pharmaceutical composition provided herein is administered parenterally. In some embodiments, a pharmaceutical composition provided herein is administered by I.P. injection. In some embodiments, a pharmaceutical composition provided herein is administered by I.V. injection. In some embodiments, a pharmaceutical composition provided herein is administered orally.Dosage and Unit Dosage f 0123] In human therapeutics, the doctor will determine the posology which he considers most appropriate according to a preventive, or curative treatment, and according to the age, weight, condition, and other factors specific to the subject to be treated.

[0124] In certain embodiments, a pharmaceutical composition provided herein is a a single unit dosage form. Pharmaceutical compositions provided herein comprise a prophylactically, or therapeutically effective amount of one or more prophylactic, or therapeutic compounds described herein.

[0125] The amount of the compound in the pharmaceutical composition and / or the amount of the pharmaceutical composition which will be effective in the prevention or treatment of a disorder, or one or more symptoms thereof, will vary with the nature and severity of the disease or disorder and the route by which the compound is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease or disorder, and the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.|0126| In certain embodiments, exemplary doses of a pharmaceutical composition comprising a compound of Formula (I) or the compound of Formula (II) include milligram or microgram amounts of the compound of Formula (I) or the compound of Formula (II) per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). In certain embodiments, the dosage of the compound provided herein (e.g., compound of Formula (I) or the compound of Formula (II)) , based on weight of the compound, administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of a subject’s body weight. In another embodiment, the dosage of the pharmaceutical composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0127] The dose can be administered according to a suitable schedule, for example, daily, once, two times, three times, or four times weekly, or once, two times, three times monthly. It may be necessary to use dosages of the pharmaceutical composition comprising a compound described herein (e.g., compound of Formula (I) or the compound of Formula (II)) outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician, or treating physician will know how, and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0128] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat, or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the compounds or pharmaceutical compositions provided herein are also encompassed by the described dosage amounts and dose frequency schedules herein. Further, when a subject is administered multiple dosages of a pharmaceutical composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition, or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0129] In certain embodiments, treatment or prevention can be initiated with one or more loading doses of a compound or pharmaceutical composition provided herein followed by one or more maintenance doses.10130] In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the compound (e.g., compound of Formula (I) or the compound of Formula (II)) in blood or serum of the subject. The steadystate concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight, and age.101311 In certain embodiments, administration of the same pharmaceutical composition may be repeated and the administrations may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated, and the administration may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months.Therapeutic Applications101321 In one aspect, the pharmaceutical composition provided herein may be useful for the treatment of any disease or disorder described herein (e.g., a proliferative, dermatological, or ophthalmological disease or disorder). In some embodiments, the disease or disorder described herein is a proliferative disease or disorder (e.g., cancer). In some embodiments, the diseases or disorder described herein is a dermatological disease or disorder. In some embodiments, the diseases or disorder described herein is an ophthalmological disease or disorder.

[0133] In some embodiments, provided herein is a method of treating cancer in a subject (e.g. , human) in need thereof, comprising administering to the individual an effective amount of a pharmaceutical composition provided herein. The treatment may be monotherapy or in a combination therapy context. In yet another aspect, provided herein is a method of treating cancer in a subject e.g., human) in need thereof, comprising administering to the individual an effective amount of a combination of a) a first therapy that comprises a pharmaceutical composition described herein and b) a second therapy useful for treating cancer. In some embodiments, the second therapy includes surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and / or chemotherapy (e.g., one or more compounds useful for treating cancer). It is understood that reference to and description of methods of treating cancer below is exemplary and that this description applies equally to and includes methods of treating cancer using combination therapy.

[0134] Examples of cancers that may be treated by the methods of the invention include, but are not limited to, adenocortical carcinoma, agnogenic myeloid metaplasia, AIDS-related cancers (e.g., AIDS-related lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bile duct cancer (e.g., extrahepatic), bladder cancer, bone cancer, (osteosarcoma and malignant fibrous histiocytoma), brain tumor (e.g.,glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g, pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodenglioma, meningioma, craniopharyngioma, haemangioblastomas, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, and glioblastoma), breast cancer, bronchial adenomas / carcinoids, carcinoid tumor (e.g, gastrointestinal carcinoid tumor), carcinoma of unknown primary, central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myeloproliferative disorders, endometrial cancer (e.g, uterine cancer), ependymoma, esophageal cancer, Ewing's family of tumors, eye cancer (e.g, intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, (e.g, extracranial, extragonadal, ovarian), gestational trophoblastic tumor, head and neck cancer, hepatocellular (liver) cancer (e.g, hepatic carcinoma and heptoma), hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), laryngeal cancer, laryngeal cancer, leukemia, lip and oral cavity cancer, oral cancer, liver cancer, lung cancer (e.g, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), lymphoid neoplasm (e.g, lymphoma), medulloblastoma, melanoma, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, oropharyngeal cancer, ovarian cancer (e.g. , ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, parathyroid cancer, penile cancer, cancer of the peritoneal, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, pleuropulmonary blastoma, lymphoma, primary central nervous system lymphoma (microglioma), pulmonary lymphangiomyomatosis, rectal cancer, renal cancer, renal pelvis and ureter cancer (transitional cell cancer), rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g, non-melanoma (e.g, squamous cell carcinoma), melanoma, and Merkel cell carcinoma), small intestine cancer, squamous cell cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, urethral cancer, vaginal cancer, vulvar cancer, Wilms' tumor, and posttransplant lymphoproliferative disorder (PTLD), abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.101351 In some embodiments, suitable examples of cancer include, breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., nonsmall cell lung cancer, small-cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestinal cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharynx cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), neurilemmoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), renal cancer (e.g., renal cell cancer, transitional cell cancer of the renal pelvis and ureter), bile duct cancer, endometrial cancer, uterine cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, sarcoma of the retina, penis cancer, testicular tumor, pediatric solid tumor (e.g., Wilms’ tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, tumor of maxillary sinus, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0136] In certain embodiments, the disease or disorder is brain cancer, liver cancer, lung cancer, ovarian cancer, gastric cancer, or colorectal cancer. In certain embodiments, the disease or disorder is liver cancer. In certain embodiments, the disease or disorder is lung cancer. In certain embodiments, the disease or di order is ovarian cancer. In certain embodiments, the disease or disorder is gastric cancer. In certain embodiments, the disease or disorder is colorectal cancer.

[0137] In certain embodiments, the disease or disorder is head and neck cancer, oral cancer, or maxillofacial cancer.

[0138] In some embodiments, the disease or disorder is brain cancer. In some embodiments, the brain cancer is glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g. , pilocytic astrocytoma, diffuse astrocytoma, or anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodenglioma, meningioma, craniopharyngioma, haemangioblastomas, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, or glioblastoma. In some embodiments, the brain cancer is glioblastoma (also called glioblastoma multiforme or grade 4 astrocytoma). In some embodiments, the glioblastoma is radiation-resistant. In some embodiments, the glioblastoma is radiationsensitive. In some embodiments, the glioblastoma may be infratentorial. In some embodiments, the glioblastoma is supratentorial. In some embodiments, the individual may be a human who has a gene, genetic mutation, or polymorphism associated with brain cancer (e.g. , glioblastoma) (e.g, NRP / B, MAGE-E1, MMACI-E1, PTEN, LOH, p53, MDM2, DCC, TP-73, Rbl, EGFR, PDGFR-a, PMS2, MLH1, and / or DMBT1) or has one or more extra copies of agene associated with brain cancer (e.g., glioblastoma) (e.g., MDM2, EGFR, and PDGR-a).

[0139] Any of the methods of treatment provided herein may be used to treat and individual (e.g., human) who has been diagnosed with or is suspected of having cancer. In some embodiments, the individual may be a human who exhibits one or more symptoms associated with cancer. In some embodiments, the individual may have advanced disease or a lesser extent of disease, such as low tumor burden. In some embodiments, the individual is at an early stage of a cancer. In some embodiments, the individual is at an advanced stage of cancer. In some of the embodiments of any of the methods of treatment provided herein, the individual may be a human who is genetically or otherwise predisposed (e.g., risk factor) to developing cancer who has or has not been diagnosed with cancer. In some embodiments, these risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (e.g., hereditary) considerations, and environmental exposure. In some embodiments, the individuals at risk for cancer include, e.g., those having relatives who have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers.10140] Any of the methods of treatment provided herein may be used to treat, stabilize, prevent, and / or delay any type or stage of cancer. In some embodiments, the individual is at least aboutany of 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, one or more symptoms of the cancer are ameliorated or eliminated. In some embodiments, the size of a tumor, the number of cancer cells, or the growth rate of a tumor decreases by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, the cancer is delayed or prevented.

[0141] In some embodiments, the disease is dermatological. In certain embodiments, the disease is selected from the group consisting of, acne scarring, actinic keratosis, age spots (liver spots), atopic dermatitis (eczema), autoimmune diseases, basal cell carcinoma, bullous pemphigoid, burning mouth syndrome, calciphylaxis, cancer, canker sore, chronic hives, connective tissue disorders, contact dermatitis, cutaneous lupus, cutaneous T-cell lymphoma, dermatitis, dermatomyositis, Ehlers-Danlos syndrome, epidermolysis bullosa, erythromelalgia, genetic skin disorders, graft-versus-host disease, granuloma annulare, graves' disease, hair diseases, hair loss, hemangioma, hidradenitis suppurativa, hypereosinophilic syndrome, hyperhidrosis, itchy skin (pruritus), keloids, Klippel-Trenaunay syndrome, lichen planus, lip cancer, lymphoma, melanoma, merkel cell carcinoma, moles, morphea, mucous membrane diseases, nail diseases, nephrogenic systemic fibrosis, neurofibromatosis, nonmelanoma skin cancer, oral lichen planus, panniculitis, pemphigus, pigmentation disorders, polymorphous light eruption, primary biliary cholangitis, psoriasis, pyoderma gangrenosum, rosacea, scleroderma, skin cancer, skin infections, spider veins, squamous cell carcinoma of the skin, Stevens-Johnson syndrome, subcutaneous fat diseases, sun allergy, varicose veins, vascular anomalies, vasculitis, vitiligo, vulvar skin disorders, and wrinkles.

[0142] In certain embodiments, the disease is ophthalmological. In certain embodiments, the disease is selected from the group consisting of age-related macular degeneration, amblyopia (lazy eye), anophthalmia and microphthalmia, astigmatism, Behcet's disease, Bietti's crystalline dystrophy, blepharitis, blepharospasm, cataracts, cerebral visual impairment (CVI), coloboma, color blindness, convergence insufficiency, comeal conditions, diabetic retinopathy, dry eye, farsightedness (hyperopia), floaters, glaucoma, idiopathic intracranial hypertension, low vision, macular edema, macular hole, macular pucker, nearsightedness (myopia), ocular histoplasmosis syndrome (OHS), pink eye, presbyopia, rare diseases, refractive errors, retinal detachment, retinitis pigmentosa, retinoblastoma, retinopathy of prematurity, Stargardt disease, Usher syndrome, uveitis, and vitreous detachment.|0143] In certain embodiments, provided herein are methods for the treatment that include the administration of an pharmaceutical composition provided herein, comprising an effective amount of the pharmaceutical composition provided herein. In certain embodiments, the methods encompass the step of administering to the subject in need thereof an amount of a compound described herein in the pharmaceutical formulation described herein effective for the treatment of disease or disorder in combination with a second agent effective for the treatment or prevention of the disease or disorder.

[0144] In certain embodiments, the subject is a treatment naive subject. In further embodiments, the subject has previously received therapy. For instance, in certain embodiments, the subject has not responded to a single agent treatment regimen.

[0145] In certain embodiments, the subject is a subject that discontinued some other therapy because of one or more adverse events associated with the other therapy. In certain embodiments, the subject has received some other therapy and discontinued that therapy prior to administration of a method provided herein. In further embodiments, the subj ect has received therapy and continues to receive that therapy along with administration of a compound provided herein. The compounds described herein can be co-administered with other therapy for treatment of the disease or disorder according to the judgment of one of skill in the art. In certain embodiments, the methods or formulations provided herein can be co-administered with a reduced dose of the other therapy for the treatment of the disease or disorder.Ki ts

[0146] In some embodiments, a pharmaceutical composition provided herein is provided in the form of a kit (i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure). In certain embodiments, the procedure is a therapeutic procedure.

[0147] In some embodiments, the pharmaceutical composition provided is a lyophilized powder and the kit further comprises a solvent for the reconstitution of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is provided in the form of an aqueous solution ready for administration.

[0148] In some embodiments, the kits can include a pharmaceutical composition provided herein, an optional second agent or composition, and instructions providing information to ahealth care provider regarding usage for treating the disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a pharmaceutical composition provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound can be maintained in the subject for at least one day.

[0149] In some embodiments, suitable packaging is provided. As used herein, “packaging” includes a solid matrix, or material customarily used in a system, and is capable of holding within fixed limits a compound provided herein and / or a second agent suitable for administration to a subject. Such materials include, glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, plastic-foil laminated envelopes, and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.EXAMPLESExample 1. Solubility of compound of Formula (II)

[0150] To optimize buffer systems and pH conditions for the formulation of compound of Formula (II), the solubility of compound of Formula (II) was measured under different pH conditions and in various buffer systems. Compound of Formula (II) was first dissolved in target buffers systems with various pH values in an initial concentration of 100 mg / mL. The mixtures were kept shaking at 700 rpm and 25 °C for 24 hours, and the pH of them were measured. If the pH values shifted, the pH-shifted mixture was readjusted back to the specific target pH value, and then was re-equilibrated for an hour. This process was repeated until no pH shift was observed. The solid and liquid were then isolated by centrifugation, and diluted for HPLC analysis. The results are summarized in Table 1-1.Table 1-1. Solubility of compound of Formula (II) in different buffers

[0151] As shown in Table 1-1, with an initial concentration of 100 mg / mL, compound of Formula (II) showed good solubility in buffer systems with pH lower than 7, but precipitation were observed under alkaline condition. Hence, compound of Formula (II) might be unstable under alkaline condition.

[0152] Following similar procedures, the solubility of compound of Formula (II) in water-for- inj ection (WFI) under different pH conditions was then measured and evaluated. The solutions of the compound of formula (II) were prepared either by dissolving the compound of formula (II) in as-prepared WFI with target pH values, or by dissolving the compound of formula (II) in WFI and then adjusting the pH. HC1 and / or NaOH were used to achieve the target pH values. The results are shown in Table 1-2. As shown in Table 1-2, compound of Formula (II) also showed good solubility in WFI (above lOOmg / mL) up to pH 7.Table 1-2. Solubility of compound of Formula (II) in WFI under different pH

[0153] To further optimize the solution for formulation of compound of Formula (II), effects of different initial concentrations of compound of Formula (II) on its solubility were investigated in the buffer systems shown in Table 1-1 and WFI. As shown in FIG. 1A-1D, with an initial concentration of lOOmg / mL or 200mg / mL, clear solutions of compound of Formula (II) were obtained up to pH 6-7 in buffer systems. However, with an initial concentration ofImg / mL or lOmg / mL, clear solutions of compound of Formula (II) could not be obtained in several pH buffers. In contrast, as shown in FIG. IE and FIG. IF, with an initial concentration of 5mg / mL, clear solutions were obtained in WFI up to pH 5-6 even after 24 hours. Therefore, WFI provided better dissolution efficiency compared to buffer systems.

[0154] The solubility of compound of Formula (II) was then evaluated in various common solubilizing systems, and the results are shown in Table 1-3. As shown in Table 3-1, cosolvents and cyclodextrin SEBEBCD clearly compromised the solubility of compound of Formula (II), and surfactants did not improve the solubility. Therefore, cosolvent, surfactant, and cyclodextrin are not necessary to achieve the desired solubility of compound of Formula (II). Pure WFI has afforded the best solubility results, and was used for stability test and further optimizations.Table 1-3. Solubility of compound of Formula (II) in solubilizing systemsExample 2. Stability of compound of Formula (II)

[0155] The stability of compound of Formula (II) and its WFI solution was measured and evaluated under different pH conditions. The results are shown in Table 2-1-1, Table 2-1-2, and FIG. 2. As shown in Table 2-1-1, Table 2-1-2, and FIG. 2, compound of Formula (II) and its WFI solution remained stable up until pH=6. Obvious degradation were detected under pH 6-9 alkaline conditions. As such, pH 3-5 are a more optimized pH range for the formulation of compound of Formula (II).Table 2-1-1. Stability of compound of Formula (II) in WFI (Timepoint: initial and Id)Table 2-1-2. Stability of compound of Formula (II) in WFI (Timepoint: 4d and 7d)

[0156] Following this, the stability of compound of Formula (II) and its WFI solution was further investigated within the pH range 3-5. Results are shown in Table 2-2-1, Table 2-2-2, and FIG. 3. As shown in Table 2-2-1, Table 2-2-2, and FIG. 3, pH 3-4 allowed for higher stability of compound of Formula (II) and its WFI solution, and therefore was a more suitable pH range for further formulation development.Table 2-2-1. Stability between pH 3-5 (Timepoint: initial and Id)Table 2-2-2. Stability between pH 3-5 (Timepoint: 3d and 7d)

[0157] Stability of compound of Formula (II) and its WFI solution was further evaluated under different temperatures. The results are shown in in Table 2-3-1, Table 2-3-2, and Table 2-3-3. The results shown in Table 2-3-1, Table 2-3-2. As indicated by the results, under -20 °C or 5 °C, pH 3-9, compound of Formula (II) and its WFI solution were stable at least over 8 days. Under 25 °C, pH 3-5, compound of Formula (II) and its WFI solution remained stable over at least 8 days. This room-temperature stability allowed for lower cost of transportation and storage of compound of Formula (II) formulations.Table 2-3-1. Stability of compound of Formula (II) WFI solution (lOOmg / mL) (Initial and - 20°C, 8 days)Table 2-3-2. Stability of compound of Formula (II) WFI solution (lOOmg / mL) (5°C, 8 days and 25°C, 8 days)Table 2-3-2. Stability of compound of Formula (II) WFI solution (lOOmg / mL) (40°C, 8 days)10158] The stability of compound of Formula (II) was also evaluated in various buffer systems with different pH values, and the results are shown in Table 2-4. For solution stability, pH buffer systems did not show obvious advantage over pure WFI, and therefore, were not necessary for the formulation of compound of Formula (II).Table 2-4. pH stability of compound of Formula (II) in buffer systems

[0159] The stability of compound of Formula (II) and its WFI solution was then evaluated under different compound of Formula (II) concentrations without any pH adjustment. The results are shown in Table 2-5 and FIG. 4. As shown in Table 2-5 and FIG. 4, pH stability of compound of Formula (II) was concentration dependent, and unexpectedly, faster degradation was detected for low concentration than high concentration. As such, the stability of compound of Formula (II) and its WFI solution was higher in higher compound of Formula (II) concentrations compared to lower compound of Formula (II) concentrations.Table 2-5. Stability of compound of Formula (II) in different concentrations10160] The stability of compound of Formula (II) WFI solution in a concentration of 200mg / mL was shown in Example 1, Table 1-2. Compound of Formula (II) WFI solution (200mg / mL) remained stable up to pH 7, but precipitation were observed under alkaline condition.Example 3. Excipient compatibility study

[0161] The compatibility of compound of Formula (II) and common excipients was evaluated over a period of at least 14 days and the results are shown in Table 3-1, Table 3-2, and Table 3-3. For each sample, the pH was adjusted to the target value via 6N HC1 solution. As shown by the results, monothioglycerol, bisulfite sodium and tromethamine showed compatibility issues with compound of Formula (II) and should be avoided in compound of Formula (II) formulations.Table 3-1. Excipient compatibility — initial solutionTable 3-2. Excipient compatibility — 25 °C, 7 daysTable 3-3. Excipient compatibility — 25 °C, 14 daysExample 4. Formulation screening[0162| In view of the solubility and stability test results, four candidate formulations were designed, prepared successfully, and set up at 5 °C and 25 °C for stability study. The designed and prepared formulations are shown in Table 4-1. The results of stability test of the four candidate formulations are shown in Table 4-2 and Table 4-3.Table 4-1. FormulationsTable 4-2. Formulation Stability* Apply the criteria of Test l.A. USP<788> (# / Container at least l Oum ) no more than 6000 / container AND(# / Container no less than 25 pm ) no more than 600 / container (Pass)Table 4-3. Formulation Stability - Accelerate Stability|0163| As shown in Table 4-3, four candidate formulations all showed small level of degradation under 25 °C over 4 weeks, but this hypersensitivity could be reduced during clinic or by proper packaging. Adding additional excipients such as benzyl alcohol did not provide clear advantage over pure compound of Formula (II) WFI solution.Example 5. Preparation of compound of Formula (II) lyophilized formulation

[0164] Formulation comprising compound of Formula (II) and mannitol was prepared via lyophilization. The formulation details are shown in Table 5-1 and the details of the lyophilization process are shown in Table 5-2. Amber vials were used for the lyophilization process, and clear solution was obtained after reconstitution (pH 3.50 KF: -1.5%).Table 5-1. Formulation detailsTable 5-2. Lyophilization details

[0165] The obtained lyophilization powder was tested for dilution performance and potential for reconstitution. The reconstitution results are shown in Table 5-3. As shown in Table 5-3, no obvious increase of impurity levels was detected at 25 °C up to 2 hours after 5-folds, 50- folds and 100-folds dilution with D5W and WFI. However, D5W showed slightly degradation level and thus better performance than WFI at 25 °C up to 24 hours.Table 5-3. Dissolution test in WFI and D5WEquivalents101661 The disclosure set forth above may encompass multiple distinct embodiments with independent utility. Although each of these embodiments has been disclosed, the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. The subject matter of the embodiments includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and / or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Alternative embodiments as in other combinations and subcombinations of features, functions, elements, and / or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different embodiment or to the same embodiment, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of this disclosure.

[0167] One or more features from any embodiments described herein or in the figures may be combined with one or more features of any other embodiments described herein or in the figures without departing from the scope of this disclosure.

[0168] All publications, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art inlight of the teachings of this disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A formulation comprising(1) an acetate salt of a compound of Formula (I):wherein n is an integer selected from 1-20, and(2) mannitol.

2. The formulation of claim 1, wherein the amount of mannitol is about 2.5 wt% of the formulation.

3. The formulation of claim 1 or 2, whereinthe the formulation is substantially free of surfactants.

4. The formulation of any of claims 1-3, whereinthe the formulation is aqueous in water for injection.

5. The formulation of any of claims 1-3, whereinthe the aqueous formulation is lyophilized.

6. An aqueous pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein n is an integer selected from 1-20, and the aqueous pharmaceutical composition has a pH of no more than 5.5.

7. The aqueous pharmaceutical composition of any one of claims 1-4 and 6, wherein the pH is about 3.5.

8. The aqueous pharmaceutical composition of any one of claims 1-4 and 6, wherein the pH is about 3.

9. The aqueous pharmaceutical composition of any of claims 1-4 and 6-8, wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof, is between 0.1 mg / mL and 250 mg / mL.

10. An aqueous pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein n is an integer selected from 1-20, and the concentration of the compound, or a pharmaceutically acceptable salt thereof, is about or greater than 25 mg / mL.

11. The aqueous pharmaceutical composition of any one of claims 1-4 and 6-10, wherein the concentration is about 50 mg / mL.

12. The aqueous pharmaceutical composition of any one of claims 1-4 and 6-10, wherein the concentration is about 100 mg / mL.

13. The aqueous pharmaceutical composition of any one of claims 1-4, and 10-12, wherein the aqueous pharmaceutical composition has a pH of less than 7.

14. The aqueous pharmaceutical composition of any of claims 1-13, wherein n is 8.

15. The aqueous pharmaceutical composition of any of claims 1-13, wherein the compound isor a pharmaceutically acceptable salt thereof.

16. The aqueous pharmaceutical composition of any of claims 6-15, wherein the compound is in an acetate salt form.

17. The aqueous pharmaceutical composition of any of claims 6-16, further comprising a pharmaceutically acceptable carrier.

18. The aqueous pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable carrier is mannitol.

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